No full-text available
To read the full-text of this research,
you can request a copy directly from the author.
Abstract
The TP53 gene (p53) is found altered in breast carcinomas in approximately 20-40% of all cases depending on tumor size and stage of the disease. It seems to be an early event in breast tumorigenesis. Several polymorphisms in the TP53 gene have been detected and their possible roles in breast cancer risk and association to type of cancer developed are discussed. The different mutation spectra seen in geographical and ethnic populations may be used to identify environmental exposure contributing to breast cancer development. The role of TP53 mutation as a prognostic marker is reviewed as well as its role as a predictor for therapy response. All data available on TP53 mutation analyses of human breast carcinomas, as well data from transgenic animal studies and experimental cell studies, support an important role for TP53 in mammary carcinogenesis.
... Ion channel expression levels may be a prognostic indicator for human malignancies. For example, ca2+-selective cation channel TPRV6 expression is a marker of prostate cancer progression in humans [12] . ...
... In addition, we compared four different sets of immune-related genes (immune checkpoints, chemokines, immune cell markers, and HLA) between groups of low and high risks. Finally, we quanti ed the abundance of immune in ltration in patients using seven software, made a comparison of the differences in immune in ltration in the groups of low and high risks, and calculated pearson correlations between genes and signatures (Riskscore) in Signature and immune cell content[8], [9], [10], [11], [12], [13]. ...
... KCNN is clinically relevant in cell cycle progression, cell migration and epithelial cell transport [11]. KCNN4 was found to be overexpressed in lung, breast, colon and prostate cancers, and its overexpression was related to the clinical prognosis of the patients [12], [13], [14], [15]. CACNB3 may act as a regulator in transcription factors or/and calcium transport [16], and is currently considered to be a key factor affecting the prognosis of cervical cancer. ...
BACKGROUND: Skin cutaneous melanoma (SKCM) is a cutaneous malignancy with a poor prognosis, and it is highly malignant and aggressive, making it the skin cancer with the highest mortality rate.
OBJECTIVE: The present study was designed to explore the effect of prognostic modeling on SKCM occurrence and prognosis through ion channel genes.
METHODS: Gene expression data and related clinical information of patients with SKCM were obtained from the TCGA and GEO databases, respectively, and the TCGA data were included as a training group. The related ion channel genes were detected from the ion channel database.A one-way cox survival analysis of ion channel modification-related genes was undertaken to screen for prognostically relevant ion channel genes using the 'survival' software package. Ion channel-related features were built with the LASSO-Cox regression model and validated against external datasets for accuracy and reproducibility in predicting prognosis in SKCM patients. Univariate and multivariate Cox analyses were undertaken in the training set to observe if the feature was independent of traditional clinical variables. The independence and robustness of signature were further validated using stratified Kaplan-Meier analysis of clinical variables. We identified gene modules with strong positive correlations in the group of low risk and performed GO/KEGG analysis of gene with strong positive correlations in the modules. Butterfly plots were then applied to vividly show the correlations between risk scores and TIP scores, eight immunotherapy prediction scores and different tumour signalling pathways. Differences in four different groups of immune-related genes (immune checkpoints, chemokines, immune cell markers, and HLA) in the groups of low- and high-risks were also compared. We identified differences in immune infiltration between the groups of low- and high-risks with 7 software, as well as genes significantly co-expressed in the group of high risk following the WGCNA algorithm, and performed functional enrichment analyses of the genomes to probe potential mechanisms of SKCM occurrence and prognosis. Finally, we assessed the sensitivity of chemotherapy versus immunotherapy in the groups of low- and high-risks.
RESULTS: Through univariate Cox analysis, we secured 330 genes, of which 30 genes were statistically significantly correlated with survival. Prognostic models of 14 genes were constructed through Lasso-Cox analysis. Signature, which consists of 14 ion-channel-related genes, had good predictive effect on SKCM 1-, 2-, and 3-year DSS. Signature is an independent prognostic factor for SKCM and its predictive effect is superior to that of traditional clinical variables. dca suggests that using our model to predict survival in SKCM patients could benefit patients. The gene enrichment in the blue module of adaptive immune-related pathways, biological processes, molecular functions, and cellular components was found to be negatively related to risk scores by immunoenrichment, and significantly positively related to the low-risk group in this study. TIP scores and 8 immunotherapy scores were negatively related to risk scores, and therefore better predicted the response to immunotherapy. The EGFR and VEGF pathways were positively related to risk scores. Therefore, there was significant heterogeneity between the groups of low- and high-risks. Correlations between genes and immune cell content in a large number of models suggests that ion channel-related genes possibly affect the pathogenesis and prognosis of SKCM by modulating the immune microenvironment. These findings revealed that the signature was a significant marker of immune rejection. Using this signature, patients in the group of low risk could be predicted to have increased immune reserve. We also concluded that the group with lower risk was a better candidate for chemotherapy by chemotherapy-related analysis.
CONCLUSIONS: The results of this study indicated that we had uncovered a prognostic model of prognostic value for SKCM patients. It also revealed that ion channel-related genes were highly correlated with the immune status and prognostic survival of patients with SKCM, and they might modulate SKCM pathogenesis in multiple ways. The results of this study would help to clarify how to develop and expand new targets for the effective management and treatment of SKCM.
... Prostate cancer was the second most prevalent with 13 152 cases (12.2%), followed by cervix uteri cancer with 10 702 cases (9.9%) and lung cancer with 8 950 cases (8.3%) (Siegel et al., 2020). The statistics seem to correlate with observations made two decades ago, where it was noted that breast cancer is the most common neoplasm among women globally and accounts for nearly one-third of newly diagnosed cancers in women (Børresen-Dale, 2003). ...
... There are several subtypes of breast cancers and each of them have different risk factors, clinical presentation, histopathological features, outcomes and responses to treatment (Børresen-Dale, 2003;Duijf et al., 2019;Mbulaiteye et al., 2011). Normally, the biological classification of breast cancers is mostly based on endocrinological gene expressions. ...
... Though, an increase in the incidence rate of breast cancer in the last decades has been observed, prognosis has also improved because of early diagnosis and advanced treatment options such as adjuvant hormone therapies, surgeries, radiation therapies and chemotherapies (Aggarwal et al., 2009;Aslam et al., 2015;Sung et al., 2021;WHO, 2021). The survival rate from the disease has also significantly improved (Børresen-Dale, 2003;WHO, 2021). Although a plethora of treatments are available, most patients experience adverse effects which affect their quality of life, and this has necessitated the need to discover new treatments for cancer with fewer adverse effects, more potent and less expensive to produce. ...
Breast cancer is a leading cause of cancer-related deaths in women globally. Even though a plethora of treatments are available, most patients experience adverse effects which affect their quality of life. The aim of this study was to investigate the utility of nine Fynbos plants (Erica magnisylvae E.G.H Oliv., Erica canescens J.C. Wendl., Erica coccinea L., Erica glabella Thunb., Erica corifolia L., Eriocephalus racemosa L., Hippia frutescens L., Salvia africana-lutea L. and an unknown Fynbos plant) in treating breast cancer. Solvent extraction of fynbos plants was performed, and crude extracts were evaluated against MDA-MB 231 cancer cell line to determine the cytotoxic activity with the mode of cell death confirmed using flow cytometry. Antioxidant activity and mass spectrometry-based metabolite profiling were performed to characterize and identify the phytochemical constituents of the extracts. The methanol extracts from E. glabella., H. frutescens and S. africana-lutea and the hexane extract from E. racemosa showed promising cytotoxic activities in the screening phase and thus were further evaluated to determine their 50% inhibitory concentrations (IC50) which were found to be < 30 µg/mL. Flow cytometry analysis of treated MDA-MB 231 cells revealed promising results for the hexane crude extract (leaves) of E. racemosa and stem methanol crude extract of H. frutescens which induced apoptosis in MDA-MB-231 cancer cell line, similar to the reference drug cisplatin. Metabolite profiling of S. africana-lutea extract, the most potent apoptosis inducer in this study, revealed the presence of phosphatidylcholines, triterpenoids, oxepane and 7-O-methylated flavonoids derivatives. It was concluded that E. racemosa and S. africana-lutea are excellent candidates for further development of therapeutic agents in the fight against cancer, given the pressing need for novel efficacious agents.
... Comprehensive genomic analysis has identified key driver genetic mutations that are responsible for therapeutic implication and outcome prediction of breast cancer. The tumor suppressor gene TP53 is found altered in breast carcinoma in~30% of all cases with prognostic implication 4 . Overexpression of ERBB2 is also an adverse prognostic indicator correlated with decreased survival in breast cancer 5 . ...
... TP53 is a tumor suppressor gene that plays a key role in many cellular pathways controlling cell proliferation, cell survival, and genomic integrity 23 . It is mutated frequently in breast cancer 4,23 and has been associated with poor prognosis 4,23,24 . The FGFR1 gene is a member of the fibroblast growth factor receptor (FGFR) family that regulates important biological processes including cell proliferation and differentiation during development and tissue repair 25 . ...
... TP53 is a tumor suppressor gene that plays a key role in many cellular pathways controlling cell proliferation, cell survival, and genomic integrity 23 . It is mutated frequently in breast cancer 4,23 and has been associated with poor prognosis 4,23,24 . The FGFR1 gene is a member of the fibroblast growth factor receptor (FGFR) family that regulates important biological processes including cell proliferation and differentiation during development and tissue repair 25 . ...
Breast carcinoma is the most common cancer among women worldwide that consists of a heterogeneous group of subtype diseases. The whole-slide images (WSIs) can capture the cell-level heterogeneity, and are routinely used for cancer diagnosis by pathologists. However, key driver genetic mutations related to targeted therapies are identified by genomic analysis like high-throughput molecular profiling. In this study, we develop a deep-learning model to predict the genetic mutations and biological pathway activities directly from WSIs. Our study offers unique insights into WSI visual interactions between mutation and its related pathway, enabling a head-to-head comparison to reinforce our major findings. Using the histopathology images from the Genomic Data Commons Database, our model can predict the point mutations of six important genes (AUC 0.68–0.85) and copy number alteration of another six genes (AUC 0.69–0.79). Additionally, the trained models can predict the activities of three out of ten canonical pathways (AUC 0.65–0.79). Next, we visualized the weight maps of tumor tiles in WSI to understand the decision-making process of deep-learning models via a self-attention mechanism. We further validated our models on liver and lung cancers that are related to metastatic breast cancer. Our results provide insights into the association between pathological image features, molecular outcomes, and targeted therapies for breast cancer patients.
... Mutated p53 is seen in 50% of human cancers, emphasizing its role in tumorigenesis, and p53 mutations are reported in 60%-80% of cases of triplenegative breast cancer (TNBC) as one of the most common genetic alterations. Mutant p53 positivity is correlated with worse prognosis in TNBC patients [1][2][3]. Immunohistochemical WT p53 tumors were associated with better breast cancer-specific survival in initial N-stage patients [4]. Hence, developing potential anticancer therapies targeting mutant p53 with the least to no side effects is essential [5]. ...
... The rationale behind our selection of drug for our drug response assay was that 5-FU has been used in clinical treatments for TNBC patients and extensively studied, while PRIMA-1 Met remains unexplored in clinical settings and has not yet cleared clinical trials for breast cancer. Most clinical cases of TNBC present with a mutation in their p53 gene, making it necessary to explore mutant p53-targeted therapeutics [1][2][3][4]. In this study, we chose a combination of both these drugs to assess for any marked change in cytotoxicity of MDA-MB-231 cells, which is the human TNBC cell line. ...
Recent advancements in 3D cancer modeling have significantly enhanced our ability to delve into the intricacies of carcinogenesis. Despite the pharmaceutical industry’s substantial investment of both capital and time in the drug screening and development pipeline, a concerning trend persists: drug candidates screened on conventional cancer models exhibit a dismal success rate in clinical trials. One pivotal factor contributing to this discrepancy is the absence of drug testing on pathophysiologically biomimetic 3D cancer models during pre-clinical stages. Unfortunately, current manual methods of 3D cancer modeling, such as spheroids and organoids, suffer from limitations in reproducibility and scalability. In our study, we have meticulously developed 3D bioprinted breast cancer model utilizing decellularized adipose tissue-based hydrogel obtained via a detergent-free decellularization method. Our innovative printing techniques allows for rapid, high-throughput fabrication of 3D cancer models in a 96-well plate format, demonstrating unmatched scalability and reproducibility. Moreover, we have conducted extensive validation, showcasing the efficacy of our platform through drug screening assays involving two potent anti-cancer drugs, 5-Fluorouracil and PRIMA-1Met. Notably, our platform facilitates effortless imaging and gene expression analysis, streamlining the evaluation process. In a bid to enhance the relevance of our cancer model, we have introduced a heterogeneous cell population into the DAT-based bioink. Through meticulous optimization and characterization, we have successfully developed a biomimetic immunocompetent breast cancer model, complete with microenvironmental cues and diverse cell populations. This breakthrough paves the way for rapid multiplex drug screening and the development of personalized cancer models, marking a paradigm shift in cancer research and pharmaceutical development.
... p53 signaling pathway is activated when cells are under stress such as DNA damage. Upon activation, p53 protein works as a transcription factor that transactivates multiple target genes that initiate cell cycle arrest, apoptosis, DNA repair and inhibit metastasis [34,35]. Breast cancer is actually reported to be the most common cancer (25.5%) in women with pathogenic TP53 mutations [36,37]. ...
... p.Arg248Leu, TP53 p.Pro278Ser, TP53 p.Asp281Ala, TP53 p.Arg280Gly, IDH1 p.Arg132His, and GNAS p.Arg201Cys) in breast neoplasm in their study. The similarity of results could highlight the pathogenic contribution of these variants in breast cancer specifically TP53 variants that cause dysregulated p53 signaling pathway which is an early incident in breast tumorigenesis [35]. In addition, TP53 variant p.Glu349fs was reported to be associated with response to PARP inhibitors but in prostate cancer [64]. ...
Background
HER2-positive breast cancer occurs in 15–20% of breast cancer patients and is characterized by poor prognosis. Trastuzumab is considered the key drug for treatment of HER2-positive breast cancer patients. It improves patient survival; however, resistance to trastuzumab remains a challenge in HER2-positive breast cancer patients. Therefore, the prediction of response to trastuzumab is crucial to choose optimal treatment regimens. The aim of the study was to identify genetic variants that could predict response to anti-HER2-targeted therapy (trastuzumab) using next-generation sequencing.
Method
Genetic variants in the hotspot regions of 17 genes were studied in 24 Formalin-Fixed Paraffin-Embedded (FFPE) samples using Ion S5 next-generation sequencing system. FFPE samples were collected from HER2‑positive breast cancer patients previously treated with anti‑HER2‑targeted treatment (Trastuzumab). Patients were divided into two groups; trastuzumab-sensitive group and trastuzumab-resistant group based on their response to targeted therapy.
Results
We identified 29 genetic variants in nine genes that only occurred in trastuzumab-resistant patients and could be associated with resistance to targeted therapy including TP53, ATM, RB1, MLH1, SMARCB1, SMO, GNAS, CDH1, and VHL. Four variants out of these 29 variants were repeated in more than one patient; two variants in TP53, one variant in ATM gene, and the last variant in RB1 gene. In addition, three genes were found to be mutated only in resistant patients; MLH1, SMARCB1 and SMO genes. Moreover, one novel allele (c.407A > G, p. Gln136Arg) was detected within exon 4 of TP53 gene in one resistant patient.
Conclusion
NGS sequencing is a useful tool to detect genetic variants that could predict response to trastuzumab therapy.
... TP53 (tumor protein p53) codes for the cellular tumor antigen p53, which has mutations in 20-40% of all breast carcinomas, depending on tumor size and stage [50]. ...
... Because it arises at an early stage of breast cancer development, several TP53 gene variants have been discovered [50] (Fig. 4). It promotes apoptosis depending on physiological conditions and cell type [34]. ...
Breast cancer is the most common female cancer worldwide. Its diagnosis and prognosis remain scanty, imprecise, and poorly documented. Previous studies have indicated that some genetic mutational signatures are suspected to lead to progression of various breast cancer scenarios. There is paucity of data on the role of AI tools in delineating breast cancer mutational signatures. This study sought to investigate the relationship between breast cancer genetic mutational profiles using artificial intelligence models with a view to developing an accurate prognos- tic prediction based on breast cancer genetic signatures. Prior research on breast cancer has been based on symp- toms, origin, and tumor size. It has not been investigated whether diagnosis of breast cancer can be made utilizing
AI platforms like Cytoscape, Phenolyzer, and Geneshot with potential for better prognostic power. This is the first ever attempt for a combinatorial approach to breast cancer diagnosis using different AI platforms.
Artificial intelligence (AI) are mathematical algorithms that simulate human cognitive abilities and solve dif- ficult healthcare issues such as complicated biological abnormalities like those experienced in breast cancer scenar- ios. The current models aimed to predict outcomes and prognosis by correlating imaging phenotypes with genetic mutations, tumor profiles, and hormone receptor status and development of imaging biomarkers that combine tumor and patient-specific features. Geneshotsav 2021, Cytoscape 3.9.1, and Phenolyzer Nature Methods, 12:841–843 (2015) tools, were used to mine breast cancer-associated mutational signatures and provided useful alternative computational tools for discerning pathways and enriched networks of genes of similarity with the overall goal of providing a systematic view of the variety of mutational processes that lead to breast cancer development. The devel- opment of novel-tailored pharmaceuticals, as well as the distribution of prospective treatment alternatives, would be aided by the collection of massive datasets and the use of such tools as diagnostic marker. Specific DNA-maintenance defects, endogenous or environmental exposures, and cancer genomic signa- tures are connected. The PubMed database (Geneshot) search for the keywords yielded a total of 21,921 genes associ- ated with breast cancer. Then, based on their propensity to result in gene mutations, the genes were screened using the Phenolyzer software. These platforms lend credence to the fact that breast cancer diagnosis using Cytoscape 3.9.1, Phenolyzer, and Geneshot 2021 reveals high profile of the following mutational signatures: BRCA1, BRCA2, TP53, CHEK2, PTEN, CDH1, BRIP1, RAD51C, CASP3, CREBBP, and SMAD3.
... TP53 transcriptionally targets hundreds of genes and regulates the expression of gene contributed to cell cycle, apoptosis, DNA repair proteins and metabolic [31,32]. Recent studies had demonstrated that mutation of TP53 increased genomic instability and served as an independent prognostic marker [33][34][35][36][37]. Therefore, we continued to compare the performance of the GILncSig and TP53 mutation status in prognosis value. ...
... We found that the AUC for the GILncSig with lower number of lncRNA was higher than that of LilncSig and MalncSig, indicating our GILncSig possessed more optimized prognostic effect. Studies show that TP53 mutation increases genomic instability and serves as an independent prognostic marker [33][34][35][36][37]. Cells with DNA damage can avoid apoptosis then transform into cancer cells in the event of TP53 mutation. ...
Emerging evidence revealed the critical roles of long non-coding RNAs (lncRNAs) in maintaining genomic instability. However, genome instability-associated lncRNAs (GILncRNAs) and their performance in clinical prognostic significance in hepatocellular carcinoma (HCC) are rarely reported. Our study constructed a computational framework integrating somatic mutation information and lncRNA expression profiles of HCC genome and we identified 88 GILncRNAs of HCC. Function enrichment analysis revealed that GILncRNAs were involved in various metabolism processes and genome instability of cancer. A genome instability-derived lncRNA-based gene signature (GILncSig) was constructed using training set data. The performance of GILncSig for outcome prediction was validated in testing set and The Cancer Genome Atlas (TCGA) set. The multivariate cox regression analysis and stratification analysis demonstrated GILncSig could serve as an independent prognostic factor for the overall survival of HCC patients. The time-dependent Receiver Operating Characteristic (ROC) curve illustrated GILncSig outperformed two recently published lncRNA signatures for overall survival prediction. The combination of GILncSig and tumor protein p53 (TP53) mutation status exhibited better prognostic performance in survival evaluation compared to TP53 mutation status alone. AC145343.1 was further validated to be a risk factor for HCC in vitro among GILncSig. Overall, our study provided a novel approach for identification of genome instability-associated lncRNAs and established an independent risk score system for outcome prediction of HCC patients, which provided a new insight for exploring in-depth mechanism and potential therapy strategy.
... Tumor suppressor gene TP53 is the most frequently mutated gene in human cancers, and the patients with TP53 mutations are known to have poor clinical outcomes [9]. Several large-scale meta-analyses have shown TP53 mutation to be an independent predictor of poor prognosis for breast cancer [10,11]. Furthermore, TP53 status is a predictive factor for chemotherapy [12,13]. ...
... The TP53 mutation has long been known as an independent predictor of poor prognosis among patients with breast cancer [10,11]. To develop a reliable diagnostic kit, we created the gene expression signature that could diagnose the TP53 gene status using microarray analysis [14]. ...
Background
TP53 status based on TP53 signature, a gene expression profile to determine the presence or absence of TP53 mutation, is an independent prognostic factor of breast cancer. The purpose of this study was to develop a simple diagnostic system for TP53 signature status.
Methods
We developed a multiplex reverse transcription–polymerase chain reaction system to determine TP53 status. Based on this system, prospectively collected 189 patients with stage I and II breast cancer were determined to have TP53 mutant signature or TP53 wild-type signature. The prognostic significance of the TP53 signature by the diagnostic system was analyzed.
Results
The diagnostic accuracy of TP53 status and reproducibility of this diagnosis system was confirmed. Using the diagnostic system, 89 patients were classified as TP53 mutant signature and the remaining 100 cases were classified as TP53 wild-type signature. Recurrence-free survival (RFS) among patients with TP53 mutant signature was significantly shorter than that among those with TP53 wild-type signature. On univariate and multivariate analyses, the TP53 signature status was an independent predictor of RFS. RFS among patients with TP53 mutant signature was significantly shorter than that among those with TP53 wild-type signature in a cohort of estrogen receptor-positive breast cancer. Although a difference was not significant, no recurrent cases was observed in TP53 wild-type signature group in triple negative breast cancer.
Conclusion
This simple and precise diagnostic system to determine TP53 signature status may help in prognostic assessment, therapeutic decision-making, and treatment optimization in patients with breast cancer.
... In response to stress conditions such as DNA damage, metabolic impairments, or oncogenic transformation, p53 can regulate the cell cycle arrest, senescence, DNA repair, and angiogenesis. [5][6][7][8][9] TP53 mutations are the most frequent genetic alteration in human cancer and occur in 20%-30% of all primary invasive breast cancers. TP53 mutations are observed in 10%-20% of luminal-like tumors, more frequently among luminal B-like tumors. ...
Purpose
The aim of this study was to evaluate the prognostic role of p53 immunohistochemical (IHC) expression in a large cohort of patients with hormone receptors (HR)-positive/Her2-negative primary invasive breast cancer.
Methods
Retrospective review of consecutive cases treated at our Breast Unit between 2003 and 2013. Patients were divided into 3 subgroups based on p53 IHC expression: null (0%), low (0.1%-49%), and high (≥50%) p53 expression.
Results
A total of 1387 patients were included in the study with a median follow-up of 86 months. After adjusting for age, size, node status, lymphovascular invasion, progesterone, and Ki67 expression, only null p53 immunophenotype was associated with worse disease-free survival (DFS) (OR 1.74, 95% IC, 1.11-2.71, P = .015) and distant recurrence-free survival (DRFS) (OR 1.73, 95% IC, 1.04-2.90, P = .036). Null p53 impacted significantly DFS and DRFS also in patients with early breast cancer.
Conclusions
p53 IHC expression affects survival and, thus can be a valuable tool in the management of patients with HR-positive/Her2-negative breast cancer
... Next, we sought to validate one example of a multiple-to-one relationship for TP53. TP53 encoding the tumor suppressor p53, which is frequently mutated in cancer [77][78][79] . Single-cell analysis identifies three putative enhancers across the genome that can regulate TP53 expression indirectly ( Fig. 4h-i). ...
Genetic studies have associated thousands of enhancers with breast cancer. However, the vast majority have not been functionally characterized. Thus, it remains unclear how variant-associated enhancers contribute to cancer. Here, we perform single-cell CRISPRi screens of 3,512 regulatory elements associated with breast cancer to measure the impact of these regions on transcriptional phenotypes. Analysis of >500,000 single-cell transcriptomes in two breast cancer cell lines shows that perturbation of variant-associated enhancers disrupts breast cancer gene programs. We observe variant-associated enhancers that directly or indirectly regulate the expression of cancer genes. We also find one-to-multiple and multiple-to-one network motifs where enhancers indirectly regulate cancer genes. Notably, multiple variant-associated enhancers indirectly regulate TP53. Comparative studies illustrate sub-type specific functions between enhancers in ER+ and ER- cells. Finally, we developed the pySpade package to facilitate analysis of single-cell enhancer screens. Overall, we demonstrate that enhancers form regulatory networks that link cancer genes in the genome, providing a more comprehensive understanding of the contribution of enhancers to breast cancer development.
... TNBC is highly heterogeneous and in turn consists of six more subtypes 32,33 with prevalent TP53 mutations and somatic mutations in other genes, variable between and within tumors 34 . Somatic mutations in TP53 are known to occur early in breast cancer 35 and Ductal Carcinoma In-Situ (DCIS), preceding invasion, and the mutation frequency increases with the grade of DCIS tumors. More than 100 different TP53 missense mutations are found in 30% of all breast tumors 36 and occurs in 88% of basal-like, 26% of luminal, and 50% of HER2+ subtypes 37 . ...
Mutations in the TP53 tumor suppressor gene occur in >80% of the triple-negative or basal-like breast cancer. To test whether neomorphic functions of specific TP53 missense mutations contribute to phenotypic heterogeneity, we characterized phenotypes of non-transformed MCF10A-derived cell lines expressing the ten most common missense mutant p53 proteins and observed a wide spectrum of phenotypic changes in cell survival, resistance to apoptosis and anoikis, cell migration, invasion and 3D mammosphere architecture. The p53 mutants R248W, R273C, R248Q, and Y220C are the most aggressive while G245S and Y234C are the least, which correlates with survival rates of basal-like breast cancer patients. Interestingly, a crucial amino acid difference at one position—R273C vs. R273H—has drastic changes on cellular phenotype. RNA-Seq and ChIP-Seq analyses show distinct DNA binding properties of different p53 mutants, yielding heterogeneous transcriptomics profiles, and MD simulation provided structural basis of differential DNA binding of different p53 mutants. Integrative statistical and machine-learning-based pathway analysis on gene expression profiles with phenotype vectors across the mutant cell lines identifies quantitative association of multiple pathways including the Hippo/YAP/TAZ pathway with phenotypic aggressiveness. Further, comparative analyses of large transcriptomics datasets on breast cancer cell lines and tumors suggest that dysregulation of the Hippo/YAP/TAZ pathway plays a key role in driving the cellular phenotypes towards basal-like in the presence of more aggressive p53 mutants. Overall, our study describes distinct gain-of-function impacts on protein functions, transcriptional profiles, and cellular behaviors of different p53 missense mutants, which contribute to clinical phenotypic heterogeneity of triple-negative breast tumors.
... Mutations in this gene are present in approximately 50% of human cancers, making it the most common target for genetic alterations in the neoplastic process [40], although in breast cancer, the frequency of TP53 gene mutations is not very high (20-30%). Nevertheless, identifying the type of mutation can lead to a potential therapeutic target and the prediction of survival in these patients [41]. The association analysis for miR-375-3p pointed to the JAK2 gene, which encodes for Janus kinase 2, a tyrosine kinase that is phosphorylated in response to the action of various cytokines [42]. ...
The expression of inflammation-related miRs bound to high-density lipoproteins (HDLs), the anti-inflammatory activity of HDLs isolated from individuals with breast cancer, and controls were determined. Forty newly diagnosed women with breast cancer naïve of treatment and 10 control participants were included. Cholesterol-loaded bone-marrow-derived macrophages were incubated with HDL from both groups and challenged with lipopolysaccharide (LPS). Interleukin 6 (IL6) and tumor necrosis factor (TNF) in the medium were quantified. The miRs in HDLs were determined by RT-qPCR. Age, body mass index, menopausal status, plasma lipids, and HDL composition were similar between groups. The ability of HDL to inhibit IL6 and TNF production was higher in breast cancer compared to controls, especially in advanced stages of the disease. The miR-223-3p and 375-3p were higher in the HDLs of breast cancer independent of the histological type of the tumor and had a high discriminatory power between breast cancer and controls. The miR-375-3p was greater in the advanced stages of the disease and was inversely correlated with the secretion of inflammatory cytokines. Inflammation-related miRs and the anti-inflammatory role of HDLs may have a significant impact on breast cancer pathophysiology.
... In breast cancer, TP53 is a well-established biomarker. It is reported to be mutated in about 20-40% of all cases and is associated with breast cancer risk and prognosis [26]. However, the upregulation of its wild type in breast adenocarcinoma samples under study do not indicate an overall poorer prognosis in breast cancer patients, as shown by the Kaplan-Meir plot, hence wet lab validation may be required to fully establish the association of its wild type overexpression with BC prognosis. ...
The bidirectional causal relationship between type 2 diabetes mellitus (T2DM) and breast cancer (BC) has been established by numerous epidemiological studies. However, the underlying molecular mechanisms are not yet fully understood. Identification of hub genes implicated in T2DM-BC molecular crosstalk may help elucidate on the causative mechanisms. For this, expression series GSE29231 (T2DM-adipose tissue), GSE70905 (BC- breast adenocarcinoma biopsies) and GSE150586 (diabetes and BC breast biopsies) were extracted from Gene Expression Omnibus (GEO) database, and analyzed to obtain differentially expressed genes (DEGs). The overlapping DEGs were determined using FunRich. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Transcription Factor (TF) analyses were performed on EnrichR software and a protein-protein interaction (PPI) network was constructed using STRING software. The network was analyzed on Cytoscape to determine hub genes and Kaplan-Meier plots were obtained. A total of 94 overlapping DEGs were identified between T2DM and BC samples. These DEGs were mainly enriched for GO terms RNA polymerase II core promoter proximal region sequence and its DNA binding, and cAMP response element binding protein, and KEGG pathways including bladder cancer, thyroid cancer and PI3K-AKT signaling. Eight hub genes were identified: interleukin 6 (IL6), tumor protein 53 (TP53), interleukin 8 (CXCL8), MYC, matrix metalloproteinase 9 (MMP9), beta-catenin 1 (CTNNB1), nitric oxide synthase 3 (NOS3) and interleukin 1 beta (IL1β). MMP9 and MYC associated unfavorably with overall survival (OS) in breast cancer patients, IL6, TP53, IL1β and CTNNB1 associated favorably, whereas NOS3 did not show any correlation with OS. Salt inducible kinase 1 (SIK1) was identified as a significant key DEG for comorbid samples when compared with BC, also dysregulated in T2DM and BC samples (adjusted p <0.05). Furthermore, four of the significant hub genes identified, including IL6, CXCL8, IL1B and MYC were also differentially expressed for comorbid samples, however at p < 0.05. Our study identifies key genes including SIK1, for comorbid state and 8 hub genes that may be implicated in T2DM-BC crosstalk. However, limitations associated with the insilico nature of this study necessitates for subsequent validation in wet lab. Hence, further investigation is crucial to study the molecular mechanisms of action underlying these genes to fully explore their potential as diagnostic and prognostic biomarkers and therapeutic targets for T2DM-BC association.
... TP53 gene mutations are shown to be associated with breast cancer (5). Moreover, breast cancer with TP53 mutations is more likely to be aggressive and resistant to chemotherapy and radiotherapy (5)(6)(7). A noninvasive method to detect TP53 mutations in TNBC might optimize treatment plans and improve the prognosis of TNBC patients. ...
Objectives:
To explore the value of T1-weighted imaging (T1WI), T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI) radiomics features reflecting TP53 mutations in patients with triple negative breast cancer (TNBC).
Study design:
This retrospective study enrolled 91 patients with TNBC with TP53 testing (64 patients in the training cohort and 27 patients in the validation cohort). A total of 2832 radiomics features were extracted from the first phase of dynamic contrast-enhanced T1WI, T2WI and ADC maps. Analysis of variance (ANOVA) and the Kruskal-Wallis-test were used for feature selection. Then, linear discriminant analysis (LDA), multilayer perceptron (MLP), logistic regression (LR), LR with LASSO, decision tree (DT), naïve Bayes (NB), random forest (RF), and support vector machine (SVM) models were used for classification.
Results:
The validation AUCs of the eight classifiers ranged from 0.74 (NB) to 0.85 (SVM). SVM attained the highest AUC (0.85) and diagnostic accuracy (0.82) of all tested models. The top 3 ranking features in the SVM model were T1-square-first order-skewness (coefficient: 1.735), T2-wavelet-LHH-GLCM-joint energy, and T2-wavelet-LHH-GLCM-inverse difference moment (coefficient: -0.654, -0.634).
Conclusions:
Radiomics-based analysis with the SVM model is recommended for the detection of TP53 mutations in TNBC. Furthermore, T1WI- and T2WI-related features could be used as noninvasive biomarkers for predicting TP53 mutations.
... The most typical genetic alterations that have been found are TP53 mutations, which are present in around 50% of all human malignancies [28]. 0-20% of breast tumors had TP53 mutations [29]. The mutation, which is linked to a poor prognosis and treatment resistance, is assumed to be an early occurrence in carcinogenesis. ...
... 74 TP53 is mutated in approximately 20-40% of all BC cases. 75,76 Mutations in TP53 can predispose cells to an increase in CIN in BC. In fact, associations between mutations in the TP53 and genomic instability in primary BC have been reported. ...
Chromosomal instability (CIN) has become a topic of great interest in recent years, not only for its implications in cancer diagnosis and prognosis but also for its role as an enabling feature and central hallmark of cancer. CIN describes cell-to-cell variation in the number or structure of chromosomes in a tumor population. Although extensive research in recent decades has identified some associations between CIN with response to therapy, specific associations with other hallmarks of cancer have not been fully evidenced. Such associations place CIN as an enabling feature of the other hallmarks of cancer and highlight the importance of deepening its knowledge to improve the outcome in cancer. In addition, studies conducted to date have shown paradoxical findings about the implications of CIN for therapeutic response, with some studies showing associations between high CIN and better therapeutic response, and others showing the opposite: associations between high CIN and therapeutic resistance. This evidences the complex relationships between CIN with the prognosis and response to treatment in cancer. Considering the above, this review focuses on recent studies on the role of CIN in cancer, the cellular mechanisms leading to CIN, its relationship with other hallmarks of cancer, and the emerging therapeutic approaches that are being developed to target such instability, with a primary focus on breast cancer. Further understanding of the complexity of CIN and its association with other hallmarks of cancer could provide a better understanding of the cellular and molecular mechanisms involved in prognosis and response to treatment in cancer and potentially lead to new drug targets.
... TP53 plays a central role in human cancer pathogenesis and is hypermutated in almost all human cancers [18]. There is strong evidence that TP53 mutation is correlated with poorer overall and diseasefree survival in breast cancer patients [19][20][21]. Recently, the comprehensive cancer genome analyses described that phosphoinositide-3 kinase (PI3K) pathway are frequently altered in human cancers [22,23]. ...
Objective
Although the tumor mutation burden (TMB) was reported as a biomarker for immunotherapy of various cancers, whether it can effectively predict the survival prognosis in breast cancer patients remains unclear. In this study, the prognostic value of TMB and its correlation with immune infiltration were explored by using multigroup studies.
Methods
The somatic mutation data of 986 breast cancer patients were obtained from TCGA database. Breast cancer patients were divided into a low-TMB group and a high-TMB group according to the quartile of TMB scores. The differentially expressed genes (DEGs) were identified by the “limma” R program. The CIBERSORT algorithm was utilized to estimate the immune cell fraction of each sample. The TIMER database was utilized to evaluate the association between CNVs of immune genes and tumor immune cell infiltration and the prognostic value of the immune cells in breast cancer.
Results
In breast cancer, TP53, PIK3CA, TTN, CDH1 and other genes were the most important mutated genes. Higher survival rate of patients was found in the low-TMB group. Among the top 10 DEGs, three of them belong to the KRT gene family. GSEA enrichment analysis showed that MAPK, Hedgehog, mTOR, TGF-bate and GnRH signaling pathways were enriched in the low-TMB group. The infiltration levels of the most of immune cells were higher in the low-TMB group (P < 0.01). Higher expression of CCL18 and TRGC1 was correlated with poor prognosis. Breast cancer patients with CCL18 copy number variations, especially arm-level gains, showed significantly decreased immune cell infiltration. In the low B cell infiltration group, the survival prognosis of breast cancer patients was poor.
Conclusions
TMB is a potential prognosis marker in breast cancer. Immune-related gene CCL18 and TRGC1 are biomarkers of poor prognosis while immune (B cell) infiltration is a biomarker of good prognosis.
... In the context of breast cancer diagnosis, detection of mutations in tumour suppressor genes such as TP-53 is of prime importance [8]. TP-53 mutations, found in 20-40% of all breast cancer cases, can be determinants of underlying cancer pathways and treatment options [9,10]. Previous work has shown that while it is possible to predict TP-53 mutation status from WSIs, the accuracy of such predictions is quite low with state of the art area under the receiver operating characteristic curve (AUC-ROC) of around 0.72 [1]. ...
How similar are two images? In computational pathology, where Whole Slide Images (WSIs) of digitally scanned tissue samples from patients can be multi-gigapixels in size, determination of degree of similarity between two WSIs is a challenging task with a number of practical applications. In this work, we explore a novel strategy based on kernelized Maximum Mean Discrepancy (MMD) analysis for determination of pairwise similarity between WSIs. The proposed approach works by calculating MMD between two WSIs using kernels over deep features of image patches. This allows representation of an entire dataset of WSIs as a kernel matrix for WSI level clustering, weakly-supervised prediction of TP-53 mutation status in breast cancer patients from their routine WSIs as well as survival analysis with state of the art prediction performance. We believe that this work will open up further avenues for application of WSI-level kernels for predictive and prognostic tasks in computational pathology.
... Metastatic infections, such as liver and cellular breakdowns in the lungs, affect a majority of patients with malignant bosom growth [28]. A comprehensive genomic analysis of bosom disease patients identified key drivers of hereditary transformations responsible for therapeutic ramifications and outcome prediction [29]. ...
Incorporating scientific research into clinical practice via clinical informatics, which includes genomics, proteomics, bioinformatics, and biostatistics, improves patients’ treatment. Computational pathology is a growing subspecialty with the potential to integrate whole slide images, multi-omics data, and health informatics. Pathology and laboratory medicine are critical to diagnosing cancer. This work will review existing computational and digital pathology methods for breast cancer diagnosis with a special focus on deep learning. The paper starts by reviewing public datasets related to breast cancer diagnosis. Additionally, existing deep learning methods for breast cancer diagnosis are reviewed. The publicly available code repositories are introduced as well. The paper is closed by highlighting challenges and future works for deep learning-based diagnosis.
... The mutation rate of the TP53 gene in BC is around 30%, and the mutation rate in TNBC can reach 54% [39]. As a tumor suppressor gene, wildtype p53 promotes cell malignant transformation and hinders cell apoptosis after mutation. ...
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer. Neoadjuvant chemotherapy was widely accepted for treating TNBC. This systematic review and meta-analysis aimed to evaluate the efficacy, safety, and survival benefit of platinum-based adjuvant therapy (PBAT) in treating TNBC. The keywords were searched in Medline, Embase, Pubmed, and Cochrane Library database up to July 24, 2022. All the randomized control trials (RCTs) comparing PBAT and non-PBAT in treating TNBC were included in our study. The pathological complete remission (pCR) and complications were compared by odds ratio (OR) and 95% confidence intervals (CIs). The overall survival (OS) and relapse-free survival (RFS) were compared by hazard ratio (HR) and 95% CIs. A total of 19 RCTs were included in our meta-analysis, among which 2,501 patients were treated with PBAT and 2,290 with non-PBAT. The patients treated with PBAT combined a significantly higher pCR rate compared to those patients treated with non-PBAT (49.8% versus 36.4%, OR = 1.27, 95%CI = 1.14–1.43, P < 0.001). Besides, patients treated with PBAT had a significantly better RFS (HR = 0.78, 95%CI = 0.63–0.95, P = 0.016), but not in OS (HR = 0.84, P = 0.304). Although the occurrence of neutropenia and nausea were slightly different between the PBAT group (51.5% and 24.4%) and the non-PBAT group (47.0% and 29.4%), the complications were acceptable in the two treatments groups. Our results demonstrated that TNBC patients treated with PBAT could achieve a higher pCR rate and better RFS benefit without a higher complication rate.
Highlights
Platinum-based adjuvant therapy provided a higher pCR rate for TNBC.
Platinum-based adjuvant therapy prolonged the RFS but without prolongingthe OS.
Neutropenia and nausea rate was different between group PBAT and non-PBAT.
... Defects in the p53 tumour suppressor gene have been linked to more than 50% of human cancers. The TP53 gene has been found altered in breast carcinomas in approximately 20-40% of all cases depending on tumor size an stage of the disease (Lise and Dale, 2003). Abnormality of this gene is one of the most significant events in lung cancers and play and important role in the tumorigenesis of lung epithelial cells (Mogi and Kkuwano, 2011). ...
Cancer is a group of diseases characterized by irregularities in cell growth, which lack the reproductive control required by their original function. Despite efforts, most currently used cytotoxic drugs have various adverse effects on patients, thus new candidates in cancer therapy are urgently needed. Benzophenanthridine alkaloids are the main metabolites of the genus Zanthoxylum (Rutaceae), species distributed worldwide in almost all regions. Alkaloids have various proven biological activities such as antibacterial, antiviral, antifungal and cytotoxic. However, in many cases the available sample quantities are not feasible to carry out multiple tests or they are very expensive due to their complexity. In this sense, computationally assisted rational drug design is a useful tool to predict the properties of molecules. This work reports the use of the free web platform PASS (Prediction of Activity Spectra of Substances) to explore the antineoplastic activity of 32 alkaloid structures as well as the mechanisms of action involved. The results obtained show that these molecules can activate the apoptotic cascade as well as inhibit key genes in oncogenesis, suggesting them as possible candidates for future in vitro studies.
... One of the remarkable targets in cancer signaling pathway is tumor protein P53 (TP53) protein, which is a multifunctional transcription factor in the wild type and is involved in cell-cycle control, DNA maintenance, genome integrity, post-DNA damage repair, and apoptosis (6). The loss of TP53 function results in the replication of damaged DNA. ...
HER2-positive metastatic breast cancer is much less frequent than other subgroups of breast cancer. Treatment options for this cancer are mostly limited to systemic chemotherapy, which leads to moderate improvements. Targeted therapy against malignant breast cancer requires the identification of reliable biomarkers for personalized medicine to obtain the maximum benefit of this therapy. Any mutations in the TP53 signaling pathway can be considered as a significant causative factor of breast cancer, for which the identification of target genes plays an important role in selecting the appropriate treatment. The use of personalized gene expression profiling could be valuable to find the direct target of the treatment in this case. The present study assessed the genetic profile of an HER2-positive metastatic breast cancer patient (with a liver metastasis) and figured out a complete and sustained response to bevacizumab. According to the results of next-generation sequencing (NGS) analysis, the patient’s genetic profile showed an increased expression of p4EBP1 and PTEN and the activation of the mTOR signaling pathway with a mutation in the TP53 gene. Based on the common treatment of similar profiling, we administrated bevacizumab/Taxol/Gemzar chemotherapy up to six courses. Accordingly, as the response to treatment was revealed by reducing the volume of the liver metastasis from 4 to 1.4 cm, metastasectomy was performed as a complementary treatment. Hence, personalized gene expression profiling not only is useful for targeted therapy but also could be recommended to avoid prescription of non-responsive drugs.
... Research has been focusing on genomic DNA from tumor to identify prognostic genetic biomarkers, in addition to routine clinical and histological factors. For instance, the alteration of TP53 gene, detected in over 20% of BC patients, has been identified as a strong predictor of poor BC survival [7][8][9]. MYC gene amplification [10,11], related to BC development and progression, has also be considered as a powerful negative prognostic factor, especially in BC patients with node-negative and hormone receptor (HR)-negative disease. Somatic aberrations of other genes, such as RB1 and ERBB2 [12][13][14], can also facilitate the prediction of BC patients' prognosis. ...
Approximately 30% of breast cancer patients suffer from disease relapse after definitive treatment. Monitoring breast cancer at baseline and disease progression using comprehensive genomic profiling would facilitate the prediction of prognosis. We retrospectively studied 101 breast cancer patients ultimately experiencing relapse and/or metastases. The baseline and circulating tumor DNA monitoring cohorts included patients with baseline tumor tissue and serial plasma samples, respectively. Samples were analyzed with targeted next‐generation sequencing of 425 cancer‐relevant genes. Of 35 patients in the baseline cohort, patients with TP53 mutations (p < 0.01), or CTCF/GNAS mutations (p < 0.01) displayed inferior disease‐free survival, and patients harboring TP53 (p = 0.06) or NOTCH1 (p = 0.06) mutations showed relatively poor overall survival, compared to patients with wild‐type counterparts. Of 59 patients with serial plasma samples, 11 patients who were newly detected with TP53 mutations had worse overall survival than patients whose TP53 mutational status remained negative (p < 0.01). These results indicate that inferior prognosis of advanced breast cancer was potentially associated with baseline TP53, CTCF and NOTCH1 alterations. Newly identified TP53 mutations after relapse and/or metastasis was another potential prognostic biomarker of poor prognosis.
... The tumor suppressor protein p53 can induce cell cycle arrest, apoptosis, senescence, or ferroptosis in response to stress signals 1,2 , and it prevents the accumulation of cancer-causing mutations that lead to the development of malignant tumors 3 . Approximately 30% of the breast tumors harbor a TP53 mutation 4 , and the frequency, spectrum, and timing of these mutations vary with the molecular subtype of the disease 5 . Although the prevalence of TP53 mutations is lower in luminal than in basallike tumors 6 , TP53 mutation is the second most common mutation in the luminal type 7 . ...
We investigated the association between TP53 mutation and 21-gene recurrence score (RS) in ER-positive/HER2-negative breast cancer (BC) using data from 141 patients who underwent TP53 sequencing and Oncotype DX® tests. We detected TP53 mutations in 18 (12.8%) patients. Most patients with TP53 mutation had a high 21-gene RS (≥26). The average 21-gene RS was higher in TP53 mutant tumors. Multivariate analysis showed that mutated TP53 is an independent factor for a high 21-gene RS. Mutated TP53 remained closely associated with high 21-gene RS in patients with low pathological risk (n = 103). In the ER+/PR+/HER2-negative subset (n = 356) of The Cancer Genome Atlas, the non-luminal A intrinsic subtype was more prevalent in the group with mutant TP53. mRNA levels of p53-regulated senescence gatekeeper and cell cycle-related genes were increased in BC with mutated TP53. Mutational analysis of TP53 helped identify endocrine-resistant tumors.
... Importantly, it is known that some of the p53 mutants, if not all, show gain-of-function rather than loss-of-function mutations, indicating that p53 mutants can induce genes that wild type p53 cannot control. Supporting this, recent studies suggest that the prognostic value of the TP53 mutation may depend on the mutated residue 6,7 , cancer type, presence of mutation in other genes 8 , and clinical backgrounds 9 . Most importantly, TP53 mutation status is not the only factor affecting the p53 signaling pathway. ...
The tumor suppressor p53, encoded by the TP53 gene, is mutated or nullified in nearly 50% of human cancers. It has long been debated whether TP53 mutations can be utilized as a biomarker to predict clinical outcomes of cancer patients. In this study, we applied computational methods to calculate p53 deficiency scores (PDSs) that reflect the inactivation of the p53 pathway, instead of TP53 mutation status. Compared to TP53 mutation status, the p53 deficiency gene signature is a powerful predictor of overall survival and drug sensitivity in a variety of cancer types and treatments. Interestingly, the PDSs predicted clinical outcomes more accurately than drug sensitivity in cell lines, suggesting that tumor heterogeneity and/or tumor microenvironment may play an important role in predicting clinical outcomes using p53 deficiency gene signatures.
... The TP53 gene is found to be altered in approximately 20-40% of all breast cancer cases in 2003 [19]. This gene is essential for the negative feedback present in cell proliferation. ...
... TP53 mutant is in approximately 20-40% of all BC cases, and TP53 is the most frequently mutated gene in BC (38). Based on the important role of TP53 in the occurrence and development of BC, we compared the expression levels of LAGE3 between patients with and without TP53 mutants. ...
The role of L Antigen Family Member 3 (LAGE3) in breast cancer (BC) has not been sufficiently studied. In this study, we explored the clinical value and biological functions of LAGE3 in BC. Comprehensive analysis of LAGE3 was carried out on The Cancer Genome Atlas, Molecular Taxonomy of Breast Cancer International Consortium and Gene Expression Omnibus datasets. Results showed that LAGE3 expression was higher in BC tissues than in normal breast tissues of public datasets and our local cohort. Moreover, its expression was higher in BC patients with larger tumor size, significant lymph node metastasis, higher tumor grade, and more advanced disease stage. High expression of LAGE3 was correlated with poor prognosis, and LAGE3 could independently predict survival of BC patients. Functional enrichment analysis revealed a correlation between LAGE3 expression and biochemical metabolism and immune-related terms and cancer-related pathways. Analysis of tumor microenvironment indicated that LAGE3 expression was associated with the immune cell infiltration and anti-cancer immunity cycle. LAGE3 expression was higher in triple-negative breast cancer (TNBC) compared to hormone receptor-positive BC, but not HER2-positive subtype. Suppression of LAGE3 expression inhibited the proliferation and induced apoptosis of TNBC cell lines. Besides, the down-regulation of LAGE3 attenuated the migration and invasion but reduced the expression level of epithelial-mesenchymal-transition related proteins in TNBC cell lines. In conclusion, this study demonstrated for the first time that LAGE3 promotes the progression of BC. Therefore, it may be a potential diagnostic and prognostic biomarker, as well as a treatment target for BC.
... Tumor suppressor gene tumor protein 53 (TP53) is involved in stopping the cell cycle and activating apoptosis, preventing uncontrolled cell growth. Mutations of this gene result in defective DNA repair and have been linked to the pathogenesis of some malignancies [23][24][25][26][27][28][29][30][31][32][33][34] . When this gene is mutated, it encodes a mutated TP53 protein that tends to accumulate in the cell nuclei, making its detection possible by immunohistochemistry 23,24,[26][27][28][29] . ...
Introduction:
Histologically speaking, architectural, and cytological features help enable the differentiation between sebaceous carcinoma and benign sebaceous lesions; occasionally, these features are insufficient to determine the benign or malignant nature of a lesion.
Objective:
The objective of the study was to determine p53 and Ki-67 expressions in benign sebaceous lesions and sebaceous carcinoma.
Materials and methods:
Analytical, observational, cross-sectional, and retrospective study conducted on a number of cases of sebaceous hyperplasia, sebaceous adenoma, sebaceoma, and sebaceous carcinoma that were diagnosed at the Dermatology Service of General Hospital of Mexico “Dr. Eduardo Liceaga.” This included the determination of epidemiological, clinical, histopathological, and immunohistochemical features. In addition, descriptive and bivariate statistics were performed.
Results:
Thirty-six cases of sebaceous lesions were included: thirteen (36.1%) cases of hyperplasia, eight (22.2%) cases of adenoma, five (13.9%) cases of sebaceoma, and ten (27.8%) cases of carcinomas. The median age was 57.5 + 15.66 years. Males were mostly affected (52.8%) and the most frequent topography was the face (91.7%). Sebaceous carcinomas exhibited the following traits: asymmetry (p = 0.006), non-circumscribed lesion (p < 0.0001), ulceration (p = 0.024), nuclear atypia (p <0.0001), individual necrosis (p = 0.003), squamous metaplasia (p = 0.017), and higher mitotic index (p = 0.005). Sebaceous carcinomas had a higher percentage of p53 and Ki-67 expression compared to benign sebaceous lesions (p = 0.001 and p = 0.001, respectively) and more frequently expressed p53 > 10% and Ki-67 > 25% (p < 0.0001 and p < 0.0001, respectively).
Conclusion:
p53 expression > 10% and Ki-67 expression > 25% are suggestive of a sebaceous carcinoma diagnosis.
Breast cancer (BC) is the type of cancer with the highest incidence and mortality rates in women in the world. In the treatment of this neoplasia, several therapies are applied, including radiotherapy, hormonal therapy, chemotherapy, and biological therapy. Although most patients respond to these types of therapy, some patients over time, develop resistance or eventually relapse. Considering the above, future therapeutic concepts in BC are being directed at individualization of therapy and escalation of treatment based on tumor biology through the use of gene therapy. In this regard, a new genomic engineering technology, called the clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein-9 (Cas9), has acquired great importance in recent years, as a potential gene editing tool, extensively applied in human cancer research and cancer treatment. The aim of this review was to describe the advantages, limitations, and applications of CRISPR gene editing technology in BC treatment. Our review emphasizes the innovative facets and profound importance of CRISPR gene editing technology within the BC treatment landscape. Additionally, it provides valuable information to consider when evaluating the risks associated with the implementation of CRISPR-Cas9 technology in BC therapy.
Triple negative breast cancers (TNBC) are a biologically aggressive form of breast cancer and constitute approximately 10-15% of all breast cancer patients. Distant metastasis, lack of clinically targeted therapies and prognostic markers, makes the disease difficult to treat. Till now not much work has been carried out on this deadly disease. This book provides an overview of TNBC etiology, its treatment strategies and prognostic markers to identify the outcome of standard therapies. Signalling pathways namely cell proliferation, angiogenesis, invasion and metastasis, apoptosis, autophagy and others involved in complicating the disease have been described in the chapters to convey an understanding about the disease mechanisms. All the possible drugs either in pre-clinical or clinical stages have also been mentioned with data that depicts their efficiency in targeting altered genes. The book also introduces the reader to herbal medicine exhibiting high potency to target TNBC, their synthetic analogs used during chemotherapy and their ability to fight against chemoresistance. The concept of phytonanotechnology has also been discussed. The book helps create awareness among a broad range of readers about TNBC. It points to prioritizing the upgradation of health care facilities and re-designing future treatment strategies to provide maximum benefit to breast cancer patients.
Background
Tetrandrine, a bisbenzyl isoquinoline alkaloid from Stephania tetrandra was used in the present study. Roots of S. tetrandra is one of the major ingredients in herbal formulations of Traditional Chinese Medicine (TCM) viz. Fang Ji, Han-Dan-Gan-Le, Han-Dan-Gan-Le, Fang-Ji-Huang-Qi-Tang and Fang-Ji-Fu-Ling-Tang and, act as diuretic, antiinflammatory and antirheumatic agent. Alkaloids are the major components of S. tetrandra roots and tetrandrine is one of the important bisbenzyl isoquinoline alkaloids in this herb.
Purpose and study design
In the present study, network pharmacology approach was used to identify major cancer signaling pathways and, protein molecules targeted by tetrandrine to induce an anticancer effect in breast cancer.
Methods
Potential targets of tetrandrine against breast cancer were selected using already published articles and public databases and, were used in Protein-Protein Interaction (PPI) network analysis, Gene Ontology (GO), and Pathway enrichment analysis.
Results
PPI network analysis showed 65 nodes, 315 edges, and a clustering coefficient of 0.493. Tetrandrine targeted mainly on the proteins of mTOR, PI3-Akt, cell cycle and MAPK signalling pathways in addition to its action on cellular, biological and molecular functions as observed by Gene Ontology and KEGG analysis.
Conclusion
Tetrandrine induces anticancer effect in breast cancer by targeting PI3K-Akt, mTOR and MAPK and cell cycle pathways.
Background:
Multiple studies have investigated the correlation of single nucleotide polymorphisms (SNPs) in leukocyte-specific protein 1 (LSP1) with susceptibility to breast cancer (BC) and have yielded inconsistent conclusions, particularly rs3817198(T > C). Consequently, we performed a meta-analysis to estimate this relationship more comprehensively.
Methods:
Four databases were utilized to locate eligible publications: PubMed, Embase, Web of Science, and China National Knowledge Infrastructure. This meta-analysis included 14 studies, including 22 reports of 33194 cases and 36661 controls. The relationship of rs3817198 polymorphism with breast cancer was estimated using odds ratios (ORs) with 95% confidence intervals (CIs). The LSP1 co-expression network was constructed by STRING, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using DAVIDE. Download TCGA breast cancer mRNA-seq data and analyze the relationship between LSP1 expression and breast cancer chemotherapy sensitivity.
Results:
The results indicated that rs3817198(T > C) was positively correlated to with breast malignancy (dominant model: OR = 1.11, 95%CI = 1.06-1.17; recessive model: OR = 1.10, 95%CI = 1.04-1.15; heterozygous model: OR = 1.09, 95%CI = 1.04-1.15; homozygous model: OR = 1.18, 95%CI = 1.09-1.28; additive model: OR = 1.09, 95%CI = 1.05-1.13), among Caucasians and Asians. However, rs3817198(T > C) may reduce the risk of breast carcinoma in Africans. Rs3817198(T > C) might result in breast carcinoma in individuals with BRCA1 and BRCA2 variants and can contribute to estrogen receptor (ER)-positive breast carcinoma. The expression of LSP1 was inversely correlated with the IC50 of doxorubicin (P = 8.91e-15, Cor = -0.23), 5-fluorouracil (P = 1.18e-22, Cor = -0.29), and cisplatin (P = 1.35e-42, Cor = -0.40).
Conclusion:
Our study identified that LSP1 rs3817198 polymorphism might result in breast malignancy, particularly among Caucasians and Asians, but lower breast cancer susceptibility in African populations. The expression of LSP1 was negatively correlated with the IC50 of doxorubicin, 5-fluorouracil, and cisplatin.
Common variants of genes involved in DNA damage correction [tumor protein p53 (TP53), murine double 2 homolog oncoprotein (MDM2) and ataxia-telengiectasia mutated (ATM)] may serve a role in cancer predisposition. The purpose of the present study was to investigate the association of five variants in these genes with breast cancer risk and clinicopathological traits in a cohort of 261 women from northern Sardinia. Polymorphic variants in TP53 (rs17878362, rs1042522 and rs1625895), MDM2 (rs2279744) and ATM (rs1799757) were determined by PCR and TaqMan single nucleotide polymorphism assay in patients with breast cancer (n=136) and healthy controls (n=125). Association with clinicopathological (e.g., age at diagnosis, lymph node involvement, clinical stage) and lifestyle factors (e.g., smoking status, alcohol intake, contraceptive use) was also evaluated. TP53 rs17878362 and rs1625895 polymorphisms were associated with decreased risk of BC diagnosis in patients older than 50 years (codominant and recessive models) and post-menopause (recessive model). Furthermore, there was a significant association between lymph node status (positive vs. negative) and ATM rs1799757-delT in dominant and additive models and between MDM2 rs2279744-allele and use of oral contraceptives. This analysis suggested that TP53 rs17878362 and rs1625895 may affect age of onset of breast cancer and ATM rs1799757 and MDM2 rs2279744 may be associated with lymph node status and prolonged use of oral contraceptives, respectively.
Le laboratoire INSERM U908 a montré le rôle déterminant du facteur de croissance NGF dans l’agressivité du cancer du sein. De précédentes études ont montré que l’inhibition de l’activité de TrkA, le récepteur du NGF, aboutissait à une diminution de la taille des tumeurs in vitro mais aussi dans des modèles pré-cliniques. Néanmoins, ces inhibiteurs ont donné lieu à des essais cliniques décevants. La résistance à ces inhibiteurs est en partie due à l’association de récepteurs membranaires. Plus précisément, mon travail de thèse a permis de démontrer qu’une forme particulière du récepteur CD44 interagit avec TrkA ce qui conduit à une résistance aux traitements. De plus, j’ai également montré l’existence d’une interaction entre TrkA et deux autres récepteurs. Ainsi, j’ai pu déterminer précisément comment ces récepteurs coopèrent afin de développer des inhibiteurs ciblant leur interaction. Ces inhibiteurs pourraient donc s’avérer efficaces pour le traitement de certains cancers du sein. Ma thèse souligne l’importance des complexes de récepteurs dans la plasticité des cellules cancéreuses et leur capacité à s’adapter pour résister aux thérapies ciblées.
Abstract
The epithelial glandular tissue forms a major part of the breast cancer origin followed by lobular glandular tissue. The initial growth of the tumor is limited to the duct or lobule, without any symptoms and metastasis. The progression of the disease includes invasion of the neighboring breast tissue (invasive breast cancer), affecting nearby lymph nodes (regional metastasis), or spreads to other organs of the body (secondary metastasis or distant metastasis). The excessive metastasis because of tumor development leads to death of the patient. Breast cancer is considered the most common cancer with 2.3 million of women diagnosed with breast tumor and 685,000 deaths reported worldwide. During the last 5 years, 7,800,000 cases of breast tumor were reported globally. Breast cancer is neither an infectious nor transmissible illness. Other than gender (female) and age, breast tumor presents no manifestation of disease for almost 40 years of the age. Some of the significant contributing factors of the disease include harmful alcohol use, age, obesity, family history, exposure to harmful radiations, and reproductive factors. Besides, some factors are responsible for aggravating the incidence of breast cancer such as age at first menstrual period, use of tobacco, age at first pregnancy, and postmenopausal hormone therapy. The age at first menstrual period and age at first pregnancy, tobacco use, and postmenopausal hormone therapy are all variables that raise the risk of breast cancer.
Keywords
Breast cancer
Epidemiology
Global distribution
Risk factors
Diagnosis
The Rho GTPase family consists of 20 genes encoding intracellular signalling proteins that influence cytoskeletal dynamics, cell migration and cell cycle progression. They are implicated in breast cancer progression but their role in breast cancer aetiology is unknown. As aberrant Rho GTPase activity could be associated with breast cancer, we aimed to determine the potential for a causal role of Rho GTPase gene expression in breast cancer risk, using two-sample Mendelian randomization (MR). MR was undertaken in 122,977 breast cancer cases and 105,974 controls, including 69,501 estrogen receptor positive (ER+) cases and 105,974 controls, and 21,468 ER negative (ER−) cases and 105,974 controls. Single nucleotide polymorphisms (SNPs) underlying expression quantitative trait loci (eQTLs) obtained from normal breast tissue, breast cancer tissue and blood were used as genetic instruments for Rho GTPase expression. As a sensitivity analysis, we undertook co-localisation to examine whether findings reflected shared causal variants or genomic confounding. We identified genetic instruments for 14 of the 20 human Rho GTPases. Using eQTLs obtained from normal breast tissue and normal blood, we identified evidence of a causal role of RHOD in overall and ER+ breast cancers (overall breast cancer: odds ratio (OR) per standard deviation (SD) increase in expression level 1.06; (95% confidence interval (CI) 1.03, 1.09; P = 5.65 × 10–5) and OR 1.22 (95% CI 1.11, 1.35; P = 5.22 × 10–5) in normal breast tissue and blood respectively). There was a consistent direction of association for ER− breast cancer, although the effect-estimate was imprecisely estimated. Using eQTLs from breast cancer tissue and normal blood there was some evidence that CDC42 was negatively associated with overall and ER + breast cancer risk. The evidence from colocalization analyses strongly supported our MR results particularly for RHOD. Our study suggests a potential causal role of increased RHOD gene expression, and, although the evidence is weaker, a potential protective role for CDC42 gene expression, in overall and ER+ breast cancers. These finding warrant validation in independent samples and further biological investigation to assess whether they may be suitable targets for drug targeting.
This paper proposes a novel fast mutation detection system that looks for mutations in the tumor suppressor gene, also known as TP53. Mutations are modifications in the nucleotide sequences of the human genome and may be caused by various factors, such as exposure to radiation, sunlight, smoking and replication errors. Mutations in TP53 are the most common cause of cancer and early detection may prevent cancer from happening. The proposed system utilizes the high matching speed of a logic-based content-addressable memory (CAM) for mutation detection along with a hamming distance calculator that specifies the exact location of the mutation. The proposed system implementation is carried on a Xilinx Virtex®-7field-programmable gate array (FPGA) and demonstrates a low match time of 0.18 μs, which is much faster compared to the state-of-the-art systems.
Metaplastic breast carcinoma (MBC) is a rare malignant breast tumor, and no effective chemotherapy unique to metaplastic carcinoma exists. As MBC is typically “triple negative”, endocrine therapy and molecular therapy targeted to Her2 might not be favorable, resulting in a poor prognosis. Anlotinib is currently being tested in patients with breast or cancer. Here, we report a successful case in which anlotinib was used to treat MBC. A 54-year-old female patient visited the hospital after the discovery of a left breast tumor 10 months prior, and tumor redness and swelling had lasted for more than one month. After admission, relevant examinations were performed. After left breast tumor puncture revealed left emulsified biological cancer, the tumor significantly increased in size, and bleeding was obvious after 2 cycles of the “EC” chemotherapy regimen. The curative effect was evaluated as progressive disease (PD). After two cycles of chemotherapy with the “PCb” regimen, the efficacy was still PD. The Karnofsky performance status (KPS) score of the patient after 4 cycles of chemotherapy was 60 points, with severe anemia, and she could not tolerate chemotherapy. The patient was given radiotherapy to stop bleeding, and the tumor further increased in size during radiotherapy. The curative effect was evaluated as PD. After a multidisciplinary consultation in our hospital, we initiated oral anlotinib (12 mg; 2 weeks on, 1 week off). The tumor significantly decreased in size after taking anlotinib, and the efficacy was evaluated as PR. Adverse reactions during treatment were controlled, and progression-free survival (PFS) reached up to 25+ months. The follow-up is ongoing. The patient has provided written informed consent for the case details and images to be published, and at the same time institutional approval was required to publish the case details, we report this case.
Breast cancer (BC) is the most frequently diagnosed cancer in women worldwide with
more than 2 million new cases in 2020. Its incidence and death rates have increased over the last three decades due to the change in risk factor profiles, better cancer registration, and cancer detection. The number of risk factors of BC is significant and includes both the modifiable factors and non-modifiable factors. Currently, about 80% of patients with BC are individuals aged >50. Survival depends on both stage and molecular subtype. Invasive BCs comprise wide spectrum tumors that show a variation concerning their clinical presentation, behavior, and morphology. Based on mRNA gene expression levels, BC can be divided into molecular subtypes (Luminal A, Luminal B, HER2-enriched, and basal-like). The molecular subtypes provide insights into new treatment strategies and patient stratifications that impact the management of BC patients. The eighth edition of TNM classification outlines a new staging system for BC that, in addition to anatomical features, acknowledges biological factors. Treatment of breast cancer is complex and involves a combination of different modalities including surgery, radiotherapy, chemotherapy, hormonal therapy, or biological therapies delivered in diverse sequences.
Background
Breast cancer is one of the most important causes of mortality in the world, and Tamoxifen therapy is known as a medication strategy for estrogen receptor-positive breast cancer. In current study, two hypotheses of Tamoxifen consumption in breast cancer cell line (MCF7) were investigated. First, the effect of Tamoxifen on genes expression profile at transcriptome level was evaluated between the control and treated samples. Second, due to the fact that Tamoxifen is known as a mutagenic factor, there may be an association between the alterations of genetic variants and Tamoxifen treatment, which can impact on the drug response.
Methods
In current study, the whole-transcriptome (RNA-seq) dataset of four investigations (19 samples) were derived from European Bioinformatics Institute (EBI). At transcriptome level, the effect of Tamoxifen was investigated on gene expression profile between control and treatment samples. Moreover, Tamoxifen is known as a mutagenic factor, therefore, its contribution to alterations of genetic variants and drug response were examined.
Results
Results achieved from RNA-seq analysis indicated the contribution of several candidate genes to tumor suppression process and consequently, the achievement of an effective treatment. For instance, XIAP-associated factor 1 (XAF1) was reported as an up-regulated gene under Tamoxifen therapy. XAF1 is a tumor suppressor that contributes to the apoptosis induction and tumor growth inhibition along with TP53. Results of gene ontology enrichment analysis of differential gene expressions indicated that most of them could considerably lead to the cell death, apoptosis, and negative regulation of proteolysis process. Findings achieved from evaluating Tamoxifen mutagenicity effect on drug response was not confirmed perfectly. The most reported candidate genes, which were related to differential genetic variants between control and treated samples, played the oncogene and tumor suppressor dual roles and also their exact roles in breast cancer were not investigated precisely.
Conclusion
At transcriptome level, Tamoxifen consumption in MCF7 cell line could be associated with candidate genes and biological pathways that contribute to the apoptosis, proteolysis, and tumor suppression. The mutagenicity effect of Tamoxifen and its contribution to drug response was not confirmed perfectly.
There is a pressing need today to mechanistically interpret sets of genomic variants associated with diseases. Here we present a tool called ‘VarSAn’ that uses a network analysis algorithm to identify pathways relevant to a given set of variants. VarSAn analyzes a configurable network whose nodes represent variants, genes and pathways, using a Random Walk with Restarts algorithm to rank pathways for relevance to the given variants, and reports P-values for pathway relevance. It treats non-coding and coding variants differently, properly accounts for the number of pathways impacted by each variant and identifies relevant pathways even if many variants do not directly impact genes of the pathway. We use VarSAn to identify pathways relevant to variants related to cancer and several other diseases, as well as drug response variation. We find VarSAn's pathway ranking to be complementary to the standard approach of enrichment tests on genes related to the query set. We adopt a novel benchmarking strategy to quantify its advantage over this baseline approach. Finally, we use VarSAn to discover key pathways, including the VEGFA-VEGFR2 pathway, related to de novo variants in patients of Hypoplastic Left Heart Syndrome, a rare and severe congenital heart defect.
Breast cancer is the most common and deadliest cancer in women worldwide. Although notable advances have been achieved in the treatment of breast cancer, the overall survival rate of metastatic breast cancer patients is still considerably low due to the development of resistance to breast cancer chemotherapeutic agents and the non-optimal specificity of the current generation of cancer medications. Hence, there is a growing interest in the search for alternative therapeutics with novel anticancer mechanisms. Recently, antimicrobial peptides (AMPs) have gained much attention due to their cost-effectiveness, high specificity of action, and robust efficacy. However, there are no clinical data available about their efficacy. This warrants the increasing need for clinical trials to be conducted to assess the efficacy of this new class of drugs. Here, we will focus on the recent progress in the use of AMPs for breast cancer therapy and will highlight their modes of action. Finally, we will discuss the combination of AMP-based therapeutics with other breast cancer therapy strategies, including nanotherapy and chemotherapy, which may provide a potential avenue for overcoming drug resistance. Keywords: Breast cancer; antimicrobial peptides; anticancer peptides; cancer therapy; combination therapy
BRCA1 and BRCA2 are tumor suppressor genes with pivotal roles in the development of breast and ovarian cancers. These genes are essential for DNA double-strand break repair via homologous recombination (HR), which is a virtually error-free DNA repair mechanism. Following BRCA1 or BRCA2 mutations, HR is compromised, forcing cells to adopt alternative error-prone repair pathways that often result in tumorigenesis. Synthetic lethality refers to cell death caused by simultaneous perturbations of two genes while change of any one of them alone is nonlethal. Therefore, synthetic lethality can be instrumental in identifying new therapeutic targets for BRCA1/2 mutations. PARP is an established synthetic lethal partner of the BRCA genes. Its role is imperative in the single-strand break DNA repair system. Recently, Olaparib (a PARP inhibitor) was approved for treatment of BRCA1/2 breast and ovarian cancer as the first successful synthetic lethality-based therapy, showing considerable success in the development of effective targeted cancer therapeutics. Nevertheless, the possibility of drug resistance to targeted cancer therapy based on synthetic lethality necessitates the development of additional therapeutic options. This literature review addresses cancer predisposition genes, including BRCA1, BRCA2, and PALB2, synthetic lethality in the context of DNA repair machinery, as well as available treatment options.
Background: Breast cancer (BC) is one of the most frequently diagnosed malignancies among females. As a huge heterogeneity of malignant tumor, it is important to seek reliable molecular biomarkers to carry out the stratification for patients with BC. We surveyed immune- associated lncRNAs that may be used as potential therapeutic targets in BC.
Methods: LncRNA expression data and clinical information of BC patients were downloaded from the TCGA database for a comprehensive analysis of candidate genes. A model consisting of immune-related lncRNAs enriched in BC cancerous tissues was established using the univariate Cox regression analysis and the iterative Lasso Cox regression analysis. The prognostic performance of this model was validated in two independent cohorts (GSE21653 and BC-KR), and compared with known prognostic biomarkers. A nomogram that integrated the immune-related lncRNA signature and clinicopathological factors was constructed to accurately assess the prognostic value of this signature. The correlation between the signature and immune cell infiltration in BC was also analyzed.
Results: The Kaplan-Meier analysis showed that the OS of Patients in the low-risk group had significantly better survival than those in the high-risk group, Clinical subgroup analysis showed that the predictive ability was independent of clinicopathological factors. Univariate/multivariate Cox regression analysis showed immune lncRNA signature is an important prognostic factor and an independent prognostic marker. In addition, GSEA and GSVA analysis as well as comprehensive analysis of immune cells showed that the signature was significantly correlated with the infiltration of immune cells.
Conclusion: We successfully constructed an immune-associated lncRNA signature that can accurately predict BC prognosis.
Breast cancer is a heterogeneous disease and has significant variability in presentation, treatment response, and prognosis.
The management of carcinoma breast is currently based on immunophenotypes and Tumour Nodes Metastasis (TNM)
staging. The aim of the study is to review the literature and to look for treatment guidelines of carcinoma breast, the role of
immunophenotypes in treatment of carcinoma breast, TP53 mutation in breast cancer, and the relationship of TP53 mutation with
immunophenotypes, histological grade, efficacy of chemotherapy, and BRCA (Breast Cancer gene) mutation. Pubmed database
was researched and a total of 510 articles were analysed. A total of one meta-analysis, one randomised controlled trial, one
literature review, nine prospective studies, and three retrospective studies were included for further analysis. It was observed that
TP53 mutation is associated with poor overall survival. It was also found to be inversely associated with the Estrogen Receptor
(ER) status and so it was seen more commonly in basal type and HER2/neu enriched breast cancer. There is a need for further
studies to establish the definite association between TP53 and immunophenotypes so that TP53 alone can be used as a guide for
management in carcinoma breast at low resource centres.
The p53 tumor suppressor gene has proven to be one of the genes most often mutated in human cancers. It involves mainly point mutations leading to amino acid substitutions in the central region of the protein which impairs normal functions. Analysis of the mutational events that target the p53 gene has revealed evidence for both exogenous and endogenous mutational mechanisms. For example, the p53 mutational spectrum reveals evidence for a direct causal effect of ultraviolet radiation in skin cancer, of aflatoxin B1 in liver cancer, and of tobacco smoke in lung cancer. This novel field, molecular epidemiology of human cancer risk, has added a new dimension to classical associative epidemiology by providing a direct link between human cancer and carcinogen exposure. For such analysis, we devised a generic software called UMD (Universal Mutation Database). It was developed as a generic software to create locus‐specific databases (LSDBs) with the 4th Dimension® package from ACI. This software includes an optimized structure to assist and secure data entry and to allow the input of various clinical data. Hum Mutat 15:105–113, 2000. © 2000 Wiley‐Liss, Inc.
A large number of different mutations in the p53 tumor suppressor gene have been identified in all types of cancer. As of
October, 1997, this database (http://perso.curie.fr/tsoussi) contained >7500 mutations. Such a substantial increase since our previous reports should enable epidemiological analyses
which were not previously possible. In order to analyse these new data, the UMD software has been improved. A new Web version
of the UMD software enables online analysis of the database. The present report describes various improvements since the last
release of the database.
We present a general method for rigorously identifying correlations between variations in large-scale molecular profiles and
outcomes and apply it to chromosomal comparative genomic hybridization data from a set of 52 breast tumors. We identify two
loci where copy number abnormalities are correlated with poor survival outcome (gain at 8q24 and loss at 9q13). We also identify
a relationship between abnormalities at two loci and the mutational status of p53. Gain at 8q24 and loss at 5q15-5q21 are
linked with mutant p53. The 9q and 5q losses suggest the possibility of gene products involved in breast cancer progression.
The analytical techniques are general and also are applicable to the analysis of array-based expression data.
p53 mutation is a common event in sporadic breast cancer being found in 15–50% of invasive carcinomas. The purpose of this study was to determine the earliest histologic stage at which p53 mutation could be detected with a widely used anti-p53 antibody (DO7, Novocastra) which recognizes both wild type and mutant forms. p53 expression was assessed immunohistochemically in 12 primary breast carcinomas with known p53 mutations and in all pre-malignant epithelial lesions surrounding these invasive cancers. Strong p53 nuclear staining was found in all of the tumors known to have missense mutations and none of the tumors with truncation mutations. In cases with intense staining in the invasive carcinoma, a similar quality of staining was also seen in all areas of DCIS (ductal carcinoma in situ) and was representative of missense p53 mutations. Lighter nuclear staining intensity was observed in up to 40% of cells in areas of hyperplasia and in up to 30% of normal breast lobules irrespective of the type of mutation found in the invasive carcinoma. This weak staining was not specific to mutated p53 and may indicate increased amounts of normal p53 protein.
We conclude that p53 inactivation occurs prior to invasion in breast carcinogenesis, with mutations being uniformly identified in DCIS associated with p53-mutated invasive carcinomas. In contrast, there is no evidence that epithelial hyperplasia or epithelial cells of the terminal duct lobular unit harbor the same mutations as their associated invasive carcinoma.
The most important subgroup of breast cancer patients for which reliable prognostic factors are needed are women without axillary lymph node involvement. Although overall, these patients have a good prognosis, it is known that 20-30% will experience a recurrence of the disease. To determine the prognostic significance of P53 tumor suppressor gene mutation, specimens from 113 primary breast cancers were evaluated for the presence of P53 alterations, as detected by cDNA sequencing of the entire coding sequence of the gene. The median follow-up for patients was 105 months. P53 gene mutation was an independent prognostic marker of early relapse and death. Our results suggest that P53 gene mutations could be an important factor to identify node-negative patients who have a poor prognosis in the absence of adjuvant therapy. Prospective studies should be designed to determine which therapy should be performed in this subgroup of patients.
Primary breast cancer tumors without axillary metastases from 206 consecutive patients in a population-based cohort were investigated with regard to the presence of an intact p53 gene using a cDNA-based sequencing method. Clinical follow-up data and outcome of node-negative patients without any adjuvant systemic therapy (n = 168) were related to locoregional radiotherapy and p53 status.
Mutations in p53 occurred in 31 node-negative breast cancer patients who did not receive any systemic adjuvant treatment, but were treated with postoperative locoregional radiotherapy or nothing. Node-negative breast cancer patients with p53 mutations had significantly improved relapse-free survival (P = .0007), breast cancer-corrected survival (P = .01), and overall survival (P = .02) rates when treated with locoregional radiotherapy. In node-negative breast cancer patients with wild-type p53, there was no statistically significant difference in outcome between patients who received locoregional radiotherapy and those who did not. Cox proportional hazards models indicate that mutant p53 is associated with worse prognosis independent of response to radiotherapy and that response to radiotherapy is qualitatively different in tumors with p53 mutations compared with those with wild-type p53.
Our clinical findings define a group of breast cancer patients in whom locoregional radiotherapy improves relapse-free, breast cancer-corrected, and overall survival. The outcome for irradiated node-negative breast cancer patients with p53 alterations indicates that irradiation can induce cell death even in the presence of p53 mutations.
A significant black/white difference in breast cancer prognosis has been observed in the United States. Alterations of p53 tumor suppressor gene in breast cancer have been associated with poor prognosis. This study was designed to test the hypothesis that p53 gene alterations are related to the difference in prognosis between black and white breast cancer patients. Formalin-fixed paraffin-embedded breast tissue blocks were available from 45 black and 47 white patients for PCR-single strand conformation polymorphism analysis and DNA sequencing. The types of p53 gene alterations were compared between blacks and whites. Associations between p53 gene alterations and survival were also evaluated. Three missense, 2 nonsense, 1 microdeletion, 1 intron, and 4 silent mutations were detected in blacks, while 7 missense, 1 microdeletion, 1 silent mutation, and 3 polymorphisms were observed in whites. Among the point mutations, G:C to A:T transitions at non-CpG sites were found in 80.0% of blacks (8 of 10) and 62.5% of whites (5 of 8). Significantly poorer survival associated with p53 gene alterations was observed for blacks (P = 0.012), but not for whites. Black patients with p53 alterations had a significant 4-5-fold excess risk of death from breast cancer than those without p53 alterations. Adjustment for stage, age, tumor histopathology, receptor status, and adjuvant treatment did not change the excess risk. The findings suggest that the types of p53 gene alterations may contribute to the racial difference in breast cancer survival.
Constant denaturant gel electrophoresis (CDGE) was used to screen 179 breast carcinomas for mutations in the conserved regions of the TP53 gene (exons 5 through 8). Mutations were found in 35 of 163 primary tumours (21%) and in 5 of 16 metastases (31%) and resided predominantly in exon 7. The majority of the mutations were G:C-->A:T transitions. Immunohistochemistry demonstrated nuclear accumulation of p53 protein in 35 of 162 primary tumours (22%) and in four of 15 metastases (27%). TP53 mutation was strongly associated with nuclear accumulation of p53 protein. In total 42 of 163 primary tumours (26%) and 5 of 16 metastases (31%) were demonstrated to contain TP53 alterations (mutation and/or nuclear protein accumulation). TP53 alteration in primary tumour was significantly associated with the following parameters: positive node status, T status > 1, negative oestrogen receptor status, negative progesterone receptor status, presence of ERBB2 gene amplification, and invasive ductal histology. Furthermore, there were statistically significant associations, independent of other prognostic factors, between TP53 alterations in primary tumour and disease-free and overall survival.
Images
Figure 1
Figure 2
Mutations in the p53 gene are among the most common genetic changes in human carcinomas. They have been found in many tumor types including colon, lung, and breast. We have used constant denaturant gel electrophoresis in order to screen samples from 109 breast carcinomas for mutations in four conserved regions, exons 5, 7, and 8, of the p53 gene. Samples were also analyzed for allelic loss of the p53 gene and of markers more distal on chromosome 17 p. Mutations were confirmed by DNA sequencing. Mutations were found in 18 of the 109 samples (16.5%). Loss of heterozygosity at 17p was detected in the majority of informative mutated cases. All cases were also screened for germ line mutations, but none were found. The results obtained were analyzed with respect to clinical parameters and prognosis. There was a significant association between p53 mutation and low content of estrogen receptor protein in the tumors (P = 0.01). An association with poor prognosis was strongly indicated by mortality rates that were 37.5% among the patients with p53 mutation and 9.4% for the control group (mean follow up, 32 months). P53 mutation was found to be the strongest negative factor against survival in a covariate survival analysis (P = 0.001).
A large number of different mutations in the p53 tumor suppressor gene have been identified in all types of cancer. As of October, 1997, this database (http://perso.curie.fr/tsoussi) contained > 7500 mutations. Such a substantial increase since our previous reports should enable epidemiological analyses which were not previously possible. In order to analyse these new data, the UMD software has been improved. A new Web version of the UMD software enables online analysis of the database. The present report describes various improvements since the last release of the database.
The mechanisms causing resistance to chemotherapeutic drugs in cancer patients are poorly understood. Recent evidence suggests that different forms of chemotherapy may exert their cytotoxic effects by inducing apoptosis. The tumor suppressor gene P53 has a pivotal role inducing apoptosis in response to cellular damage. In vitro investigations have shown intact p53 to play a critical role executing cell death in response to treatment with cytotoxic drugs like 5-fluorouracil, etoposide and doxorubicin. Recently, mutations in the P53 gene were found to confer resistance to anthracyclines in a mouse sarcoma tumor model, and overexpression of the p53 protein (which, in most cases, is due to a mutated gene) was found to be associated with lack of response to cisplatin-based chemotherapy in non-small cell lung cancer. Previous studies have shown mutations in the P53 gene or overexpression of the p53 protein to predict a poor prognosis, but also a beneficial effect of adjuvant radiotherapy or chemotherapy in breast cancer. In this study we present data linking specific mutations in the P53 gene to primary resistance to doxorubicin therapy and early relapse in breast cancer patients.
The aim of this investigation was to examine the possibility of analysing TP53 mutations in archival paraffin-embedded material with the constant denaturant gel electrophoresis (CDGE) method. We extracted DNA from 193 archival primary breast carcinoma samples, diagnosed in 1981-83; further analysis was possible for 186 of these. TP53 mutations in exons 5-8 were detected with CDGE in 30 samples (16.1%) and 17 of these mutations were confirmed by sequencing. Immunohistochemistry demonstrated TP53 nuclear accumulation in 58 tumours (31%). A strong association between the presence of TP53 mutations and TP53 immunostaining was observed (P < 0.001). Our mutation and immunohistochemistry results are in agreement with other findings based on fresh tumour tissue. TP53 abnormalities were significantly related to high S-phase fraction, low oestrogen receptor (ER) content and high tumour grade. Survival of patients with TP53 abnormalities, in the group as a whole, did not differ from patients with normal TP53. Our study did, however, show that patients with abnormal TP53 had a significantly shorter post-recurrence survival (P = 0.005) than patients with normal TP53.
Images
Figure 1
Figure 2
We have studied a total of 36 tumours from 28 patients with germline mutations to the TP53 gene for loss of heterozygosity at TP53 using techniques of both direct sequencing and restriction fragment length polymorphism analysis. All patients were from families conforming to the definition of classical Li-Fraumeni syndrome (LFS) or were Li-Fraumeni-like (LFL). The data we have obtained show that loss of the wild-type TP53 gene is observed in under half (44%) of all tumours, and that the pattern of LOH at TP53 may be mutation specific. LOH has been observed in premalignant as well as invasive tumours. Two tumours (6%) show loss of the mutant allele and retention of the wild-type. To confirm that TP53 is indeed the target for LOH events on chromosome 17, we have used additional microsatellite repeats to examine patterns of allelic imbalance along the length of chromosome 17. Data from this analysis indicate that TP53 is the target of loss, but reveal some other interesting patterns of allelic imbalance at other loci on chromosome 17.
The tumour-suppressor gene TP53 is frequently mutated in breast tumours, and the majority of the mutations are clustered within the core domain, the region involved in DNA binding. We searched for alterations in this central domain of the TP53gene in 222 human breast cancer specimens using polymerase chain reaction-single-strand conformation analysis (PCR-SSCA) followed by sequencing. TP53 gene mutations were observed in 66 tumours (31%), including three tumours that contain two mutations. Fifty-four (78%) of these mutations were missense point mutations, one was a nonsense mutation and four were deletions and/or insertions causing disruption of the protein reading frame, whereas four mutations were either silent or a polymorphism (at codon 213; n = 6). Interestingly, the majority of missense mutations were observed at codon 248. The outcome has been related with patient and tumour characteristics, and with prognosis in 177 patients who were eligible for analysis of both relapse-free and overall survival (median survival for patients alive was 115 months). There was no significant association between the frequency of TP53 mutations and menopausal or nodal status, or tumour size. In a Cox univariate analysis, TP53 gene mutation was significantly associated with poor relapse-free survival (RFS: P = 0.02) but not with overall survival (OS: P = 0.07). In a Cox multivariate analysis, including classical prognostic factors, TP53 gene mutation independently predicted poor RFS and OS (RHR = 1.8 and 1.6 respectively). Unexpectedly, the median relapse-free survival of patients with a polymorphism at codon 213 or with a silent mutation was shorter (median 11 months) than the median relapse-free survival of patients with or without a TP53 gene mutation (median 34 or 48 months respectively). In an exploratory subset analysis, mutations in codons that directly contact DNA were related with the poorest relapse-free (P < 0.05) and overall survival (P < 0.02). These data imply that in the analysis of the prognostic value of TP53, the type of mutation and its biological function should be considered.
Controversy continues regarding the prognostic utility of detection of p53 gene abnormalities in node-negative breast cancer. To resolve this, we used a rapid and nonisotopic PCR-single strand conformation polymorphism method to screen for mutations in exons 4-8 of the p53 gene in primary tumors from 422 node-negative breast cancer patients. The prevalence of p53 mutation in the exons tested was 18%. p53 mutation was significantly associated with several markers of poor prognosis including larger tumor size, high tumor grade, low hormone receptor content, increased expression of MIB-1 (Ki-67), amplification of the HER-2/neu oncogene, and accumulation of the p53 protein. After a median duration follow-up period of 74 months, the parameters of tumor diameter > or =20 mm, HER-2/neu oncogene amplification, and p53 mutation were found to be associated with a statistically significant shortened duration of disease-free and overall survival, but not the parameters of tumor grade, hormone receptor levels, or p53 expression. The poor prognosis associated with p53 mutation was observed primarily in patients with a tumor diameter of > or =20 mm. In multivariate analysis, p53 mutation was a risk factor for increased risk of recurrence and death from breast cancer independent of tumor size, hormone receptor levels, HER-2/neu amplification, and MIB-1 expression. We conclude that a relatively simple and rapid single strand conformation polymorphism method of determining p53 mutation status in node-negative breast cancers can provide independent prognostic information.
The p53 mutational status of 226 representative primary breast cancer samples, derived from a population-based cohort, was analyzed using cDNA-based sequencing. The results were compared with those obtained with immunohistochemistry (IHC) on microwave-treated paraffin sections and the p53 specific luminometric immunoassay (LIA) on cytosols, all from the same individuals. Thirty-seven mutations were found using cDNA sequencing and were categorized into A) missense mutations in the evolutionarily conserved regions; B) missense mutations outside the evolutionarily regions; and C) deletions, insertions and nonsense mutations. Using optimal cut-off values, LIA detected 15 of 16 missense mutations in category A, in which IHC detected all 16. In category B, 10 of 13 and 7 of 13 mutations were detected, respectively. Some of the samples in category A had a very high p53 protein content when measured with the LIA, the reason for this being discussed. IHC detected 0 of 5 stop codon and 0 of 3 deletions/insertions mutations, while the LIA method detected 2 of 5 stop codon mutations and 1 of 3 deletion/insertion mutations. Compared with cDNA sequencing, protein analyses using optimal cut-off values resulted in an overall sensitivity and specificity of 64.9% and 89.9%, respectively, for the LIA method. Corresponding values were 72.2% and 92% for IHC. In addition, patients from whom p53 mutations could be detected by cDNA sequencing had a statistically significant (p = 0.0137) shorter survival, which was not readily apparent using the alternative LIA or IHC approaches at optimal cut-off values.
Several retrospective studies have suggested p53 gene mutation as an adverse prognostic indicator in breast cancer patients, based on a selective growth advantage of p53 mutant cancer cells and their presumed resistance to current adjuvant therapy regimens. A cohort of 90 Caucasian midwestern breast cancer patients was analyzed prospectively (60 months of follow‐up) with a rigorous mutation detection methodology. The presence of a p53 gene mutation was the single most adverse prognostic indicator for recurrence (p = 0.0032) and death (p = 0.0001), and was associated with poor response to both adjuvant (p = 0.0001) and palliative (p = 0.006) therapy. Analysis of the p53 gene with appropriate mutation detection methodology markedly improves the prediction of early recurrence, treatment failure, and death in breast cancer patients. Int. J. Cancer (Pred. Oncol.) 89:32–38, 2000. © 2000 Wiley‐Liss, Inc.
We examined the association between mutation of the p53 gene and survival in a large cohort of breast cancer patients. Using a rapid, non‐isotopic single‐strand conformation polymorphism (SSCP) method we screened for mutations in exons 4–10 of the p53 gene in 375 primary breast cancers from patients with a median follow‐up of 57 months. Mutations were found in 19% of tumours. Statistically significant associations were found between p53 mutation and histological grade, hormone receptor status, ploidy and S‐phase fraction. No association was found between p53 mutation and axillary lymph node involvement, histological type, tumour size, vascular invasion or patient age. In univariate survival analysis, p53 mutation was strongly associated with poor prognosis. This was maintained in the lymph node‐negative and hormone receptor‐positive patient subgroups. In multivariate analysis, p53 mutation was associated with poor survival independent of lymph node status, estrogen receptor status and S‐phase fraction. Our results demonstrate the feasibility of using a rapid and simple polymerase chain reaction‐SSCP screening procedure to detect p53 gene mutation in breast cancer for the provision of prognostic information. Int. J. Cancer 74:642–647, 1997.© 1997 Wiley‐Liss, Inc.
The prognostic significance of p53 gene abnormalities was investigated in 919 primary breast‐cancer patients. p53 expression and tumour‐cell proliferation fraction determined by MIB‐1 count, p53 exon 5 and 6 mutations and HER‐2/neu oncogene amplification were detected by immunohistochemistry, PCR‐SSCP and slot‐blot hybridization, respectively. Increased MIB‐1 count, p53 expression, HER‐2/neu oncogene amplification and p53 mutations were detected in 33%, 29%, 10% and 8% of tumours, respectively. Statistically significant associations were observed between p53 expression or MIB‐1 count and age below 50 years, high‐grade tumours, medullary carcinomas, and absence of hormone receptors. p53 mutations were associated with increased MIB‐1 count, HER‐2/neu oncogene amplification and absence of hormone receptors, but not with age, tumour size or grade, histological subtype, or the number of axillary nodes involved. After a median follow‐up of 66 months, p53 expression was observed to be associated with significant increases in risk of both relapse and death from breast cancer, but not after adjusting for the effect of other parameters. In these analyses, MIB‐1 count, and not HER‐2/neu oncogene amplification, was an independent predictor of prognosis. In node‐negative patients, only p53 exon 5 and 6 mutations and MIB‐1 count were associated with a statistically significant increase in risk of death from breast cancer, independent of tumour size and ER concentration. We conclude that tumour‐cell proliferation fraction, as measured by MIB‐1 count, is the most useful parameter of breast‐cancer prognosis, with the exception of ER, tumour size and the number of axillary nodes involved. © 1996 Wiley‐Liss, Inc.
The p53 tumor suppressor gene has proven to be one of the genes most often mutated in human cancers. It involves mainly point mutations leading to amino acid substitutions in the central region of the protein which impairs normal functions. Analysis of the mutational events that target the p53 gene has revealed evidence for both exogenous and endogenous mutational mechanisms. For example, the p53 mutational spectrum reveals evidence for a direct causal effect of ultraviolet radiation in skin cancer, of aflatoxin B1 in liver cancer, and of tobacco smoke in lung cancer. This novel field, molecular epidemiology of human cancer risk, has added a new dimension to classical associative epidemiology by providing a direct link between human cancer and carcinogen exposure. For such analysis, we devised a generic software called UMD (Universal Mutation Database). It was developed as a generic software to create locus-specific databases (LSDBs) with the 4th Dimension® package from ACI. This software includes an optimized structure to assist and secure data entry and to allow the input of various clinical data. Hum Mutat 15:105–113, 2000. © 2000 Wiley-Liss, Inc.
The prognostic value of p53 immunohistochemical expression (IE) in breast carcinoma is a controversial issue, and it is difficult to compare the results obtained by different studies. We analyzed 37 articles dealing with p53 IE and clinical outcome, published between 1991 and 1995. These studies involve a population of >9,800 patients. Twelve articles (which we define as positive studies) demonstrate an independent prognostic value for p53 IE. Eleven articles show that p53 IE may be only of "borderlineprognostic value. Fourteen articles (which we define as negative studies) do not show any prognostic value for p53 IE. The length of the follow-up in positive studies was usually shorter than that of negative studies (60 versus 100 months): such a difference could be relevant, since p53 overexpression may differently influence short-term and long-term prognosis. Node-negative patients represent the prevailing population among negative studies, while there is a more balanced distribution between node-negative and node-positive cases in positive studies: a challenging hypothesis is that this difference may be related to the effect of systemic adjuvant therapy. A stimulating hypothesis is that p53 overexpression could be a marker to predict response to therapy, but data are not conclusive. Further fields of investigation include the relationship between p53 and tumor angiogenesis and between p53 and some of the p53-induced proteins (such as mdm2 and p21/WAF1). In conclusion, the prognostic and predictive value of p53 overexpression appears weaker than hoped, and it is premature to use it as a decision-making parameter when choosing among various therapeutic options for the individual patient.
Reviewing studies of alterations of the TP53 tumor suppressor gene in human breast carcinomas gives cautious optimism about TP53 alterations as a prognostic marker in this disease. For the time being, breast carcinomas should be screened for TP53 alterations at both the protein and gene levels. Improved mutational screening techniques are needed for this purpose. We consider constant denaturant gel electrophoresis, a modification of denaturing gradient gel electrophoresis, to represent such an improvement. With the recent development of the BioRad D GENE system, constant denaturant gel electrophoresis screening for TP53 mutations can easily be performed on large series of breast carcinomas.
Differences in patterns of p53 gene mutation in different types of cancers support the idea that analysis of acquired alterations in this gene will be useful as a {open_quotes}mutagen test{close_quotes}. We are studying the pattern of p53 gene mutation in sporadic breast carcinomas in high and low risk populations. All translated exons and adjacent splice regions have been analyzed in 53 primary breast cancers from Midwestern U.S. Caucasian women. A total of 21 mutations were found in exons 2-11 and splice regions (39.6%). The mutations include 8 missense, 4 nonsense, 1 splice site point mutation, and 8 microdeletions. Comparisons of the pattern of mutations within exons 5-9 show that the frequency of missense mutations (44%) was lower in breast cancers of U.S. Midwestern women than in most tumor types and in breast cancers in other populations. Compared to breast cancers reported in a Scottish population, Midwestern U.S. women have a high frequency of microdeletion mutations (p=0.006) and a low frequency of G:C-T:A transversions (p=0.046). These findings suggest that environmental or endogenous factors contribute to p53 mutagenesis in mammary tissue to different extents among different populations. The presence of a mutation was associated with shorter time to disease recurrence (p=0.05) and shorter survival (p=0.003) (median duration of follow-up 19 months). Both putative dominant negative missense-type mutations (missense and in-frame microdeletions; p=0.001) and null mutations (hemizygous nonsense and frameshift mutations; p=0.007) were associated with poor prognosis. Thus, tumors with missense p53 mutations associated with altered binding to other proteins, altered transcriptional regulation and a dramatic increase in p53 protein concentration have similar clinical outcomes to tumors with null mutations associated with truncated or garbled proteins.
The aim of our study was to evaluate if p53 mutations, especially those in the L2/L3 domains of the p53 gene, add prognostic information for node-positive and steroid receptor positive breast cancer patients. Two hundred and five tumour samples from a randomised clinical trial of 596 lymph node- and steroid receptor positive breast cancer patients were included. All patients had been randomly allocated to receive 20mg of adjuvant tamoxifen (TAM) daily for 2 years or TAM plus one cycle of low-dose, short-term chemotherapy. For detection of p53 mutations we used in vitro amplification by polymerase chain reaction and consecutively performed temperature gradient gel electrophoresis (PCR-TGGE) and direct sequencing. We found p53 mutations in 42/205 (20%) cases: 16/42 (38%) p53 mutations occurred within the L2/L3 domains of the p53 gene, and 26/42 (62%) outside the L2/L3 domains. p53 mutation served as a statistically significant parameter in predicting disease-free survival in univariate (P=0.02) and multivariate (P=0.009) analysis. For overall survival, no significant differences were observed. Patients with tumours that had p53 mutations within the L2/L3 domains of the gene showed no significant difference to those with mutations outside the L2/L3 domains for disease-free survival. For overall survival, mutations in the L2/L3 domains showed a marginally significant difference (P=0.05) in multivariate analysis, but not in univariate analysis (P=0.13). We conclude that mutation in the L2/L3 domains of the p53 gene is not an independent prognostic indicator of disease outcome for patients suffering from breast cancer with lymph node metastases and positive steroid receptors.
We examined the association between mutation of the p53 gene and survival in a large cohort of breast cancer patients. Using a rapid, non-isotopic single-strand conformation polymorphism (SSCP) method we screened for mutations in exons 4–10 of the p53 gene in 375 primary breast cancers from patients with a median follow-up of 57 months. Mutations were found in 19% of tumours. Statistically significant associations were found between p53 mutation and histological grade, hormone receptor status, ploidy and S-phase fraction. No association was found between p53 mutation and axillary lymph node involvement, histological type, tumour size, vascular invasion or patient age. In univariate survival analysis, p53 mutation was strongly associated with poor prognosis. This was maintained in the lymph node-negative and hormone receptor-positive patient subgroups. In multivariate analysis, p53 mutation was associated with poor survival independent of lymph node status, estrogen receptor status and S-phase fraction. Our results demonstrate the feasibility of using a rapid and simple polymerase chain reaction-SSCP screening procedure to detect p53 gene mutation in breast cancer for the provision of prognostic information. Int. J. Cancer 74:642–647, 1997.© 1997 Wiley-Liss, Inc.
Background. There is increasing evidence linking development and progression of cancer to an accumulation of mutations at the genomic level. The most frequently mutated gene known to date in sporadic breast cancer appears to be the tumor suppressor gene p53. This study was designed to determine the frequency of p53 gene mutations in primary breast cancer, to correlate the presence of p53 mutations with established clinicopathologic parameters, including the estrogen receptor (ER) and progesterone receptor (PR) status, and to assess the prognostic significance of p53 mutations regarding patient survival.
HER-2/neu and p53 are two molecular markers that have been the focus of investigation in patients with invasive breast carcinoma. However, most of the published data have relied on immunohistochemical detection of the proteins as a surrogate marker of the underlying genetic alterations, a detection method that often gives variable results due to technical factors. In addition, there are limited data documenting HER-2/neu amplification and p53 mutations in the various histologic subtypes of ductal carcinoma in situ (DCIS). The authors evaluated a series of microdissected, pure DCIS lesions comprising a spectrum of morphologic subtypes (comedo, micropapillary, papillary, cribriform, and solid) and their corresponding normal breast tissue for genetic aberrations in HER-2/neu and p53.
HER-2/neu amplification was determined by differential polymerase chain reaction, and p53 mutations were identified by single-strand conformation polymorphism analysis.
HER-2/neu amplification was identified in 12 of 30 DCIS samples (40%), and p53 mutations were identified in 6 of 30 DCIS samples (20%). The genetic alterations were not present in any of the normal breast tissue samples. HER-2/neu amplification occurred predominantly in the comedo subtype (69% vs. 18% of the noncomedo subtype; P = 0.008) and in lesions of high nuclear grade (63% vs. 14% of low grade; P = 0.01). There was no difference in the frequency of p53 mutations among the subtypes or between low grade and high grade lesions. No correlation between the presence of the two genetic alterations was observed.
The presence of HER-2/neu amplification, but not p53 mutations, correlates with histologic subtype and nuclear grade. The relatively frequent occurrence of HER-2/neu amplification and p53 mutations in DCIS tissue and their absence in normal breast tissue suggest that these genetic aberrations are important early in breast duct carcinogenesis. Cancer 2000;89:2153–60.
TP53 accumulation in human primary breast carcinomas was studied by a quantitative luminometric immunoassay (LIA), and TP53 gene alterations, exons 5–8, were examined by single-strand conformation polymorphism (SSCP) analysis. In 48 of 142 breast tumor samples, a TP53 gene alteration was identified. In tumor samples without a TP53 gene alteration, the median cytosolic TP53 protein level, as determined by LIA, was 0.4 ng/mg protein (range 0–70.8 ng/mg protein), whereas the median TP53 protein level for tumor samples with a TP53 gene alteration was 10 times higher, i.e., 4.1 ng/mg protein (range 0.1–176.0 ng/mg protein). Despite a significant correlation between the outcome of LIA and SSCP, a disagreement was found in 22% of cases analyzed. Significant correlations were found between TP53 protein accumulation and low estrogen receptor content, and with a shorter relapse-free as well as overall survival, with a median duration of follow-up of 100 months. Due to its rapid and easy performance on routinely prepared cytosols, the LIA for TP53 protein may be useful in evaluating the prognostic impact of TP53 protein accumulation in human primary breast cancer. © 1996 Wiley-Liss, Inc.
Alterations in the p53 tumor suppressor gene are the most frequent genetic changes found in breast cancer, with an incidence reported in a range of 15 to 50%. The incidence of p53 alterations is approximately 15% for in situ carcinoma, while for invasive node-positive disease it is 2 to 3 times higher. This high rate of alteration suggests that the gene plays a central role in the development of breast cancer.The p53 gene functions as a negative regulator of cell growth. Alterations in the gene lead to loss of its usual negative growth regulation and more rapid cell proliferation. Since p53 alteration can reflect a more advanced state of progression and a higher rate of proliferation, breast tumors that have a p53 alteration could have a greater probability of having micrometastasis. p53 alterations could therefore be a prognostic factor for recurrence after primary local therapy. Consistent with this hypothesis, several independent studies using different methodologies have found that breast tumors with altered p53 have a worse prognosis and are also more likely to have other poor prognostic factors.
Genomic DNA copy number alterations are key genetic events in the development and progression of human cancers. Here we report a genome-wide microarray comparative genomic hybridization (array CGH) analysis of DNA copy number variation in a series of primary human breast tumors. We have profiled DNA copy number alteration across 6,691 mapped human genes, in 44 predominantly advanced, primary breast tumors and 10 breast cancer cell lines. While the overall patterns of DNA amplification and deletion corroborate previous cytogenetic studies, the high-resolution (gene-by-gene) mapping of amplicon boundaries and the quantitative analysis of amplicon shape provide significant improvement in the localization of candidate oncogenes. Parallel microarray measurements of mRNA levels reveal the remarkable degree to which variation in gene copy number contributes to variation in gene expression in tumor cells. Specifically, we find that 62% of highly amplified genes show moderately or highly elevated expression, that DNA copy number influences gene expression across a wide range of DNA copy number alterations (deletion, low-, mid- and high-level amplification), that on average, a 2-fold change in DNA copy number is associated with a corresponding 1.5-fold change in mRNA levels, and that overall, at least 12% of all the variation in gene expression among the breast tumors is directly attributable to underlying variation in gene copy number. These findings provide evidence that widespread DNA copy number alteration can lead directly to global deregulation of gene expression, which may contribute to the development or progression of cancer.
The p53 tumor suppressor gene has proven to be one of the genes most often mutated in human cancers. It involves mainly point mutations leading to amino acid substitutions in the central region of the protein which impairs normal functions. Analysis of the mutational events that target the p53 gene has revealed evidence for both exogenous and endogenous mutational mechanisms. For example, the p53 mutational spectrum reveals evidence for a direct causal effect of ultraviolet radiation in skin cancer, of aflatoxin B1 in liver cancer, and of tobacco smoke in lung cancer. This novel field, molecular epidemiology of human cancer risk, has added a new dimension to classical associative epidemiology by providing a direct link between human cancer and carcinogen exposure. For such analysis, we devised a generic software called UMD (Universal Mutation Database). It was developed as a generic software to create locus-specific databases (LSDBs) with the 4(th) Dimension(R) package from ACI. This software includes an optimized structure to assist and secure data entry and to allow the input of various clinical data.
Familial cancer syndromes have helped to define the role of tumor suppressor genes in the development of cancer. The dominantly
inherited Li-Fraumeni syndrome (LFS) is of particular interest because of the diversity of childhood and adult tumors that
occur in affected individuals. The rarity and high mortality of LFS precluded formal linkage analysis. The alternative approach
was to select the most plausible candidate gene. The tumor suppressor gene, p53, was studied because of previous indications
that this gene is inactivated in the sporadic (nonfamilial) forms of most cancers that are associated with LFS. Germ line
p53 mutations have been detected in all five LFS families analyzed. These mutations do not produce amounts of mutant p53 protein
expected to exert a trans-dominant loss of function effect on wild-type p53 protein. The frequency of germ line p53 mutations
can now be examined in additional families with LFS, and in other cancer patients and families with clinical features that
might be attributed to the mutation.
The complete coding region of the p53 gene was sequenced from 316 consecutively presented breast cancers, of which 97 were lymph node positive and 206 were node negative. The p53 status was related to prognosis and effect of adjuvant therapy. In all, 69 individual mutations, 29 in node-positive tumours, were demonstrated throughout the whole coding sequence. The mutation sites were partly different for node-positive and node-negative patients. p53 mutations in the evolutionary conserved regions II and V were associated with significantly worse prognosis. Adjuvant systemic therapy, especially with tamoxifen, along with radiotherapy seemed to be of less value to p53 mutation- and lymph node-positive tumours.
Reviewing studies of alterations of the TP53 tumor suppressor gene in human breast carcinomas gives cautious optimism about TP53 alterations as a prognostic marker in this disease. For the time being, breast carcinomas should be screened for TP53 alterations at both the protein and gene levels. Improved mutational screening techniques are needed for this purpose. We consider constant denaturant gel electrophoresis, a modification of denaturing gradient gel electrophoresis, to represent such an improvement. With the recent development of the BioRad D GENE system, constant denaturant gel electrophoresis screening for TP53 mutations can easily be performed on large series of breast carcinomas.
We determined the pattern of mutations in exons 2-11 and adjacent intronic regions in breast cancers from Midwestern US white women. Twenty-one mutations were detected in 53 tumors (39.6%). Comparisons of the pattern of mutations within exons 5-9 showed that the frequency of missense mutations (44%) was lower in breast cancers of US Midwestern women than in most tumor types including breast cancers in other populations. Compared to breast cancers reported in a Scottish population, US women had a high frequency of G:C-->T:A transversions (P = 0.046). These findings suggest that environmental or endogenous factors contribute to p53 mutagenesis in mammary tissue to different extents among different populations. With a median follow-up of 19 months, the presence of a mutation was associated with shorter time to disease recurrence (P = 0.05) and shorter survival (P = 0.003). Putative dominant negative missense-type mutations (missense and in-frame microdeletions; P = 0.001) and null mutations (hemizygous nonsense and frameshift mutations; P = 0.007) were equally ominous. Thus, tumors with missense p53 mutations resulting in over-expression of a dysfunctional but otherwise intact protein have a clinical outcome similar to tumors with null mutations resulting in a truncated or garbled protein.
There is increasing evidence linking development and progression of cancer to an accumulation of mutations at the genomic level. The most frequently mutated gene known to date in sporadic breast cancer appears to be the tumor suppressor gene p53. This study was designed to determine the frequency of p53 gene mutations in primary breast cancer, to correlate the presence of p53 mutations with established clinicopathologic parameters, including the estrogen receptor (ER) and progesterone receptor (PR) status, and to assess the prognostic significance of p53 mutations regarding patient survival.
We examined the p53 gene in genomic DNA samples from 192 primary breast cancers. Using denaturant gradient gel electrophoresis, the authors analyzed exons 5-9 in all tumors for mutations and performed DNA sequencing in 20 tumors to identify the exact nature of the p53 mutations.
p53 gene alterations were identified in 43 of the 192 tumors (22%), the majority localized in exons 5 and 6. DNA sequencing showed mostly missense mutations resulting from G or C substitutions. p53 mutations were found more often in tumors of younger women (P = 0.002), Afro-American women (P = 0.05), and in tumors lacking ER (P = 0.03), PR (P = 0.04), or both (P = 0.06). There were no significant correlations with family history, tumor size, histologic grade or type, nodal status, or disease stage. The overall survival rates showed no significant difference between patients with mutant and wild-type p53 tumors. The same was true when the comparison was limited to node-negative patients or patients with ER-positive or ER-negative tumors. Finally, there was no significant difference in survival between patients with tumors harboring mutations in exons 5 and 6 versus exons 7-9.
The results of this and other studies demonstrate a consistent relationship between ER-positive tumors and wild-type p53 on one hand and ER-negative cancers and p53 mutations on the other. Our data do not support a significant prognostic role for p53 mutations in predicting survival.
Acquired mutations in TP53 as well as immunohistochemically detectable protein expression have been implicated as prognostic factors for breast cancer. We have evaluated the relationship between mutations detected in 119 breast tumours and various clinicohistopathological indices, stratifying the mutations according to the functional domains as defined by the recent elucidation of the crystal structure of the protein. Patients with missense mutations located in regions encoding parts of the protein involved in zinc-binding had significantly decreased disease-free and overall survival relative to patients whose tumours had mutations in other domains. These results indicate that these biochemically defined domains also have biological relevance in terms of breast cancer disease course, and suggest that some mutations in TP53, more than others, can contribute to the development of clinically more aggressive and perhaps treatment resistant breast tumours. When confirmed, this will be of potential importance in predicting the clinical behaviour of breast cancer and its responsiveness to therapy.
Abnormalities in the TP53 tumour suppressor gene were evaluated in 106 unselected breast carcinomas and compared to clinical outcome of the disease. Tumours were screened for p53 abnormalities using immunohistochemical staining and polymerase chain reaction-constant denaturant gel electrophoresis (PCR-CDGE) analysis, followed by PCR and direct sequencing. Allelic loss at the TP53 locus was determined with polymorphic markers by comparing normal and tumour DNA. For approximately half of the patients, abnormal p53 protein expression in serum was determined by an ELISA assay. p53 abnormalities, detected as mutations and/or nuclear staining, were found in 37.6 (38/101) of cases. Nuclear staining for p53 protein could be identified in 33.7% of the tumours. Mutations in exons 5-8 were detected in 18.9% of the tumours, and an association was found between mutations and nuclear staining. Allelic loss in the TP53 region on 17p was more frequent in tumours showing changes in the TP53 gene (72.7%) compared to tumours with no mutation (45.8%). Serum levels of p53 antibodies showed no association with either TP53 mutations or nuclear staining. Women with TP53 mutations in their tumours had an elevated risk of dying during the study period (RR (relative risk) = 3.4, P = 0.014). The effects of p53 positive staining were similar (RR = 3.2, P = 0.013). Considering all abnormalities, mutation and/or staining, the relative risk of dying from breast cancer was 3.5 (P = 0.008).
Human cancer cells with a mutated p53 tumor-suppressor gene have a selective growth advantage and may exhibit resistance to ionizing radiation and certain chemotherapeutic agents. To examine the prognostic value of mutations in the p53 gene, a cohort of 90 Midwestern Caucasian breast cancer patients were analyzed with methodology that detects virtually 100% of all mutations. The presence of a p53 gene mutation was by far the single most predictive indicator for recurrence and death (relative risks of 4.7 and 23.2, respectively). Direct detection of p53 mutations had substantially greater prognostic value than immunohistochemical detection of p53 overexpression. Analysis of p53 gene mutations may permit identification of a subset of breast cancer patients who, despite lack of conventional indicators of poor prognosis, are at high risk of early recurrence and death.
The prognostic significance of p53 gene abnormalities was investigated in 919 primary breast-cancer patients. p53 expression and tumour-cell proliferation fraction determined by MIB-1 count, p53 exon 5 and 6 mutations and HER-2/neu oncogene amplification were detected by immunohistochemistry, PCR-SSCP and slot-blot hybridization, respectively. Increased MIB-1 count, p53 expression, HER-2/neu oncogene amplification and p53 mutations were detected in 33%, 29%, 10% and 8% of tumours, respectively. Statistically significant associations were observed between p53 expression or MIB-1 count and age below 50 years, high-grade tumours, medullary carcinomas, and absence of hormone receptors. p53 mutations were associated with increased MIB-1 count, HER-2/neu oncogene amplification and absence of hormone receptors, but not with age, tumour size or grade, histological subtype, or the number of axillary nodes involved. After a median follow-up of 66 months, p53 expression was observed to be associated with significant increases in risk of both relapse and death from breast cancer, but not after adjusting for the effect of other parameters. In these analyses, MIB-1 count, and not HER-2/neu oncogene amplification, was an independent predictor of prognosis. In node-negative patients, only p53 exon 5 and 6 mutations and MIB-1 count were associated with a statistically significant increase in risk of death from breast cancer, independent of tumour size and ER concentration. We conclude that tumour-cell proliferation fraction, as measured by MIB-1 count, is the most useful parameter of breast-cancer prognosis, with the exception of ER, tumour size and the number of axillary nodes involved.
The P53 tumor-suppressor gene is an advantageous tool for analyzing the molecular epidemiology of cancer. We describe the utility of the P53 gene as a 'mutagen test' and a prognostic indicator in breast cancer. Aspects of study design and methodology are discussed. Two major conclusions emerge: (1) there is an extraordinary diversity of mutational patterns among cohorts, hinting that the unique biology of mammary cells results in exposure to high doses of a diversity of ingested lipophilic mutagens; and (2) mutations in the P53 gene predict poor outcome in breast cancer.
Alterations of the TP53 gene were analyzed in samples from 87 primary breast cancer patients, using molecular and immunohistochemical approaches. Mutations were detected in 17% of the samples, using polymerase chain reaction (PCR) and constant denaturant gel electrophoresis (CDGE) on exons 5-8 of the TP53 gene, and were confirmed by sequencing. Abnormal TP53 protein staining was found in 55% of the primary samples, using the monoclonal TP53 antibody DO7. A statistically significant association was found between TP53 mutations and abnormal protein staining (p = 0.002). Our results suggest that dysfunction of the TP53 protein is associated with tumor progression, as we found an association between TP53 abnormalities and accumulation of genetic lesions, measured as overall allelic imbalance (AI), homogeneously staining regions (HSR) and strong ERBB2 overexpression. Furthermore, patients with TP53 mutation had a highly elevated risk of dying from breast cancer during the study period (p < 0.001, RR = 10.68) at a median follow-up time of 42 months. Abnormal TP53 staining was much more frequent than the mutations, but it was not of prognostic significance, whereas strong staining was an independent prognostic factor. We therefore conclude that loss of functional TP53 leads to genetic instability, resulting in poorer short-term prognosis, and that only strong staining of TP53, and not abnormal protein staining in general, is of prognostic significance.
We examined the association between mutation of the p53 gene and survival in a large cohort of breast cancer patients. Using a rapid, non-isotopic single-strand conformation polymorphism (SSCP) method we screened for mutations in exons 4-10 of the p53 gene in 375 primary breast cancers from patients with a median follow-up of 57 months. Mutations were found in 19% of tumours. Statistically significant associations were found between p53 mutation and histological grade, hormone receptor status, ploidy and S-phase fraction. No association was found between p53 mutation and axillary lymph node involvement, histological type, tumour size, vascular invasion or patient age. In univariate survival analysis, p53 mutation was strongly associated with poor prognosis. This was maintained in the lymph node-negative and hormone receptor-positive patient subgroups. In multivariate analysis, p53 mutation was associated with poor survival independent of lymph node status, estrogen receptor status and S-phase fraction. Our results demonstrate the feasibility of using a rapid and simple polymerase chain reaction-SSCP screening procedure to detect p53 gene mutation in breast cancer for the provision of prognostic information.
In 150 surgically resected primary breast carcinomas that had axillary lymph-node metastases, we examined the incidence of loss of heterozygosity on chromosomes 16p, 16q, 17p, 17q, and 18q, point mutation of the p53 tumor-suppressor gene, nuclear immunoreaction of p53 protein, and amplifications of the c-erbB-2 and int-2 oncogenes by Southern blotting, single-strand conformation polymorphism analysis, and immunohistochemistry. We analyzed the association of these factors and conventional prognostic parameters with outcome of the patients, using Cox's univariate and multivariate analyses. The univariate analysis revealed that nuclear p53 immunoreaction, p53 mutation, and c-erbB-2 amplification as well as the number of metastatic lymph nodes, histological grade, and hormone-receptor statuses were significant prognostic indicators for both recurrence and cancer death. p53 immunoreaction was correlated more strongly with a poor prognosis than p53 mutations. The combination of p53 and c-erbB-2 effectively identified the high-risk patient group, and even among Grade 3 cases the subgroup with these alterations tended to have poorer clinical outcomes. The multivariate analysis including p53, c-erbB-2, and conventional factors. Lymph node status, grade, and p53 had independent impacts on the survival of patients. Under identical adjuvant systemic therapies, prognoses differed between the patient groups with and without alterations of p53 or c-erbB-2. Appropriate combinations of conventional factors with nuclear p53 immunoreaction and c-erbB-2 amplification would help to identify highly aggressive node-positive breast carcinomas and would aid stratification of patient groups in randomized clinical trials of adjuvant systemic therapies.
