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Heterogeneity in the clinical phenotype of TP53 mutations in breast cancer patients
Abstract
TP53 mutation is a strong independent marker for survival in breast cancer with some heterogeneity in the clinical phenotype of various types of mutations. Based on 315 patients with breast carcinoma, we suggest a new model for the differentiation of TP53 mutations. Although TP53 mutation in general was associated with aggressive tumor/patient characteristics, missense mutations outside any conserved or structural domain did not affect the clinical outcome (risk of disseminated disease and death). In contrast, patients with missense mutations affecting amino acids directly involved in DNA or zinc binding displayed a very aggressive clinical phenotype. Null mutations (including missense mutations disrupting the tetramerization domain) and the remaining missense mutations displayed an intermediate aggressive clinical phenotype. When patients with primary early breast cancer were divided into three groups (wild-type together with missense mutations outside structural/conserved domains, null mutations and missense mutations with intermediate clinical phenotype, and very aggressive missense mutations), disease-specific survival rates were 89%, 58%, and 35% (5-year actuarial values, P < 0.0001), respectively. In a Cox proportional hazards analysis, separation of TP53 mutations according to these criteria eliminated the prognostic importance of all investigated classical factors except nodal status.
... Among the 34 tumors with TP53 mutations, the overall subclassifications were 56% missense (19), 21% frameshift (7), 21% nonsense (7), and 3% splice site (1). The comparison of p53 IHC patterns with TP53 mutation status is shown in Table 5A. ...
... Additionally, studies have shown that certain TP53 mutation types are associated with specific p53 IHC patterns with missense mutations typically resulting in accumulation of p53 protein, while frameshift, nonsense and splice site mutations may result in a null pattern [7]. Alsner et al. reported that the clinical outcome for breast cancer patients is significantly different based on different TP53 mutation types [6,19]. Their studies showed that missense mutations involved in DNA or zinc binding were associated with the worst outcome, while null mutations and missense mutations within structural/conserved domains were associated with similar but significantly worse outcomes compared to patients with wild-type TP53 [6]. ...
Purpose
The importance of a TP53 mutation has been demonstrated in several tumor types, including breast cancer (BC). However, the accuracy of p53 protein expression as a predictor of gene mutation has not been well studied in BC. Therefore, we evaluated p53 protein expression associated with TP53 mutations in breast cancers from 64 patients.
Methods
TP53 mutation was examined using next-generation sequencing (NGS). p53 protein expression was examined using immunohistochemistry (IHC).
Results
Among the 64 BCs, 55% demonstrated abnormal expression patterns including 27% overexpression, 22% null, 6% equivocal with 45% having a wild-type pattern. A TP53 mutation was present in 53% (34/64) of tumors including 30% (19/64) demonstrating a missense mutation, 11% (7/64) with a frameshift mutation, 11% (7/64) with a nonsense mutation, and 3% (1/64) with a splice site mutation. Abnormal expression of p53 protein was present in 33 of 34 (97%) tumors carrying a TP53 mutation; conversely, a wild-type pattern was present in 28 of 30 (93%) tumors without a detectable mutation (p < 0.0001). The majority of BCs with a p53 IHC overexpression pattern (15/17, 88%) contained a missense TP53 mutation; while the majority of BCs with a null pattern (12/14, 86%) contained a truncating mutation (p < 0.0001). The BCs with a null pattern are associated with a high Nottingham histological grade and a triple-negative phenotype when compared to those demonstrating overexpression (p < 0.05).
Conclusion
These findings suggest that p53 IHC can be a potential surrogate for TP53 mutations in BC. Different p53 expression patterns may correlate with specific TP53 genetic mutations in BC.
... Beyond indisputable important role as a tumor suppressor, p53 acts as a transcription factor regulating diverse array of genes involved in various cellular processes [25]. Mutations of p53 are frequently present (25%) in BC [26] and specially the triple-negative BC (TNBC) cases with mutant p53 have poor prognosis [27]. In the current study, the regulatory role of the tumor suppressor gene p53 is investigated revealing its negative impact on NIS gene expression in BC. ...
... In quest of identifying important NIS transcriptional regulators, here we report the presence of multiple p53 response elements on the human NIS promoter sequence. The p53 protein is a critical tumor suppressor and nearly one-third of all breast cancers have p53 gene mutations, which are associated with high histological grade and clinical aggressiveness [26]. In this context, we hypothesized that p53 status in BC cells may have profound impact on observed NIS expression and subsequently its function in terms of iodide transport activity. ...
Purpose:
Aberrant expression of human sodium iodide symporter (NIS) in breast cancer (BC) is well documented but the transcription factors (TF) regulating its aberrant expression is poorly known. We identify the presence of three p53 binding sites on the human NIS promoter sequence by conducting genome-wide TF analysis, and further investigate their regulatory role.
Methods:
The differences in transcription and translation were measured by real-time PCR, luciferase reporter assay, site-directed mutagenesis, in vivo optical imaging, and chromatin immunoprecipitation. The relation of NIS and p53 in clinical samples was judged by TCGA data analysis and immunohistochemistry.
Results:
Overexpression of wild-type p53 as a transgene or pharmacological activation by doxorubicin drug treatment shows significant suppression of NIS transcription in multiple BC cell types which also results in lowered NIS protein content and cellular iodide intake. NIS repression by activated p53 is further confirmed by non-invasive bioluminescence imaging in live cell and orthotropic tumor model. Abrogation of p53-binding sites by directional mutagenesis confirms reversal of transcriptional activity in wild-type p53-positive BC cells. We also observe direct binding of p53 to these sites on the human NIS promoter. Importantly, TCGA data analysis of NIS and p53 co-expression registers an inverse relationship between the two candidates.
Conclusion:
Our data for the first time highlight the role of p53 as a negative regulator of functional NIS expression in BC, where the latter is a potential targeted radioiodine therapy candidate. Thus, the study provides an important insight into prospective clinical application of this approach that may significantly impact the patient with mutant versus wild-type p53 profile.
... In normal cells, ubiquitylation and proteasome activity destroy the p53 protein, which has a short half-life [49]. Mutations in the p53 gene stabilize a protein post-transcriptionally, causing cell accumulation [50], 18-25% of initial breast tumors have p53 mutations [51]. The IHC-detected p53 expression in the breast cancer was associated with an aggressive, metastatic phenotype and awful outcomes [52,53]. ...
It was found that patients with comorbidities of obesity and diabetes have a high risk of breast cancer occurrence and face worse breast cancer outcomes. Though several reports showed the reinforced link between obesity, diabetes, and prediabetes with breast cancer, the underlying molecular mechanism is still unknown. The present study aimed to investigate the underlying molecular link between increased risks of breast cancer due to coincident diabetes or obesity using a spontaneous obese rat model with impaired glucose tolerance (WNIN/GR-Ob rat). A single dose of solubilized DMBA suspension (40 mg/kg body weight) was orally administered to the animals at the age of 60 days to induce breast tumors. The tumor incidence, latency period, tumor frequency, and tumor volume were measured. Histology, immunohistochemistry, and immunoblotting were performed to evaluate the tumor morphology and expression levels of signal molecules. It was observed that the onset of breast tumor and latency period per tumor development were early in GR-Ob rats compared to respective lean rats. It was found that 62% of obese rats were bearing tumors, and in comparison, only 21% of the lean animals developed breast tumors. Overexpression of ER, PR, Ki67, and p53 markers was observed in tumor tissues of obese rats in comparison with lean rats. The levels of the hallmarks of cell proliferation and angiogenesis involved in IGF-1/PI3K/Akt/GSK3β/β-catenin signaling pathway molecules were upregulated in obese rat breast tumors compared to lean rats. Furthermore, obesity with prediabetes is associated with changes in IGF-1 signaling and acts on PI3K/Akt/GSK3β/β-catenin signaling, which results in quick cell proliferation and development of breast tumors in obese rats than the lean rats. These results indicate that the onset of the tumor and its development was faster in a spontaneous obese rat model with impaired glucose tolerance than their lean counterparts, with a higher percentage of tumor incidence.
... In normal cells, ubiquitylation and proteasome activity destroy the p53 protein, which has a short half-life [50]. Mutations in the p53 gene stabilize a protein post-transcriptionally, causing cell accumulation [51], 18-25% of initial breast tumors have p53 mutations [52]. The IHC-detected p53 expression in breast cancer was associated with an aggressive, metastatic phenotype and worse outcomes [53,54]. ...
Patients with comorbidities of obesity and diabetes are recognized to be at high risk of breast cancer development and face worse breast cancer outcomes. Though several reports showed the reinforced link between obesity, diabetes, and prediabetes with breast cancer, the underlying molecular mechanisms are still unknown. The present study aimed to investigate the underlying molecular link between increased risks of breast cancer due to coincident diabetes or obesity using a spontaneous obese rat model with impaired glucose tolerance (WNIN/GR-Ob rat). A single dose of solubilized DMBA suspension (40 mg/kg body weight) was orally administered to the animals at the age of 60 days to induce breast tumors. The tumor incidence, latency period, tumor frequency, and tumor volume were measured. Histology, immunohistochemistry, and immunoblotting were performed to evaluate the tumor morphology and expression levels of signal molecules. The development of mammary tumors in GR-Ob rats was characterized by early onset and shorter latency periods compared to control lean rats. While 62% of obese rats developed breast tumors, tumor development in lean rats was only 21%. Overexpression of ER, PR, Ki67, and p53 markers was observed in tumor tissues of obese rats in comparison with lean rats. The levels of the hallmarks of cell proliferation and angiogenesis involved in IGF-1/PI3K/Akt/GSK3β/β-catenin signaling pathway molecules were upregulated in obese rat breast tumors compared to lean rats. Furthermore, obesity with prediabetes is associated with changes in IGF-1 signaling and acts on PI3K/Akt/GSK3β/β-catenin signaling, which results in rapid cell proliferation and development of breast tumors in obese rats than the lean rats. These results indicate that tumor onset and development were faster in spontaneous obese rat models with impaired glucose tolerance than in their lean counterparts.
... E-cadherin -маркер межклеточной адгезии эпителиальных клеток, утрата его экспрессии в раковых клетках является признаком частичной потери эпителиального фенотипа [22,23]. p53 -транскрипционный фактор, регулирующий клеточный цикл, выполняет функцию супрессора образования злокачественных опухолей [24][25][26]. Прогностическая значимость указанных белков при РМЖ отмечается в ряде исследований [27]. Т-лимфоциты CD8 + (цитотоксические) и CD4 + (регуляторные)одни из ключевых участников клеточного звена иммунитета у больных РМЖ, их прогностическая и предиктивная значимость также установлена целым рядом исследований [20,21,[28][29][30][31][32]. ...
Aim. To increase the efficacy of systemic breast cancer therapy and reduce inappropriate prescriptions using individual immunohistochemical tumor characteristics, as well as to develop prognostic scales to ensure a tailored approach to adjuvant systemic treatment in breast cancer patients.
Materials and methods. We conducted a comprehensive study that included collection of literature data on clinical, pathomorphological, prognostic, and predictive factors of breast cancer, as well as a retrospective cohort study using the data from the cancer registry. We also performed histological and immunohistochemical examination of tumor tissue samples from breast cancer patients (for the retrospective cohort study) and statistical data analysis. A total of 1,216 patients with T1–2N0M0 breast cancer were included in this study. Histological and immunohistochemical examinations of tissue samples (paraffin blocks) were conducted in the laboratory of N. N. Petrov National Medical Research Center of Oncology. We stained slides for both routinely used markers (including estrogen receptors, progesterone receptors, HER2, and Ki-67) and other markers (CK14, FOXA1, FOXP3, PD-L1, P53, SMA, androgen receptors, E-cadherin, CD4, CD8, CK5 / 6, EGFR).We analyzed risk factors for lethal outcomes in patients from this group to develop prognostic scales and compared their results.
Results. We evaluated the most clinically and statistically significant factors affecting mortality. Using logistic regression, we chose 10 factors that had the greatest impact on the outcomes and then produced several scales, includinga 10-point regression scale (based on 10 most significant factors identified). Survival analysis in high-risk and low-risk patients using the regression scale demonstrated significant differences between these groups (р <0.00001). The assessment of adjuvant chemotherapy efficacy in the combined group of intermediate- and high-risk patients (as estimated by the regression model) showed that intermediate- and high-risk patients receiving adjuvant chemotherapy had significant differences in their survival (р = 0.0057). The regression scale for 10-year prognosis demonstrated sufficient sensitivity (58.05 %), specificity (69.47 %) and ef fectiveness (63.76 %).
Conclusion. Our regression prognostic scale includes markers with a high prognostic value. The multifactorial approach used in the developed regression scale for breast cancer 10-year prognosis increases its accuracy and reliability.
... 11 p53 mutations were found in 18-25% of breast carcinomas. 12 These mutations were mostly found in basal type and Her2 enriched breast carcinomas than in luminal type of breast cancers. 13 But, if found in luminal A breast cancers, these mutations caused increased risk of both early and late recurrences with ongoing aromatase inhibitor treatment. ...
Tumours of the cerebellopontine angle are mostly vestibular schwannomas with metastasis being a rare diagnosis. But, metastasis if present, are usually from a breast or a lung primary. We presented a case of a 67 year old postmenopausal lady with luminal. A carcinoma left breast who developed a recurrence on aromatase inhibitor with bone metastasis. She also presented with a cerebellopontine angle tumour which, because of its unusual presentation, presence of a recurrent breast disease with metastasis and mutation testing, raised the suspicion of a brain metastasis but was finally confirmed to be a vestibular schwannoma by histopathology.
... TP53 is the most frequently mutated gene in TNBC, which is found in 80% of total cases of TNBC, which is a much more frequent molecular event than in other BC subtypes [21,22]. These mutations generally result in cytogenetic changes and increased genetic instability, along with a higher probability of loss of heterozygosity [23,24]. ...
Triple-negative breast cancer (TNBC) is known as one of the most aggressive forms of breast cancer (BC), exhibiting high rates of disease progression and poor prognosis due to the lack of clear therapeutic targets and rapid development of tumor resistance to certain chemotherapeutic regimens. TNBC is considered a highly heterogeneous form of BC and is defined by the lack of estrogen receptor (ER) and progesterone receptor (PR) expression, and human epidermal growth factor receptor 2 (HER2) overexpression, thereby rendering the tumors non-susceptible to the targeted treatments. In recent years, significant progress was achieved in understanding TNBC pathogenesis to find a novel target for drug development. Currently, the recommended first-line treatment for TNBC is combined chemotherapy exhibiting a broad spectrum of the adverse systemic effects, also giving a rise to frequent cases of multidrug resistance in patients in later stages. Apart from that, the only targeted treatments that have been approved so far are anti-PD-L1 and PARP inhibitors, which demonstrated the moderate benefits only in the selected TNBC patient groups. Thus, discovering new targets and development of novel drugs for TNBC treatment is of the utmost need. The review focuses on the diverse molecular mechanisms of TNBC pathogenesis, including P53 mutations, RB1 loss, altered signaling pathways, etc. The review also describes the current aspects of diagnostic approaches, molecular and histological classifications, and current treatment recommendations. The molecular mechanisms underlying TNBC resistance to chemotherapy are also discussed. Lastly, the attractive druggable targets for TNBC therapy are also described. This is also supported by the ongoing phases I/II of the clinical trials for TNBC patients.
... Mutation(s) in the zinc binding domain have been correlated with tumor metastasis in breast cancers. In addition, metastasis free five year survival rate of breast cancer patients with TP53 missense mutation in zinc binding domain, mutations in other domains and wild-type TP53 was found to be 32, 48 and 76% respectively [49,50]. ...
Background
Pancreatic adenocarcinoma is one of the most aggressive malignancies with extremely low survival rate. Studies have shown that the exploration of key genes can provide a basis for targeted treatment of these patients. The genomic architecture of the Pakistani pancreatic adenocarcinoma patients remains unexplored. Keeping the scenario in place, the current study aims to analyse 88 cancer related genes in Pakistani pancreatic adenocarcinoma patients in order to elucidate candidate gene(s) for targeted molecular therapy.
Methods and results
A total 18 patients were included in the study initially and FFPE tumor samples were obtained. After confirmation of diagnosis and appropriate tumor content, DNA was extracted. Based on the quality and quantity of the extracted DNA, six pancreatic adenocarcinoma tumor samples were selected. Following to this, all the samples were subjected to targeted sequencing (Axen Cancer Panel 1). Variant detection was done and clinical significance of identified variants was assessed using ClinVar database. Targeted sequencing of tumor samples revealed a total of 29 alterations in the coding region of various genes. Among these five pathogenic variants were found in KRAS, BRCA1, TP53 and APC genes.
Conclusion
This is the first study that explores genes involved in pancreatic adenocarcinoma from the Pakistani population. Results obtained from the pilot study can guide us about the key genetic players in the Pakistani pancreatic adenocarcinoma population. This can lead to our better understanding of the molecular targeted therapies for these patients and designing future researches on larger sample size.
... In primary and metastatic tumors, p53 mutation is detected at a relatively constant frequency and is highly enriched in the xenografts [79]. Another retrospective study in primary early breast carcinomas revealed that p53 mutation is an independent predictor of distant metastasis and overall survival [80]. Furthermore, since p53 mutations often lead to a stabilized p53 protein, one study used immunohistochemistry staining to evaluate p53 status in visceral metastasis breast cancer. ...
Metastasis contributes to the vast majority of cancer-related mortality. Regulatory mechanisms of the multistep invasion-metastasis cascade are being unraveled. TP53 is the most frequently mutated gene across human cancers. Accumulating evidence has shown that mutations of TP53 not only lead to loss of function or dominant negative effects, but also promotes a gain of function. Specifically, gain of function mutant p53 promotes cancer cell motility, invasion, and metastasis. Here, we summarize the mechanisms and functions of mutant p53 that foster metastasis in different types of cancers. We also discuss the prognostic value of mutant p53 and current status of therapeutic strategies targeting mutant p53. Future studies will shed light on discovering novel mechanisms of mutant p53-driven cancer metastasis and developing innovative therapeutics to improve clinical outcomes in patients harboring p53 mutations.
... В исследовании J. Alsner и соавт. (2000) продемонстрировано, что мутации, затрагивающие аминокислоты, необходимые для связывания ДНК, ассоциированы с крайне агрессивным течением заболевания, в то время как нулевые или миссенс-мутации не показали определенных результатов [104]. ...
Breast cancer, being the most common type of malignant diseases, remains a significant challenge for both clinicians and fundamental researchers. The implementation of screening mammography, as well as adjuvant and neoadjuvant systemic therapy has made a significant progress in tackling the disease. The studies aimed at the assessment of novel biomarkers of breast cancer, alternative to standard ones, are becoming increasingly relevant. A number of new markers, such as p53, CK5/6, SMA, p63, PHH3, E-cadherin, EGFR, FOXA1, androgen receptors, TILs etc., have demonstrated their high predictive and/or prognostic value in multiple studies. New findings suggest that evaluation of novel biomarkers in breast cancer requires further thorough analysis.
Recent studies have identified the role of biomarkers in choosing an optimal treatment strategy for breast cancer, estimated the prognostic value of biomarkers associated with tumor proliferative activity (including cyclin D1, G1-cyclin-dependent kinases 4 and 6, and cyclin-dependent kinases 8/19), specified the role of phospho-histone H3 (which is a proliferation marker that can be used to determine tumor grade), and evaluated the prognostic value of androgen receptors and other biomarkers. Multiple studies have also analyzed the expression of various biomarkers and their impact on overall and relapse-free survival.
... 16 Both types of mutations (null and missense) have been observed in the same cancer type. 11 TP53 mutations are seen in 18-25% of primary breast cancers 2,17 and in approximately 80% of TNBCs, which is markedly more frequent than in other breast cancer subtypes. 2,18,19 Mutations in TP53 are predominantly missense mutations, producing mutant p53 proteins. ...
Background:
Most triple-negative breast cancers (TNBCs) have a high histologic grade, are associated with high endoplasmic stress, and possess a high frequency of TP53 mutations. TP53 missense mutations lead to the production of mutant p53 protein and usually show high levels of p53 protein expression. Tumor-infiltrating lymphocytes (TILs) accumulate as part of the anti-tumor immune response and have a strong prognostic and predictive significance in TNBC. We aimed to elucidate the association between p53 expression and the amount of TILs in TNBC.
Methods:
In 678 TNBC patients, we evaluated TIL levels and expression of endoplasmic stress molecules. Immunohistochemical examination of p53 protein expression was categorized into three groups: no, low, and high expression.
Results:
No, low, and high p53 expression was identified in 44.1% (n = 299), 20.1% (n = 136), and 35.8% (n = 243) of patients, respectively. Patients with high p53 expression showed high histologic grade (p < .001), high TIL levels (p = .009), and high expression of endoplasmic reticulum stress-associated molecules (p-eIF2a, p = .013; XBP1, p = .007), compared to patients with low p53 expression. There was no significant difference in disease-free (p = .406) or overall survival rates (p = .444) among the three p53 expression groups.
Conclusions:
High p53 expression is associated with increased expression of endoplasmic reticulum stress molecules and TIL influx.
... To date, breast cancer research has been heavily focused on exploring the contributions of hyperactive growth and hormone receptor signaling, inherited and sporadic gene mutations, oncogene amplification, loss of tumor suppressor proteins, and cancer heterogeneity in the development and progression of breast cancer. For instance, mutations in the breast cancer genes BRCA1 and BRCA2 as well as the TP53 gene have all been well characterized in breast cancer [38][39][40][41]. Aberrations in the P13K/AKT signaling pathway, which regulates the cell cycle and cell proliferation, are also well documented [42]. ...
Cancer research has been heavily geared towards genomic events in the development and progression of cancer. In contrast, metabolic regulation, such as aberrant metabolism in cancer, is poorly understood. Alteration in cellular metabolism was once regarded simply as a consequence of cancer rather than as playing a primary role in cancer promotion and maintenance. Resurgence of cancer metabolism research has identified critical metabolic reprogramming events within biosynthetic and bioenergetic pathways needed to fulfill the requirements of cancer cell growth and maintenance. The tumor suppressor protein p53 is emerging as a key regulator of metabolic processes and metabolic reprogramming in cancer cells—balancing the pendulum between cell death and survival. This review provides an overview of the classical and emerging non-classical tumor suppressor roles of p53 in regulating mitochondrial dynamics: mitochondrial engagement in cell death processes in the prevention of cancer. On the other hand, we discuss p53 as a key metabolic switch in cellular function and survival. The focus is then on the conceivable roles of p53 in breast cancer metabolism. Understanding the metabolic functions of p53 within breast cancer metabolism will, in due course, reveal critical metabolic hotspots that cancers advantageously re-engineer for sustenance. Illustration of these events will pave the way for finding novel therapeutics that target cancer metabolism and serve to overcome the breast cancer burden.
... TNBCs have an increased propensity to metastasize and high rate of relapse, the majority of deaths from this disease are a result of distant disease [21]. A number of genes and proteins have been identified with altered expression in TNBC, like EGFR (epidermal growth factor receptor) [22,23], PARPs [poly (ADP-ribose) polymerase] [24,25], VEGF (vascular endothelial growth factor) [26], p53 [27,28], TOP-2A (Topoisomerase 2 Alpha) [29] and so on. Till now, some of the markers have been tested for diagnostic and prognostic purposes. ...
Background
Recent studies have shown that laminin subunit alpha 4 (LAMA4) plays an important role in carcinogenesis. However, its molecular biological function in triple-negative breast cancer (TNBC) has not been entirely clarified. This study investigated the expression of LAMA4 in TNBC and its effect on cell proliferation, migration and invasion. Furthermore, we also identified the potential miRNA directly targeting LAMA4.
Methods
Western blot, Real-time quantitative PCR (qPCR) and immunohistochemical staining (IHC) were used to detect the expression of LAMA4 in TNBC. The effects of LAMA4 on TNBC cell proliferation, migration and invasion were also explored in vitro. The potential miRNA that targets LAMA4 was determined by dual luciferase reporter assay and verified by qPCR and western blot analysis.
Results
Our study showed LAMA4 mRNA (p = 0.001) and protein (p = 0.005) expression in TNBC tissue samples were elevated compared with adjacent normal tissue samples, and LAMA4 was mainly expressed in the cytoplasm of breast carcinoma cells. Knockdown of LAMA4 inhibited TNBC cell proliferation, migration and invasion in vitro. Moreover, further study revealed that LAMA4 was a putative target of miR-539, and miR-539 negatively regulated LAMA4 expression by directly targeting its 3′-UTR.
Conclusions
Our study suggested that miR-539 suppressed the expression of LAMA4. LAMA4 plays an important role in tumor progression and may be an important target in treatment of TNBC.
... This study showed that TP53 mutation was an independent parameter of poor prognosis (19). It seems that the exact type and the position of the mutation differently influence disease outcome (19,21,22). Our data did not show a significantly worse OS in patients with and those without TP53 mutations, although a trend to-wards worse survival in TP53 mutation carriers was observed. ...
Purpose
This study aimed to investigate the incidence of core domain TP53 mutations in Serbian breast cancer patients in view of their possible correlation with prognostic parameters, tumor characteristics and clinical disease course.
Methods
145 breast cancer patients were included. Data on clinical disease course were available for 100 patients including 30 node-negative and 70 node-positive patients. After surgery, node-positive patients underwent adjuvant chemotherapy, mostly CMF. TP53 mutations were detected by PCR-SSCP.
Results
31 mutations were found in 27/145 patients including 4/59 node-negative patients and 23/83 node-positive patients (4 double mutations). 26/31 TP53 mutations were found in patients with invasive ductal carcinoma and only 2 in patients with invasive lobular carcinoma. The presence of TP53 mutations was correlated with clinical disease course in premenopausal node-positive patients (n=70). 11/20 patients with TP53 mutations relapsed. Within the first 24 months of follow-up, significantly shorter disease-free intervals were observed in TP5. 3-mutated patients.
Conclusions
TP53 mutations correlated only with nodal status and ductal histology. The significance of the predominant distribution of TP53 mutations in tumors with a ductal histology for the aggressive behavior of these tumors has yet to be proved, since the favorable biological features of tumors with a lobular histology do not result in a better prognosis. Early relapse in mutated- TP5. 3 carriers may support data on its predictive value with respect to adjuvant CMF.
... Interestingly, p53 mammary tumor gene expression was increased in all n-3 PUFAcontaining dietary groups, wherein PGE 2 is antagonized. p53 promotes cell cycle arrest and apoptosis [48] and is mutated in 18%-25% of primary breast carcinomas [49]; however, n-3 PUFA from either plant or murine sources increased its expression, which coincided with increased tumor apoptosis and reduced cell proliferation. ...
Marine-derived n-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been shown to inhibit mammary carcinogenesis. However, evidence regarding plant-based α-linolenic acid (ALA), the major n-3 PUFA in the Western diet, remains equivocal. The objective of this study was to examine the effect of lifelong exposure to plant- or marine-derived n-3 PUFAs on pubertal mammary gland and tumor development in MMTV-neu(ndl)-YD5 mice. It is hypothesized that lifelong exposure to n-3 PUFA reduces terminal end buds during puberty leading to delayed tumor onset, volume and multiplicity. It is further hypothesized that plant-derived n-3 PUFAs will exert dose-dependent effects. Harems of MMTV-FVB males were bred with wild-type females and fed either a (1) 10% safflower (10% SF, n-6 PUFA, control), (2) 10% flaxseed (10% FS), (3) 7% safflower plus 3% flaxseed (3% FS) or (4) 7% safflower plus 3% menhaden (3% FO) diet. Female offspring were maintained on parental diets. Compared to SF, 10% FS and 3% FO reduced (P<.05) terminal end buds at 6 weeks and tumor volume and multiplicity at 20 weeks. A dose-dependent reduction of tumor volume and multiplicity was observed in mice fed 3% and 10% FS. Antitumorigenic effects were associated with altered HER2, pHER-2, pAkt and Ki-67 protein expression. Compared to 10% SF, 3% FO significantly down-regulated expression of genes involved in eicosanoid synthesis and inflammation. From this, it can be estimated that ALA was 1/8 as potent as EPA+DHA. Thus, marine-derived n-3 PUFAs have greater potency versus plant-based n-3 PUFAs.
... Previous studies have demonstrated that the incidence of p53 mutations differs between various types of cancer, ranging from near universal (~96% for serous ovarian cancer) to rare occurrence (<10% for thyroid cancer) (18). The incidence of p53 mutations is between 18 and 25% for primary breast carcinomas (19). It has also been demonstrated that GOF mutant p53 may be able to upregulate CXC chemokines and enhance cell migration (20)(21)(22)(23). ...
The present study aimed at investigating the underlying molecular mechanisms for patients following cytokine-induced killer (CIK) therapy, particularly involving the alterations in p53-associated signaling pathways, to elucidate whether CIK therapy serves a function in cancer treatment. Samples of blood were collected from patients with breast cancer prior to and following CIK therapy. Two group samples were used for RNA sequencing (RNA-Seq) to determine the alterations in gene expression levels following CIK therapy and one for the quantitative polymerase chain reaction (qPCR), to analyze the reliability of RNA-Seq results. The genes that may encode proteins associated with p53 pathways were selected and analyzed. The expression levels of 8 genes were analyzed, including tumor suppressor protein 53 (TP53), murine double minute homolog 2 (MDM2), ribosomal protein L11 (RPL11), ribosomal protein S23 (RPS23), sirtuin 1, histone deacetylase 1, tuberous sclerosis complex 1 (TSC1) and mechanistic target of rapamycin (mTOR), and alterations in expression levels following CIK therapy were determined. However, only RPL11 and RPS23 were identified to exhibit marked alterations in expression levels (FDR<0.05), which was considered to be due to individual distinctions. qPCR analysis revealed that the expression levels of the RPL11, TP53 and TSC1 genes were downregulated, and those of the RPS23 and MDM2 genes were upregulated following CIK therapy. Only MDM2 exhibited a marked alteration in the gene expression level following CIK therapy. Alterations in the expression levels of TP53, RPL11 and TSC1 were associated with those of MDM2, RPS23 and mTOR, respectively.
... p53 protein expression is associated with TP53 mutation status but is not a reliable surrogate in breast cancer cell lines Functional abrogation of TP53 through germline (Li-Fraumeni syndrome) or somatic mutation is an important driver of breast cancer development, particularly in HER2? and TN disease [29,30]. Missense mutations can disrupt feedback signaling and/or stabilize the protein, resulting in accumulation within the nucleus (so-called ''over-expression''). ...
Purpose:
Cell lines are extremely useful tools in breast cancer research. Their key benefits include a high degree of control over experimental variables and reproducibility. However, the advantages must be balanced against the limitations of modelling such a complex disease in vitro. Informed selection of cell line(s) for a given experiment now requires essential knowledge about molecular and phenotypic context in the culture dish.
Methods:
We performed multidimensional profiling of 36 widely used breast cancer cell lines that were cultured under standardised conditions. Flow cytometry and digital immunohistochemistry were used to compare the expression of 14 classical breast cancer biomarkers related to intrinsic molecular profiles and differentiation states: EpCAM, CD24, CD49f, CD44, ER, AR, HER2, EGFR, E-cadherin, p53, vimentin, and cytokeratins 5, 8/18 and 19.
Results:
This cell-by-cell analysis revealed striking heterogeneity within cultures of individual lines that would be otherwise obscured by analysing cell homogenates, particularly amongst the triple-negative lines. High levels of p53 protein, but not RNA, were associated with somatic mutations (p = 0.008). We also identified new subgroups using the nanoString PanCancer Pathways panel (730 transcripts representing 13 canonical cancer pathways). Unsupervised clustering identified five groups: luminal/HER2, immortalised ('normal'), claudin-low and two basal clusters, distinguished mostly by baseline expression of TGF-beta and PI3-kinase pathway genes.
Conclusion:
These features are compared with other published genotype and phenotype information in a user-friendly reference table to help guide selection of the most appropriate models for in vitro and in vivo studies, and as a framework for classifying new patient-derived cancer cell lines and xenografts.
... Any disruption of this function due to a mutation in p53 gene is done due to cellular stress by many pathways which are dependent on upstream regulatory kinase. 18-25% of primary breast carcinoma showed p53 mutation [52]. According to a study, expression of p53 is significantly higher in TNBC comparatively than non-TNBC, which indicates in worse prognosis of TNBC [32]. ...
Breast cancer is the most common malignancy in women globally, in which triple-negative breast cancer (TNBC) is more aggressive with poor prognosis and very less response to targeted hormone based treatment. It is a major cause of deaths among the women with breast cancer because of very few treatment options. The biomarkers could be a product of cancerous cell or molecule generated in response to cancer. It is used to understand the mechanism, prognosis, diagnosis as well as target for design and discovery of new drugs. The purpose of the study is to give a brief review on markers of TNBC.
... Patients with locally advanced breast cancer (LABC) have poor prognosis when treated with grammed cell death in response to DNA damage in the presence of oncogenic triggers [2,45]. Intact p53 has been shown to induce apoptosis in response to ionizing radiation, whereas loss of p53 function has been reported to enhance cellular resistance to a number of chemotherapeutic agents [17,26,27]. ...
... T-, were further separated, while through recursive partitioning, T+ patients were further divided. In other words, BC patients were classified into T+, P+T-and P-T-, while T-, P+T+ and P-T+ in the decision tree.This is unexpected, since it was reported that TP53 mutations are strong characteristic of the TN phenotype [32,42,43], but the decision tree shows no direct correlation between TP53 and TN, implying the subtleness of their correlation. More importantly, the decision tree result presented the double mutation class of PIK3CA and TP53, confirming the importance of co-static interaction between these two genes. ...
Breast cancer (BC) patients can be clinically classified into three types, called ER+, PR+, and HER2+, indicating the name of biomarkers and linking treatments. The serious problem is that the patients, called “triple negative” (TN), who cannot be fallen into any of these three categories, have no clear treatment options. Thus linking TN patients to the main three phenotypes clinically is very important. Usually BC patients are profiled by gene expression, while their patient class sets (such as PAM50) are inconsistent with clinical phenotypes. On the other hand, location-specific sequence variants are expected to be more predictive to detect BC patient subgroups, since a variety of somatic, single mutations are well-demonstrated to be linked to the resultant tumors. However those mutations have not been necessarily evaluated well as patterns to predict BC phenotypes. We thus detect patterns, which can assign known phenotypes to BC TN patients, focusing more on paired or more complicated nucleotide/gene mutational patterns, by using three machine learning methods: limitless arity multiple procedure (LAMP), decision trees, and hierarchical disjoint clustering. Association rules obtained through LAMP reveal a patient classification scheme through combinatorial mutations in PIK3CA and TP53, consistent with the obtained decision tree and three major clusters (occupied 182/208 samples), revealing the validity of results from diverse approaches. The final clusters, containing TN patients, present sub-population features in the TN patient pool that assign clinical phenotypes to TN patients.This paper is an extended and detailed version on a pilot study conducted in Yotsukura et al. (Brief Bioinform, to appear).
... Furthermore, BC patients were classified into Tþ, Pþ TÀ and PÀTÀ in LAMP, whereas they were classified into TÀ, P þ Tþ and PÀTþ in the decision tree. This is unexpected, as it was reported that TP53 mutations are a strong characteristic of the TN phenotype [59,71,72], but the decision tree shows no direct correlation between TP53 and TN. More importantly, the decision tree result presented the double mutation class of PIK3CA and TP53, confirming the importance of co-static interaction between these two genes. ...
Triple-negative (TN) breast cancer (BC) patients have limited treatment options and poor prognosis even after extant treatments
and standard chemotherapeutic regimens. Linking TN patients to clinically known phenotypes with appropriate treatments is
vital. Location-specific sequence variants are expected to be useful for this purpose by identifying subgroups within a disease
population. Single gene mutational signatures have been widely reported, with related phenotypes in literature. We thoroughly
survey currently available mutations (and mutated genes), linked to BC phenotypes, to demonstrate their limited performance
as sole predictors/biomarkers to assign phenotypes to patients. We then explore mutational combinations, as a pilot study,
using The Cancer Genome Atlas Research Network mutational data of BC and three machine learning methods: association rules
(limitless arity multiple procedure), decision tree and hierarchical disjoint clustering. The study results in a patient classification
scheme through combinatorial mutations in Phosphatidylinositol-4,5-Bisphosphate 3-Kinase and tumor protein 53, being consistent
with all three methods, implying its validity from a diverse viewpoint. However, it would warrant further research to select
multi-gene signatures to identify phenotypes specifically and be clinically used routinely.
... The p53 gene functions as a tumor suppressor, preventing cancer [27,28]. The capability that p53 status affects biological behavior was raised in a previous study in which the presence of p53 mutations in aggressive breast cancer was demonstrated [29,30]. Hence, the data presented here signify that T1 breast cancer, at a relatively early stage, with high 18 F-FDG, may be related to aggressive breast cancer, and careful monitoring may be necessary. ...
Purpose
The objective of this study was to investigate the relationship between diversity of 18F-fluorodeoxyglucose (18F-FDG) uptake of primary tumor in positron emission tomography (PET) and various clinicopathologic factors in breast cancer of same pathologic T1, T2 stage.
Methods
A total of 258 patients with invasive ductal breast cancer were enrolled in this study. All patients underwent 18F-FDG PET-CT before surgery. Patients were divided into two groups according to tumor size based on the pathologic T stage, and maximum standardized uptake value (SUVmax) of 2.5, respectively.
Results
On the univariate analysis, estrogen receptor (ER), tumor size, lymphovascular invasion, p53, pathologic N status (pN) and Nottingham tumor grade (NG) were associated with high SUVmax in T1 and T2 breast cancer. On the multivariate logistic regression, tumor size and NG remained significant variables dividing high and low SUVmax. In the T1 group, ER, p53 and NG were significantly associated with high SUVmax on the univariate analysis. In this group, p53 and NG remained significant variables for dividing high and low SUVmax on the multivariate logistic regression. In the T2 group, only NG was associated with high SUVmax on the univariate analysis.
Conclusions
NG showed an association with 18F-FDG uptake in both T1 and T2 breast cancer independently; however, p53 in T1 breast cancer.
... Different types of TP53 mutations have been reported as having different functional effects and prognostic values 38,39 . However, reports of these associations are inconsistent 17,37,[40][41][42][43] . In our study, missense and nonmissense mutations were significantly associated with RFS (missense mutation vs. wild; HR = 1.80; nonmissense mutation Table 2. Multivariate Cox's proportional hazards models for relapse-free survival in NTUH cohort (A) and breast cancer-specific mortality in METABRIC cohort (B) and comparison of added prognostic information by TP53 in the two cohorts (C). ...
IHC4 and PAM50 assays have been shown to provide additional prognostic information for patients with early breast cancer. We evaluated whether incorporating TP53 mutation analysis can further enhance their prognostic accuracy. We examined TP53 mutation and the IHC4 score in tumors of 605 patients diagnosed with stage I-III breast cancer at National Taiwan University Hospital (the NTUH cohort). We obtained information regarding TP53 mutation and PAM50 subtypes in 699 tumors from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort. We found that TP53 mutation was significantly associated with high-risk IHC4 group and with luminal B, HER2-enriched, and basal-like subtypes. Despite the strong associations, TP53 mutation independently predicted shorter relapse-free survival (hazard ratio [HR] = 1.63, P = 0.007) in the NTUH cohort and shorter breast cancer-specific survival (HR = 2.35, P = <0.001) in the METABRIC cohort. TP53 mutational analysis added significant prognostic information in addition to the IHC4 score (∆ LR-χ(2) = 8.61, P = 0.002) in the NTUH cohort and the PAM50 subtypes (∆ LR-χ(2) = 18.9, P = <0.001) in the METABRIC cohort. We conclude that incorporating TP53 mutation analysis can enhance the prognostic accuracy of the IHC4 and PAM50 assays.
... First, an ataxiatelangectasia mutated proteins released in response to the DSB, second, a pathway dependent on INK4 gene product, p14ARF activated by oncogenes, and finally, a pathway induced by chemotherapy drugs and ultraviolet light and is independent of the above two pathways [80,81] . p53 mutations are seen in 18%-25% of primary breast carcinomas (Table 4) [82] . p53 plays an important role in breast cancer prognosis. ...
Breast cancer is an intrinsically heterogeneous disease. In the world about 1 million cases of breast cancer are diagnosed annually and more than 170000 are triplenegative. Characteristic feature of triple negative breast cancer (TNBC) is that it lacks expression of oestrogen, progesterone and human epidermal growth factor receptor-2/neu receptors. They comprise 15%-20% of all breast cancers. We did a systematic review of PubMed and conference databases to identify studies published on biomarkers in TNBC. We included studies with biomarkers including: Epidermal growth factor receptor, vascular endothelial growth factor, c-Myc, C-kit and basal cytokeratins, Poly(ADP-ribose) polymerase-1, p53, tyrosinase kinases, m-TOR, heat and shock proteins and TOP-2A in TNBC. We also looked for studies published on synthetic lethality and inhibition of angiogenesis, growth, and survival pathways. TNBC is a complex disease subtype with many subclasses. Majority TNBC have a basal-like molecular phenotype by gene expression profiling. Their clinical and pathologic features overlap with hereditary BRCA1 related breast cancers. Management of these tumours is a challenge to the clinician because of its aggressive behaviour, poor outcome, and absence of targeted therapies. As the complexity of this disease is being simplified over time new targets are also being discovered for the treatment of this disease. There are many biomarkers in TNBC being used in clinical practice. Biomarkers may be useful as prognostic or predictive indicators as well as suggest possible targets for novel therapies. Many targeted agents are being studied for treatment of TNBC. © The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
... Intra-tumor heterogeneity, the molecular differences between cells within an individual tumor, has clinical implications (37,38). One model of drug resistance is that subpopulations in a heterogeneous tumor are selected for during drug treatment (39). ...
Compared to normal cells, tumor cells have undergone an array of genetic and epigenetic alterations. Often, these changes underlie cancer development, progression, and drug resistance, so the utility of model systems rests on their ability to recapitulate the genomic aberrations observed in primary tumors. Tumor-derived cell lines have long been used to study the underlying biological processes in cancer, as well as screening platforms for discovering and evaluating the efficacy of anti-cancer therapeutics. Multiple -omics measurements across more than a thousand cancer cell lines have been produced following advances in high-throughput technologies and multi-group collaborative projects. These data complement the large, international cancer genomic sequencing efforts to characterize patient tumors, such as The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC). Given the scope and scale of data that has been generated, researchers are now in a position to evaluate the similarities and differences that exist in genomic features between cell lines and patient samples. As pharmacogenomics models, cell lines offer the advantages of being easily grown, relatively inexpensive, and amenable to high-throughput testing of therapeutic agents. Data generated from cell lines can then be used to link cellular drug response to genomic features, where the ultimate goal is to build predictive signatures of patient outcome. This review highlights the recent work that has compared -omics profiles of cell lines to primary tumors, and discusses the advantages and disadvantages of cancer cell lines as pharmacogenomic models of anticancer therapies.
Copyright © 2015, American Association for Cancer Research.
... The early detection is necessary to treat and improve the survival of breast cancer patients. In patient with breast cancer, gene amplification of HER2 which is a member of the epidermal growth factor receptor family, is found to be present in 15-30% newly diagnosed breast cancer cases and the mutations in the tumor suppressor gene p53 is presented in 18%-25% of primary breast carcinomas (Alsner at al., 2000;Kotoe at el., 2009). The overexpression of the p53 and HER-2/neu oncogenes are the two most common genetic abnormalities associated with breast cancer (Alsner at el., 2000). ...
Breast cancer is the common cause of death among women in most countries worldwide, with rapidly increases in the developing countries, including Vietnam. To establish the potential biomarker is an attempt of researchers in the world, one of the biomarkers is the disruptions of the genetic material such as the epigenetics including DNA methylation. In present study, with the aim towards using the hypermethylation at CpG islands of promoter of candidate genes as the biomarker for breast cancer in Vietnamese population, sensitive methyl specific PCR (MSP) was carried out to analyze the hypermethylation status of the panel of candidate genes including BRCA1, p16INK4α , GSTP1, RASSF1A and Cyclin D2 gene in 115 samples including 95 breast cancer specimens and 20 normal breast tissues from another disease (not breast cancer) which were obtained from Ho Chi Minh City Medical Hospital, Vietnam. The results indicated that the hypermethylation of one or more genes occurred in all total of 95 tumor specimens (100% diagnostic coverage) with the frequencies for methylation of each genes reach to 82.1% (pBRCA1, Cyclin D2, p16INK4α , GSTP1, and RASSF1A gene, respectively. In addition, the DNA hypermethylation of the panel of candidate genes increase the possibility to be breast cancer with high incidence via calculated of odd ratio (p
... The early detection is necessary to treat and improve the survival of breast cancer patients. In patient with breast cancer, gene amplification of HER2 which is a member of the epidermal growth factor receptor family, is found to be present in 15-30% newly diagnosed breast cancer cases and the mutations in the tumor suppressor gene p53 is presented in 18%-25% of primary breast carcinomas (Alsner at al., 2000;Kotoe at el., 2009). The overexpression of the p53 and HER-2/neu oncogenes are the two most common genetic abnormalities associated with breast cancer (Alsner at el., 2000). ...
Breast cancer, a leading cause of death among women in most countries worldwide, is rapidly increasing in incidence in Vietnam. One of biomarkers is the disruption of the genetic material including epigenetic changes like DNA methylation. With the aim of finding hypermethylation at CpG islands of promoter of BRCA1 gene, belonged to the tumor suppressor gene family, as the biomarker for breast cancer in Vietnamese population, sensitive methyl specific PCR (MSP) was carried out on 115 samples including 95 breast cancer specimens and 20 normal breast tissues with other diseases which were obtained from Ho Chi Minh City Medical Hospital, Vietnam. The result indicated that the frequency of BRCA1 hypermethylation reached 82.1% in the cases (p<0.001). In addition, the DNA hypermethylation of this candidate gene increased the possibility to be breast cancer with high incidence via calculated odd ratios (p<0.05). In conclusion, hypermethylation of this candidate gene could be used as the promising biomarker application with Vietnamese breast cancer patients.
... In addition, sequencing of the p53 gene in all breast cancers would be expensive and time-consuming for routine practice [70,71,73] . A higher tumour grade, negative ER and PR status, and the more aggressive basal subtype were associated with abnormal p53 immunohistochemical expression or p53-positive status [70,72,73] . ...
The biological characteristics of the tumour are used to estimate prognosis and select appropriate systemic therapy for patients with (breast) cancer. The advent of molecular technology has incorporated new biomarkers along with immunohistochemical and serum biomarkers. Immunohistochemical markers are often used to guide treatment decisions, to classify breast cancer into subtypes that are biologically distinct and behave differently, and both as prognostic and predictive factors. Steroid hormone receptors, markers of tumour proliferation, and factors involved in angiogenesis and apoptosis are of scientific interest. In this review we will provide information on the immunohistochemical markers used in the management of breast cancer patients using available data from the literature. We consider the utility of established immunohistochemical markers, and discuss the challenges involved in integrating novel molecular markers into clinical practice.
... In this study, we identified PIK3CA mutations in 35.2% and TP53 mutations in 15.2% of breast tumors. Previous studies have identified PIK3CA mutation in 10.3-37.5% of the HER2-positive breast cancer cases [23][24][25][26] and p53 mutations in 18%-25% of primary breast carcinomas [27]. TP53 mutations generally have a poor prognostic power, which may be due to the screening approach used [28]. ...
Breast cancer is the most common malignancy and the leading cause of cancer deaths in women worldwide. While specific genetic mutations have been linked to 5-10% of breast cancer cases, other environmental and epigenetic factors influence the development and progression of the cancer. Since unique mutations patterns have been observed in individual cancer samples, identification and characterization of the distinctive breast cancer molecular profile is needed to develop more effective target therapies. Until recently, identifying genetic cancer mutations via personalized DNA sequencing was impractical and expensive. The recent technological advancements in next-generation DNA sequencing, such as the semiconductor-based Ion Torrent sequencing platform, has made DNA sequencing cost and time effective with more reliable results. Using the Ion Torrent Ampliseq Cancer Panel, we sequenced 737 loci from 45 cancer-related genes to identify genetic mutations in 105 human breast cancer samples. The sequencing analysis revealed missense mutations in PIK3CA, and TP53 genes in the breast cancer samples of various histologic types. Thus, this study demonstrates the necessity of sequencing individual human cancers in order to develop personalized drugs or combination therapies to effectively target individual, breast cancer-specific mutations.
... Portanto, em geral, a presença de mutação tende a indicar um pior prognóstico e o tipo de mutação ocorrida pode ser um indicador de tumores biologicamente mais agressivos. Estes resultados estão de acordo com Alsner et al. 24 , que agruparam as mutações presentes em tumores de mama segundo a sua localização e participação na estrutura da proteína resultante, constatando, portanto, que o tipo de mutação está diretamente associado à agressividade do tumor. ...
Breast cancer is the leading cause of death due to cancer among women in Brazil and, the State of Rio de Janeiro presents the highest mortality coefficient of this disease in the country. Studies have shown that many genetic and molecular factors may be related to the outcome of cases. The aim of this study was to describe the frequency and types of mutations in the tumor suppressor gene TP53 in 120 patients with diagnosis of invasive breast carcinoma recruited from the Instituto Nacional de Câncer (INCA), Rio de Janeiro from1995 to 1997, and to analyze the associations between these mutations and risk factors, and tumor characteristics, including the presence of TP53 mutations, and risk of death. The molecular analysis detected TP53 alterations in 22 cases (18.3%), of which 2 cases presented 2 mutations each; a polymorphism in exon 6 was observed in 1 case. The mutations found were: 14 missense, 2 nonsense, 2 silent, 2 deletions, 1 insertion and 3 located in introns which probably did not change the protein. The analysis of risk factors in relation to TP53 mutations showed that only tobacco consumption had an association (adjusted OR = 0.24 (0.06-0.88)). Multivariate analysis showed that only tumor aggressiveness showed an OR indicative of risk (3.98, IC 95% 1.25-12.72).These results are in agreement with previous studies, which report that the presence of TP53 mutations may indicate more aggressive breast tumors biologically although this is not the only parameter to be considered.
... Végran et al. [14] also suggested that only missense mutations occurring in the DNA binding domain were significantly associated with worse disease-free survival and overall survival. Alsner et al. [23] showed that patients with missense mutations affecting the DNA binding or zinc binding domains displayed a very aggressive phenotype with short survival. These findings are supported by our data showing that missense mutation of the p53 gene is an independent prognostic factor and is associated with poor clinical outcome, although overall p53 mutation was not an independent prognostic factor. ...
The p53 gene is one of the most frequently mutated genes in breast cancer. We investigated the patterns and biologic features of p53 gene mutation and evaluated their clinical significance in Korean breast cancer patients.
Patients who underwent p53 gene sequencing were included. Mutational analysis of exon 5 to exon 9 of the p53 gene was carried out using polymerase chain reaction-denaturing high performance liquid chromatography and direct sequencing.
A total of 497 patients were eligible for the present study and p53 gene mutations were detected in 71 cases (14.3%). Mutation of p53 was significantly associated with histologic grading (p<0.001), estrogen receptor and progesterone receptor status (p<0.001), HER2 status (p<0.001), Ki-67 (p=0.028), and tumor size (p=0.004). The most frequent location of p53 mutations was exon 7 and missense mutation was the most common type of mutation. Compared with patients without mutation, there was a statistically significant difference in relapse-free survival of patients with p53 gene mutation and missense mutation (p=0.020, p=0.006, respectively). Only p53 missense mutation was an independent prognostic factor for relapse-free survival in multivariate analysis, with an adjusted hazard ratio of 2.29 (95% confidence interval, 1.08-4.89, p=0.031).
Mutation of the p53 gene was associated with more aggressive clinicopathologic characteristics and p53 missense mutation was an independent negative prognostic factor in Korean breast cancer patients.
... Both of the mutations were found in COSMIC and reported in other lung cancer studies (Fouquet et al., 2004;Liu et al., 2002;Mori et al., 2004;Pelosi et al., 2012;The Cancer Genome Atlas, 2012). One of the mutations (G266E) is a loss-of-function mutation (Alsner et al., 2000;Fernandez-Cuesta et al., 2012;Pfaff et al., 2010), while the other mutation (G199V) is an anti-apoptotic gain-of-function mutation that promotes cell survival through the signal transducer and activator of transcription-3 (STAT3) pathway (Kim et al., 2009). Knockdown experiments of G199V p53 mutants demonstrated a level of anti-tumor activity similar to high doses of chemotherapeutic agents, suggesting that inhibition of G199V p53 mutants may be beneficial for cancer treatment (Kim et al., 2009). ...
The detection of somatic single nucleotide variants is a crucial component to
the characterization of the cancer genome. Mutation calling algorithms thus far
have focused on comparing the normal and tumor genomes from the same
individual. In recent years, it has become routine for projects like The Cancer
Genome Atlas (TCGA) to also sequence the tumor RNA. Here we present RADIA (RNA
and DNA Integrated Analysis), a method that combines the patient-matched normal
and tumor DNA with the tumor RNA to detect somatic mutations. The inclusion of
the RNA increases the power to detect somatic mutations, especially at low DNA
allelic frequencies. By integrating the DNA and RNA, we are able to rescue back
calls that would be missed by traditional mutation calling algorithms that only
examine the DNA.
RADIA was developed for the identification of somatic mutations using both
DNA and RNA from the same individual. We demonstrate high sensitivity (84%) and
very high specificity (98% and 99%) in real data from endometrial carcinoma and
lung adenocarcinoma from TCGA. Mutations with both high DNA and RNA read
support have the highest validation rate of over 99%. We also introduce a
simulation package that spikes in artificial mutations to real data, rather
than simulating sequencing data from a reference genome. We evaluate
sensitivity on the simulation data and demonstrate our ability to rescue back
calls at low DNA allelic frequencies by including the RNA. Finally, we
highlight mutations in important cancer genes that were rescued back due to the
incorporation of the RNA.
Software available at https://github.com/aradenbaugh/radia/
... The association between p53 alterations and clinical outcome in breast cancer has been the subject of numerous investigations [56] . The possibility that p53 status influences biological behavior was raised in an early study in which the presence of p53 mutations in aggressive breast cancer was demonstrated [57] . The majority of studies support an association between worse survival and the presence of p53 mutations. ...
Abstract
Breast cancer has emerged as a grave danger in the last 50 years. It represented 35.1% of total cancer in women in Egypt National Cancer Institute (NCI) series. Changes in cell loss factor could have a major impact on tumor growth or regression. A large percentage of cell loss from tumors was due to apoptosis. P53 is a tumor suppressor gene that plays a critical role in preventing human cancer formation. In response to a variety of stress signals p53 becomes activated and induces cell cycle arrest and/or apoptosis.
We Aimed to: 1. Study the immunohistochemical profile of p53 in breast carcinoma. 2. Assess its prognostic value in relation to clinico-pathological prognostic factors of breast carcinoma.
Subjects and Methods: This study included 45 specimens of breast carcinoma. Patient’s age, tumor size and local aggressive changes, history of recurrence and/or presence of distant metastasis were obtained. H&E stained sections were evaluated for the presence of benign breast disease, histo-pathological tumor type, and tumor grade, presence of in situ component, lymphocytic infiltration, lymphovascular invasion, and axillary lymph node status. P53 immunostaining was done to detect its expression using the avidin-biotin peroxidase method.
Results: P53 was weakly expressed in 11% of areas of benign breast disease. P53 was negative in all cases of low grade ductal carcinoma in situ (DCIS), positive in 2/3 of intermediate grade DCIS, and positive in all cases of high grade DCIS. All grade I invasive breast carcinoma (IBC) were negative for p53, 50% of grade II and 91% of grade III IBC were positive for p53. P53 expression increased significantly with increased tumor grade of IBC (p<0.006), lymphovascular invasion (p<0.003) and lymphocytic infiltration (p<0.004). No significant correlation between p53 expression and lymph nodal status.
Conclusions: P53 is an indicator for poor prognosis in breast cancer being positively correlated to tumor grade, presence of lymphovascular invasion. P53 may modulate the immune response in breast cancer being positively correlated with prominent lymphocytic infiltration.
... However, missense mutations within the p53 gene result in protein that is stabilized through posttranscriptional modification and accumulation within the cell nucleus. Mutations in the tumor suppressor gene p53 are present in 18%-25% of primary breast carcinomas 8 . Among the prognostic factors analyzed in studies focusing on breast cancer, an absence of p53 mutations appears to predict longer disease-free (DFS) and overall survival (OS) following primary therapy. ...
In the study, we analyzed role of p53 in predicting outcome in visceral metastasis breast cancer (VMBC) patients. 97 consecutive VMBC patients were studied. P53 positivity rate was 29.9%. In the p53-negative group, median disease free survival (DFS), and time from primary breast cancer diagnosis to death (OS1), time from metastases to death (OS2) were 25, 42.5, and 13.5 months, respectively. In the p53-positive group, they were 10, 22, and 8 months, respectively. Statistically significant differences in DFS and OS1 were detected between the p53-negative and p53-positive subtypes. However, p53 appears to have no influence on OS2. In Cox regression analysis, p53 expression and TNM stage were predictive factors of DFS. In the multivariate analysis, p53 expression and the duration of DFS correlated with OS1, but not for OS2. Taken together, our data indicate p53 showing predicting role in OS1 for VMBC, but not for OS2.
... Portanto, em geral, a presença de mutação tende a indicar um pior prognóstico e o tipo de mutação ocorrida pode ser um indicador de tumores biologicamente mais agressivos. Estes resultados estão de acordo com Alsner et al. 24 , que agruparam as mutações presentes em tumores de mama segundo a sua localização e participação na estrutura da proteína resultante, constatando, portanto, que o tipo de mutação está diretamente associado à agressividade do tumor. ...
Breast cancer is the leading cause of death due to cancer among women in Brazil and, the State of Rio de Janeiro presents the highest mortality coefficient of this disease in the country. Studies have shown that many genetic and molecular factors may be related to the outcome of cases. The aim of this study was to describe the frequency and types of mutations in the tumor suppressor gene TP53 in 120 patients with diagnosis of invasive breast carcinoma recruited from the Instituto Nacional de Câncer (INCA), Rio de Janeiro from1995 to 1997, and to analyze the associations between these mutations and risk factors, and tumor characteristics, including the presence of TP53 mutations, and risk of death. The molecular analysis detected TP53 alterations in 22 cases (18.3%), of which 2 cases presented 2 mutations each; a polymorphism in exon 6 was observed in 1 case. The mutations found were: 14 missense, 2 nonsense, 2 silent, 2 deletions, 1 insertion and 3 located in introns which probably did not change the protein. The analysis of risk factors in relation to TP53 mutations showed that only tobacco consumption had an association (adjusted OR = 0.24 (0.06-0.88)). Multivariate analysis showed that only tumor aggressiveness showed an OR indicative of risk (3.98, IC 95% 1.25-12.72).These results are in agreement with previous studies, which report that the presence of TP53 mutations may indicate more aggressive breast tumors biologically although this is not the only parameter to be considered.
... It has been reported that patients with mutations effecting or disrupting the zink binding domain L2 (codon 163-195) and L3 (236 -251) have worse prognosis than patients with mutations outside L2/L3 domains (Borresen, Andersen et al. 1995). Mutations affecting amino acids directly involved in DNA binding (Figure 3), many of these residing in the L2/L3 domain, were related with the worst prognosis (Berns, Foekens et al. 2000) and displayed aggressive phenotype with a short survival (Alsner, Yilmaz et al. 2000). Mutations causing loss of the native protein structure have also been associated with poor prognosis (Powell, Soong et al. 2000). ...
... Patients with locally advanced breast cancer (LABC) have poor prognosis when treated with grammed cell death in response to DNA damage in the presence of oncogenic triggers [2,45]. Intact p53 has been shown to induce apoptosis in response to ionizing radiation, whereas loss of p53 function has been reported to enhance cellular resistance to a number of chemotherapeutic agents [17,26,27]. ...
Purpose: The aim of this prospective trial was to eval- uate the feasibility and outcome of breast conservation therapy for patients with locally advanced breast cancer af- ter neoadjuvant chemotherapy. We studied also the value of p53 and MDR1 as predictors to neoadjuvant chemother- apy. Results: The overall response (CR+PR) was 87.9%, with a clinical complete response rate of 29.3%. Six pa- tients had a pathological complete response and 10 pa- tients had only minimal residual disease. Median follow- up from the start of chemotherapy was 24 months (range 6 to 40). Twenty two patients (43%) underwent BCS with actuarial 3-year disease-free and overall survival of 58% and 75% respectively. Cosmetic results were good to ex- cellent in 77.2% of the patients. Modified radical mastec- tomy was done in 29/51 (56.9%) patients with actuarial 3- year disease-free and overall survival of 60% and 78% re- spectively. In 13 out of 58 patients (22.4%), p53 mutations could be identified, including eight point mutations, three
... The second mutation that was observed in this research is GAT→AAT transition at codon 184, which put Asn instead of Asp in the protein chain. Such mutation has been identified in breast (35) and colorectal (8) and recently in liver (36) cancers. There is a report of an association between smoking and such mutation in lung cancer (37). ...
P53 is an important tumor suppressor, which is mutated in later stages of many cancers and leads to resistance to chemotherapy. The aim of this study was to reveal mutations of TP53 in colorectal cancer in Kerman province.
A total of Forty-three colon cancer specimens as paraffin block or fresh tissues, which passed stage IIIA, were selected. Three exons 5, 7 and 8 of P53 were amplified by PCR technique and sequenced directly.
The results showed two deletions at codon 140 and 142 in one tumor sample. GAT→AAT mutation at codon 184, and CGG→TGG mutation at codon 248 were seen in some tumor samples. Some mutations were also observed in middle of intron 7 in some tumor or normal tissues.
Some of those patients with mutation in P53 gene had metastasis in other organs. Therefore, genetic test before chemotherapy is helpful for successful treatment.
... The tumor suppressor gene, p53, is located on short arm of chromosome 17. Mutations in the tumor suppressor gene p53 are present in 18%-25% of primary breast carcinomas [12]. Preclinical data have shown that cells with mutated p53 might be resistant to radiation or chemotherapeutics [13]. ...
Introduction. Biological markers as Her2/neu, p53, and hormonal receptors (HmRs) may be reliable parameters for prognostic assessment of patients of locally advanced breast cancer (LABC). This work aims at assessing the potential value of these biological markers for the prediction of disease outcome after neoadjuvant taxane-based chemotherapy and its implication on the surgical role. Patients and Methods. From March 2006 to September 2011, 95 patients with LABC were treated by neoadjuvant taxane-based chemotherapy given at intervals of 3 weeks. Expression of Her2/neu and p53 was examined in the initial tissue biopsy by using ELISA technique. Status of HmRs was determined using a commercial enzyme immunoassay. Three weeks after the third cycle, patients underwent surgical resection followed by 3 more cycles of taxane-based chemotherapy and radiotherapy as an adjuvant therapy. Relations of Her2/neu overexpression to p53, HmRs, and conventional prognostic factors were analyzed. Results. Median followup was 61 months. The 5-year DFS and OAS rates were significantly higher in patients with positive HmRs than in those with negative HmRs, patients with Her2- than those with Her2+ breast cancer, and patients with intact p53 breast cancer than those with inactive p53. HER-2 overexpression was statistically significant associated with loss of HmR positive immunostaining (P < 0.0001), grade III breast cancer (P < 0.0001), advanced nodal status (P = 0.0039), and younger (<50 years) age (P = 0.0108). Conclusion. Her2/neu overexpression was associated with poor DFS and OAS rates, as it was significantly associated with negative HmR and high grade.
Purpose: Somatic driver mutations in TP53 are associated with triple negative breast cancer (TNBC) and poorer outcomes. Breast cancers in women of African ancestry (AA) are more likely to be TNBC and have somatic TP53 mutations than cancers in non-Hispanic White (NHW) women. Missense driver mutations in TP53 have varied functional impact including loss-of-function (LOF) or gain-of-function (GOF) activity, and dominant negative (DNE) effects. We aimed to determine if there were differences in somatic TP53 mutation types by patient ancestry or TNBC status.
Methods: We identified breast cancer datasets with somatic TP53 mutation data, ancestry, age, and hormone receptor status. Mutations were classified for functional impact using published data and type of mutation. We assessed differences using Fisher’s exact test.
Results: From 96 breast cancer studies, we identified 2964 women with somatic TP53 mutations: 715 (24.1%) Asian, 258 (8.7%) AA, 1931 (65.2%) NHW, and 60 (2%) Latina. The distribution of TP53 mutation type was similar by ancestry. However, 35.8% of tumors from NHW individuals had GOF mutations compared to 29% from AA individuals (p=0.04). Mutations with DNE activity were positively associated with TNBC (OR=1.37, p=0.03) and estrogen receptor (ER) negative status (OR=1.38; p=0.005).
Conclusions: Somatic TP53 mutation types did not differ by ancestry overall, but GOF mutations were more common in NHW women than AA women. ER negative and TNBC tumors are less likely to have DNE+ TP53 mutations which could reflect biological processes. Larger cohorts and functional studies are needed to further elucidate these findings.
Previous studies have shown that reactive oxygen species (ROS) such as superoxide or hydrogen peroxide generated at low levels can exert a tumor-promoting role via a redox-signaling mechanism. Reports also suggest that both tumorigenesis and tumor growth are associated with enhanced ROS formation. However, whether ROS levels or ROS-derived oxidative marker levels increase during tumor growth remains unknown. In this study, in vivo bioluminescence imaging with a boronate-based pro-luciferin probe was used to assess ROS formation. Additionally, probe-free cryogenic electron paramagnetic resonance was used to quantify a characteristic aconitase [3Fe4S]+ center that arises in the tumor tissue of mouse xenografts from the reaction of the native [4Fe4S]2+ cluster with superoxide. Results indicated that tumor growth is accompanied by increased ROS formation, and revealed differences in oxidant formation in the inner and outer sections of tumor tissue, respectively, demonstrating redox heterogeneity. Studies using luciferin and pro-luciferin probes enabled the assessment of tumor size, ROS formation, and bioenergetic status (e.g., ATP) in luciferase-transfected mice tumor xenografts. Probe-free ex vivo low-temperature electron paramagnetic resonance can also be translated to clinical studies.
Breast cancer is a highly frequent oncological disease diagnosed mainly in female population with lethal end in majority of cases. The sporadic form of breast cancer develops due to a broad scale of non-genetic risk factors. Familial form of breast cancer represents 5-10% of all cases of breast cancer. In contrast with sporadic forms, the risk factors in familial forms of breast cancer are defined as disruptions of particular genes. BRCA1/2 genes rank among those that highly affect the onset of breast cancer. The genes with low effect on the onset of familial form of breast cancer are referred to as genes with low penetrance. The products of these genes are the proteins directly cooperating with BRCA1/2 proteins in the processes that are of great importance in the appropriate course of the cell cycle and DNA repair. The participation of low penetrance genes in these processes is of particular significance in the onset of familial form of breast cancer.
In this article, the controversial issue of breast-conserving therapy (lumpectomy followed by whole breast irradiation) is reviewed. Given the relatively recent identification of the BRCA1 and BRCA2 genes in the mid-1990s, the expense associated with testing, and the inherent selection biases, the available literature has inherent limitations with relatively small patient numbers and lack of prospective randomized trials in this subset of patients. However, a number of retrospective and case–control studies have demonstrated acceptable results with breast-conserving surgery and radiation, though without active prophylactic measures to reduce secondary malignancies late local in-breast relapses and contralateral secondary breast cancer events remain an issue. Acknowledging the limitations in the available data, there does not appear to be any evidence of compromised normal tissue reactions or compromised long-term survival rates in women electing breastconserving surgery and radiation.
The tumor suppressor gene TP53 (OMIM #191117) is one of the most frequently altered genes in human cancers. Somatic gene mutations are the preferred mode of inactivation in many cancer types. These mutations have been shown, in various experimental models, to promote cell proliferation and resistance to anti-neoplastic effects of radio- and chemotherapeutic agents. It was thus expected that TP53 mutations may be useful prognostic and predictive markers in cancer. While a prognostic marker provides information on the risk of relapse and death independently of treatment, a predictive marker provides information on the potential benefit of a specific treatment. Many studies have investigated, in various clinical settings, the prognostic and predictive value of TP53 mutation status in cancer patients. Despite many studies showing a poor prognosis associated with TP53-mutated status, no consensus results have been produced that could support clinical applications. Here, we review these studies, in particular those performed in the context of specific treatment regimen.
Objective
The aim of this study was to explore the relationship between p53 gene and triple-negative breast cancer (TNBC), and determine that whether p53 gene could be a new effective therapeutic target.
Methods
We identified studies with quantitative data on the relation of p53 gene and TNBC through searching 12 databases online (Oct. 1999–Oct. 2012) and reviewing the references, which were written in English or Chinese. Summary estimates of odds ratio (OR) was calculated using the fixed-effects model or the random-effects model as appropriate.
Results
We identified 12 eligible studies with 1532 cases of TNBC patients and 6329 controls of non-TNBC patients. The test for homogeneity resulted in χ2 = 200.16 (P < 0.05), it showed significant heterogeneity so that a random effect model was applied. Our results showed that the expression of p53 gene could be much stronger in TNBC group than that in non-TNBC group [OR = 2.10, 95% confidence interval (CI) = 1.21–3.65]. In ethnicity-subgroup analysis, we found that in Caucasian group, the expression of p53 gene were stronger in TNBC group (OR = 2.60, 95% CI = 1.21–5.57), but there was no statistical significance in Asian group (OR = 1.69, 95% CI = 0.83–3.45).
Conclusion
P53 gene could be an effective predictor and a good therapeutic target for TNBC patients in the future, especially in Caucasian. Further researches focusing on p53 gene would gain a breakthrough in the treatment of TNBC.
Finding reliable molecular markers for early diagnosis, prognosis and prediction of response to treatment is a major challenge
for cancer management. A marker of prognosis provides information on the risk of relapse and death independently of treatment,
whereas a predicitve marker provides information on the potential benefit of a specific treatment (Lonning, 2003). An early
diagnostic marker helps to identify lesions at high risk of malignant transformation. Clinical stage, tumor size and morphological
grade are the most reliable factors of prognosis. Among numerous molecular markers that have been tested most recently, only
a few are used in clinical practice. In breast cancer for example, estrogen and progesterone receptors are used routinely
as predictive markers for tumor response to anti-hormone therapy. However, about 30 % of patients with positive receptor status
(expected to benefit from anti-hormone treatment) will face a therapeutic failure, showing the limitations of these markers.
Breast cancer is the most prevalent disease and cause of death among women in Northern Europe and the USA. The incidence rate
is still increasing, and despite early diagnosis and improved treatment, the mortality is still high. Breast cancer is a very
heterogeneous disease and less than 10% of the diagnosed cases are believed to be caused by an inherited factor. The information
on tumor specific genomic alterations has dramatically increased during the past decade, and seen in relation to the effect
on survival and treatment efficiency, these genomic changes may prove to act as prognostic and predictive factors. The introduction
of methods to screen the entire genome for alterations has led to important knowledge of tumor biology, progression and targets
of therapy. This chapter describes the different kinds of genomic alterations found in the tumor, the methods to assess them
and examples of correlations between the changes and prognostic or predictive parameters
A search of the Cancer Family Registry of the National Cancer Institute revealed 24 kindreds with the syndrome of sarcoma, breast carcinoma, and other neoplasms in young patients. Cancer developed in an autosomal dominant pattern in 151 blood relatives, 119 (79%) of whom were affected before 45 years of age. These young patients had a total of 50 bone and soft tissue sarcomas of diverse histological subtypes and 28 breast cancers. Additional features of the syndrome included an excess of brain tumors (14 cases), leukemia (9 cases), and adrenocortical carcinoma (4 cases) before age 45 years. These neoplasms also accounted for 73% of the multiple primary cancers occurring in 15 family members. Six of these patients had second cancers linked to radiotherapy. The diversity of tumor types in this syndrome suggests pathogenetic mechanisms which differ from hereditary cancers arising in single organs or tissues. The syndrome is presently diagnosed on clinical grounds; laboratory markers are needed to identify high-risk individuals and families and to provide insights into susceptibility mechanisms that may be shared by a wide variety of cancers.
The three-dimensional structure of the oligomerization domain (residues 319 to 360) of the tumor suppressor p53 has been solved by multidimensional heteronuclear magnetic resonance (NMR) spectroscopy. The domain forms a 20-kilodalton symmetric tetramer with a topology made up from a dimer of dimers. The two primary dimers each comprise two antiparallel helices linked by an antiparallel beta sheet. One beta strand and one helix are contributed from each monomer. The interface between the two dimers forming the tetramer is mediated solely by helix-helix contacts. The overall result is a symmetric, four-helix bundle with adjacent helices oriented antiparallel to each other and with the two antiparallel beta sheets located on opposing faces of the molecule. The tetramer is stabilized not only by hydrophobic interactions within the protein core but also by a number of electrostatic interactions. The implications of the structure of the tetramer for the biological function of p53 are discussed.
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.
The status of p53 was investigated in breast tumours arising in germ-line carriers of mutant alleles of BRCA1 and BRCA2 and in a control series of sporadic breast tumours. p53 expression was detected in 20/26 (77%) BRCA1-, 10/22 (45%) BRCA2-associated and 25/72 (35%) grade-matched sporadic tumours. Analysis of p53 sequence revealed that the gene was mutant in 33/50 (66%) BRCA-associated tumours, whereas 7/20 (35%) sporadic grade-matched tumours contained p53 mutation (P<0.05). A number of the mutations detected in the BRCA-associated tumours have not been previously described in human cancer databases, whilst others occur extremely rarely. Analysis of additional genes, p16INK4, Ki-ras and beta-globin revealed absence or very low incidence of mutations, suggesting that the higher frequency of p53 mutation in the BRCA-associated tumours does not reflect a generalized increase in susceptibility to the acquisition of somatic mutation. Furthermore, absence of frameshift mutations in the polypurine tracts present in the coding sequence of the TGF beta type II receptor (TGF beta IIR) and Bax implies that loss of function of BRCA1 or BRCA2 does not confer a mutator phenotype such as that found in tumours with microsatellite instability (MSI). p21Waf1 was expressed in BRCA-associated tumours regardless of p53 status and, furthermore, some tumours expressing wild-type p53 did not express detectable p21Waf1. These data do not support, therefore, the simple model based on studies of BRCA-/- embryos, in which mutation of p53 in BRCA-associated tumours results in loss of p21Waf1 expression and deregulated proliferation. Rather, they imply that proliferation of such tumours will be subject to multiple mechanisms of growth regulation.
Inheritance of germ-line mutant alleles of BRCA1 and BRCA2 confers a markedly increased risk of breast cancer and we have previously reported a higher incidence of p53 mutations in these tumours than in grade matched sporadic tumours. We have now characterized these p53 mutants. The results of these studies identify a novel class of p53 mutants previously undescribed in human cancer yet with multiple occurrences in BRCA-associated tumours which retain a profile of p53-dependent activities in terms of transactivation, growth suppression and apoptosis induction which is close or equal to wild-type. However, these mutants fail to suppress transformation and exhibit gain of function transforming activity in rat embryo fibroblasts. These mutants therefore fall into a novel category of p53 mutants which dissociate transformation suppression from other wild-type functions. The rarity of these mutants in human cancer and their multiple occurrence in BRCA-associated breast tumours suggests that these novel p53 mutants are selected during malignant progression in the unique genetic background of BRCA1- and BRCA2-associated tumours.
Many studies have investigated the association between alterations in the p53 gene and clinical outcome of breast cancer, and most investigators have reported poorer overall and disease-free survival (as indicated by a relative hazard (RH) greater than one) in breast cancer cases with somatic mutations in p53. However, different studies have produced widely differing RH estimates, ranging from no risk (RH = 1) to a relative hazard of 23, and not all of these results have been statistically significant. We have therefore reviewed all the published studies that have investigated the association between somatic mutations in the p53 gene and breast cancer prognosis and used standard techniques of meta-analysis to combine the results of these studies to produce a more precise estimate of the prognostic significance of p53 mutations. Eleven studies investigated overall survival in a total of 2319 unselected cases. The RH estimates from these ranged from 1 to 23.4 with a combined RH estimate of 2.0 (confidence interval 1.7-2.5). Three studies investigated the role of p53 in node-negative patients and in these, the combined estimate of RH was 1.7 (1.2-2.3). For three studies of node-positive breast cancer the combined risk estimate was 2.6 (1.7-3.9). The inclusion of p53 mutation screening in large breast cancer clinical trials seems warranted in the light of these results. Analysis of large numbers of cases matched for stage and therapy will allow definitive clarification of the value of p53 mutational status in prognostication, and possibly choice of therapy.
p53 gene encodes a transcription factor with tumor suppressive properties and to date, somatic mutation of this gene is the most common genetic event in human cancer. A relational database has been developed to facilitate the retrieval and analysis of these mutations at the International Agency for Research on Cancer (IARC) and it currently contains information on over 8000 individual tumors and cell lines. Many factors may influence the detection and reporting of mutations, including selection of tumor samples, study design, choice of methods, and quality control. There is also concern that several biases may affect the way data appear in the literature. Minimizing these biases is an essential methodological issue in the development of mutation databases. In this paper, we review and discuss these main sources of bias and make recommendations to authors in order to minimize bias in mutation detection and reporting.
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.
In order to establish a large panel of normal and tumour DNA from primary breast cancer patients, we looked for a source of easily accessible, good quality breast tumour DNA. Following routine hormone receptor analysis at the hospital the leftover pellets contained the nuclei from the tumour tissue. We collected 670 pellets over a period of 2 1/4 years and isolated a large amount of DNA (on average 400 μg per pellet). To control the quality of this tumour DNA, we analysed 41 pellets and matching normal DNA for loss of heterozygosity (LOH), with 11 microsatellite markers along chromosome 17. This chromosome is well described for breast cancer. LOH is a sensitive method, requiring good quality and pure tumour DNA. Contamination with normal DNA will blur the results. We found a high rate of LOH, ranging from 33 to 74%, which is in agreement with other reports, and therefore recommend this rich source of breast tumour DNA for molecular biological analysis.
The p53 protein has proven to be central in tumorigenesis by its cell cycle regulatory properties and both gene mutations and protein accumulation have been associated with poor prognosis in breast cancer. The present study was undertaken to investigate the prognostic significance of gene mutations, p53 protein accumulation and of loss of heterozygosity (LOH) at the TP53 locus in young (age < 37 years) breast cancer patients. In total, gene mutations were found in 21 of the 123 patients (17%), LOH in 20 of the 47 informative cases (43%) and protein accumulation in 47 of the 102 available cases (46%). Log rank analysis revealed no significant association between survival and TP53 mutations (in general), p53 protein accumulation or LOH. However, missense mutations localised to the zinc binding domain were significantly (P = 0.0007) associated with poorer prognosis. As indicated in this as well as other studies, p53 protein accumulation is frequently found in young breast cancer patients, but this protein overexpression appears to be of minor significance for survival. Nevertheless, the present report also suggests that specific mutations contribute substantially to tumour aggressiveness.
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.
Activating mutations of p53 promote tumor progression. The mutant protein adopts a characteristic conformation, which lacks the growth suppressor function of wild-type p53. We show that mutant p53 can drive cotranslated wild-type p53 into the mutant conformation: a similar effect in vivo would block wild-type suppressor function with dominant negative effect. The cotranslational effect of mutant p53 on wild-type conformation depends upon interaction between nascent polypeptides and oligomerization of the full-length proteins. We also show that oligomers of p53 proteins can be induced to change conformation in a cooperative manner. Cell growth stimulation induces a similar conformational change in p53, and our present results indicate that this may involve allosteric regulation.
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.
Mutations in the p53 tumor suppressor are the most frequently observed genetic alterations in human cancer. The majority of
the mutations occur in the core domain which contains the sequence-specific DNA binding activity of the p53 protein (residues
102-292), and they result in loss of DNA binding. The crystal structure of a complex containing the core domain of human p53
and a DNA binding site has been determined at 2.2 angstroms resolution and refined to a crystallographic R factor of 20.5
percent. The core domain structure consists of a beta sandwich that serves as a scaffold for two large loops and a loop-sheet-helix
motif. The two loops, which are held together in part by a tetrahedrally coordinated zinc atom, and the loop-sheet-helix motif
form the DNA binding surface of p53. Residues from the loop-sheet-helix motif interact in the major groove of the DNA, while
an arginine from one of the two large loops interacts in the minor groove. The loops and the loop-sheet-helix motif consist
of the conserved regions of the core domain and contain the majority of the p53 mutations identified in tumors. The structure
supports the hypothesis that DNA binding is critical for the biological activity of p53, and provides a framework for understanding
how mutations inactivate it.
We report that the expression of murine or human mutant p53 proteins in cells with no endogenous p53 proteins confers new or additional phenotypes upon these cells. Mutant p53 proteins expressed in cell lines lacking p53 resulted in either enhanced tumorigenic potential in nude mice ((10)3 cells) or enhanced plating efficiency in agar cell culture (human SAOS-2 cells). Also, mutant human p53 alleles, unlike the wild-type p53 protein, could also enhance the expression of a test gene regulated by the multi-drug resistance enhancer-promoter element. These data demonstrate a gain of function associated with p53 mutations in addition to the loss of function shown previously to be associated with mutations in this tumour suppressor gene.
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.
Several years ago, a comparison of the amino acid sequences of p53 proteins from a variety of species enabled us to reveal structural features of this protein, giving clues to its function. Since then, numerous studies on the biochemical, immunological and biological functions of p53 as well as on its structure (including crystallography data) have provided considerable insight into the multifunctional aspects of p53. The purpose of this review is to present the most recent data concerning the various structural features of the p53 protein with special emphasis on its flexibility, which plays a key role in regulation of its biological activity.
The author would like to thank Maureen Murphy, Stuart Lutzker, and Deborah Freedman for critical input and advice. The author regrets the lack of citations for many important observations mentioned in the text, but their omission is made necessary by restrictions in the preparation of review manuscripts. The author thanks T. Barney for her help with the manuscript.
We present a simple nonradioactive assay based on polymerase chain reaction (PCR) in combination with denaturing gradient gel electrophoresis (DGGE), which allows comprehensive mutation scanning of the entire coding sequence and splice junctions of the p53 gene in one analytical step. The key features of the present method are (1) all fragments can be amplified using one common PCR protocol; (2) all fragments can be scanned for mutations on a single "broad-range" denaturing gradient gel; and (3) all fragments were tailored by the attachment of appropriate GC clamps and otherwise manipulated to consist of only two melting domains in order to maximize resolution of mutations by DGGE. The entire procedure starting with a sample of genomic DNA can be completed within 6 hr and has the potential to detect any sequence variation, irrespective of its location in the p53 gene. The mutation detection sensitivity was demonstrated by the analysis of 26 constructed control mutations distributed over the whole of the p53 gene. We have applied the method to genetic diagnosis in 43 cases of colorectal cancer. Overall, a point mutation, microdeletion, or microinsertion was found in 26 (61%) of the tumors. In addition to missense and frameshift mutations within exons 4-8, a 20-bp insertion in exon 11 was found in one sample, illustrating the importance of comprehensive gene scanning for reliable diagnosis.
The beta-strand 326-333 is a key structural element in the formation of p53 tetramers. To investigate the contribution of its amino acid residues, an alanine scan was performed. The oligomerisation and DNA-binding properties of the mutant proteins were compared with those of wild-type proteins in vitro and analysed on the basis of the crystal structure of the p53 tetramerisation domain at 1.5 A resolution. Two categories of mutant proteins were identified. Phe328Ala, Leu330Ala and Ile332Ala mutant proteins are inactive for DNA binding and oligomerisation, while the Glu326Ala, Tyr327Ala, Thr329Ala, Gln331Ala and Arg333Ala mutant proteins have properties similar to those of wild-type proteins. These results suggest that single mutations within the p53 tetramerisation domain destabilise the structure of the whole protein, inhibiting its DNA-binding activity. Furthermore, the mutation of leucine 330 to alanine within the tetramerisation domain of the Arg175His protein abolishes the dominant negative effect of this mutant. This shows that the beta-strand 326-333 is a key structural element that mediates the dominant negative effect of p53 mutants.
Tumor suppressor genes are generally viewed as being recessive at the cellular level, so that mutation or loss of both tumor suppressor alleles is a prerequisite for tumor formation. The tumor suppressor gene, p53, is mutated in approximately 50% of human sporadic cancers and in an inherited cancer predisposition (Li-Fraumeni syndrome). We have analyzed the status of the wild-type p53 allele in tumors taken from p53-deficient heterozygous (p53+/-) mice. These mice inherit a single null p53 allele and develop tumors much earlier than those mice with two functional copies of wild-type p53. We present evidence that a high proportion of the tumors from the p53+/- mice retain an intact, functional, wild-type p53 allele. Unlike p53+/- tumors which lose their wild-type allele, the tumors which retain an intact p53 allele express p53 protein that induces apoptosis following gamma-irradiation, activates p21(WAF1/CIP1) and Mdm2 expression, represses PCNA expression (a negatively regulated target of wild-type p53), shows high levels of binding to oligonucleotides containing a wild-type p53 response element and prevents chromosomal instability as measured by comparative genomic hybridization. These results indicate that loss of both p53 alleles is not a prerequisite for tumor formation and that mere reduction in p53 levels may be sufficient to promote tumorigenesis.
p53 is altered in about 50 % of cancers. Most of the p53 mutants have lost the wild-type tumour suppressor activity but show oncogenic properties. The majority of the p53 alterations are missense mutations of residues located in its DNA binding domain (DBD). Only a few mutations concern residues in its tetramerisation domain (TD). However, the study of mutant proteins identified in tumors that do not form tetramers has shown that they have lost the wild-type activity like most of the p53 DBD mutants. Here, we show that two of such mutant proteins, Arg342Pro and Leu344Pro are not dominant negative and do not stimulate the expression of a reporter gene under the control of the multi-drug resistance gene-1 (MDR-1). This suggests that to be oncogenic, p53 mutants need to form tetramers. Accordingly, the dominant negative effect and the ability of a tetrameric mutant protein, Asp281Gly, to stimulate the MDR-1 promoter are abolished when its TD is rendered non-functional by the mutation of leucine 344 to a proline residue. These results suggest that mutations in the TD, are less selected in tumors than mutations in the DBD because they do not lead to oncogenic proteins.
The tumor suppressor p53 gene is the most frequently mutated gene in human cancer. To date, more than 10,000 mutations have been described in the literature, and these data are available in various electronic formats on the World Wide Web. Here we describe the structure and format of the different p53 datasets maintained and curated at the International Agency for Research on Cancer (IARC) in Lyon, France. These include p53 somatic mutations (more than 10,000 entries), p53 germline mutations (144 entries), and p53 polymorphisms (13 entries), with the somatic mutations organized into a relational database using AccessTM. The main features of these datasets are (1) controlled entry with standardized format and restricted vocabulary, (2) inclusion of annotations on individual characteristics and exposures, and (3) a classification of pathologies based on the International Classification of Diseases for Oncology (ICD-O). In addition, several interfaces have been developed to analyze the data in order to produce mutation spectra, codon analyses, or visualization of the mutation with the tertiary structure of the protein. All datasets and tools for analysis are available at http://www.iarc.fr/p53/homepage.
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 20 mg 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 have analyzed a panel of 14 cases of childhood adrenocortical tumors unselected for family history and have identified germline TP53 mutations in >80%, making this the highest known incidence of a germline mutation in a tumor-suppressor gene in any cancer. The spectrum of germline TP53 mutations detected is remarkably limited. Analysis of tumor tissue for loss of constitutional heterozygosity, with respect to the germline mutant allele and the occurrence of other somatic TP53 mutations, indicates complex sequences of genetic events in a number of tumors. None of the families had cancer histories that conformed to the criteria for Li-Fraumeni syndrome, but, in some families, we were able to demonstrate that the mutation had been inherited. In these families there were gene carriers unaffected in their 40s and 50s, and there were others with relatively late-onset cancers. These data provide evidence that certain TP53 alleles confer relatively low penetrance for predisposition to the development of cancer, and they imply that deleterious TP53 mutations may be more frequent in the population than has been estimated previously. Our findings have considerable implications for the clinical management of children with andrenocortical tumors and their parents, in terms of both genetic testing and the early detection and treatment of tumors.
TP53 gene-mutation and protein expression of p53 are described as being of prognostic importance for the outcome of breast cancer. The present study was therefore carried out to evaluate whether TP53 mutation would be a feasible prognostic marker in the routine diagnostic evaluation of breast cancer, and, in particular, to analyse the relationship between TP53 mutation and nodal status. Tumour material was obtained from women with sporadic early breast cancer. Gene mutations in exon 2-11 were identified using denaturing gradient gel electrophoresis (DGGE) as the initial scanning procedure and characterized by sequencing. All patients were treated according to the guidelines of the Danish Breast Cancer Cooperative Group for the DBCG 89 protocols. The results were correlated with clinico-pathological parameters and the prognosis evaluated by uni- and multivariate analysis using local control, freedom from distant metastasis, disease-free survival, and overall survival as endpoints. The study included 294 patients. TP53 mutations were found in 23% of cases. Mutations were significantly more frequent in tumours from patients who were node-positive and with tumours characterized as being ductal, large of size, with a high degree of anaplasia, and oestrogen receptor negative. Using univariate analysis, it was found that distant metastasis, disease-free, and overall survival were correlated to tumour size, nodal status, degree of anaplasia, oestrogen receptor status, and TP53 mutation. In addition, overall survival was also correlated to age and menopausal status. When analysed according to nodal status, TP53 mutation was found to have a significantly poor survival probability in each of the subgroups. A Cox proportional hazard analysis, including all 294 patients, demonstrated that positive nodal status and TP53 mutation were the only parameters that had an independent poor influence on the risk of developing distant metastasis and reduced recurrence-free survival. The same factors together with postmenopausal status were found to be significantly associated with increased risk of death. TP53 mutation is a strong marker for the prediction of overall and disease-free survival in breast cancer, irrespective of nodal status. A better understanding of the role of the p53 pathway, including analysis of different types of TP53 mutations, is required in order further to investigate the prognostic potential of this marker.
IARC p53 mutation database: a relational database to compile and analyze p53 mutations in human tumors and cell lines p53 mutation as a genetic trait of typical medullary breast carcinoma
- T Hernandez-Boussard
- P Rodriguez-Tome
- R Montesano
- P Hainaut
- P De Cremoux
- A V Salomon
- S Liva
- R Dendale
- B Bouchind 'homme
- E Martin
- X Sastre-Garau
- H Magdelenat
- A Fourquet
- T Soussi
Hernandez-Boussard, T., Rodriguez-Tome, P., Montesano, R., and
Hainaut, P. IARC p53 mutation database: a relational database to
compile and analyze p53 mutations in human tumors and cell lines.
IARC. Hum. Mutat., 14: 1– 8, 1999.
19. de Cremoux, P., Salomon, A. V., Liva, S., Dendale, R.,
Bouchind'homme, B., Martin, E., Sastre-Garau, X., Magdelenat, H.,
Fourquet, A., and Soussi, T. p53 mutation as a genetic trait of typical
medullary breast carcinoma. J. Natl. Cancer Inst., 91: 641– 643, 1999.
20. Dittmer, D., Pati, S., Zambetti, G., Chu, S., Teresky, A. K., Moore,
M., Finlay, C., and Levine, A. J. Gain of function mutations in p53. Nat.
Genet., 4: 42– 46, 1993.
Determination and use of p53 in the management of cancer patients with special focus on breast cancer: a review
- J Bergh
Bergh, J. Determination and use of p53 in the management of
cancer patients with special focus on breast cancer: a review. In: J. G.
Genetic risk and breast cancer survival: another link in the chain of evidence Are there low-penetrance TP53 alleles? Evidence from childhood adrenocortical tumors
- W Burke
- M B Laya
- J M Varley
- G Mcgown
- M Thorncroft
- L A James
- G P Margison
- G Forster
- D G Evans
- M Harris
- A M Kelsey
- J M Birch
Burke, W., and Laya, M. B. Genetic risk and breast cancer survival:
another link in the chain of evidence. J. Natl. Cancer Inst., 91: 201–203,
1999.
26. Varley, J. M., McGown, G., Thorncroft, M., James, L. A., Margison, G. P., Forster, G., Evans, D. G., Harris, M., Kelsey, A. M., and
Birch, J. M. Are there low-penetrance TP53 alleles? Evidence from
childhood adrenocortical tumors. Am. J. Hum. Genet., 65: 995–1006,
1999.