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LOH and CNV patterns of A, blood; B, normal colon tissue; and C, tumor from 15 pMMR patients ordered by gender and tumor TNM stages. Chromosome regions with CL-LOH (blue), CN-LOH (grey), CG-LOH (red), Copy Gain (black), and Homozygous Deletion (cyan) are shown. Green dots on the left and right sides mark the centromere location
Source publication
Chromosome instability (CIN) is widely observed in both sporadic and hereditary colorectal cancer (CRC). Defects in APC and WNT signaling are primarily associated with CIN in hereditary CRC, but the genetic causes for CIN in sporadic CRC remain elusive. Using high-density SNP array and exome data from The Cancer Genome Atlas, we characterized loss...
Contexts in source publication
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... colon tissue samples from the 15 patients showed large variances in the number of LOH and CNV events, compared to blood (Figure 1). This was exemplified by A6-3807 and A6-5660 which have genetic aberrations across whole autosomes, compared to AA-3529 that had only two aberrations (1 CL-LOH and 1 copy gain region). The normal colon tissue samples from A6-3807 and A6-5660 were distant normal (>2 cm away from the corresponding tumor) and had zero percentage of tumor nuclei, therefore their extensive genetic aberrations were unlikely a sign of contamination. Sorting of the patients by tumor TNM stage and gender indicated no association between the amount of genetic aberrations in normal colon tissue with either the tumor stage or sex of the CRC patients. Seventy percent of the CL-LOH and 40% of the copy gain in the normal colon tissues had concurrent genetic aberrations in their matched blood sample (Table ...
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... nine patients had at least one copy gain region (mean = 140 KB, SD = 59 KB), respectively. Over the entire 18q region, 10 patients had at least two putative short regions of copy gain ( Figure 1A and Table S1). These were considered putative since visualization of these regions indicated only slight increase in log R ratio (data not ...
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... determine whether the recurrent copy gain signals on 18q were specific to pMMR patients, we further analyzed blood samples from 24 patients with dMMR tumors using the same parameters. The result indicated that only four patients (16.7%) had two or more aberrations on 18q, which was significantly lower than pMMR patients (66.7%, P < 0.05). Visual inspection ( Figure S1) indicated that the blood sample of dMMR patients had more wide spread aberrations on chromosome 17, 19, and 22q than pMMR patients. In the pMMR cases, the amount of genetic aberration was much higher in tumor samples than that of normal colon tissue or blood. The highest frequency of LOH was observed on 18q, which had an average of 52% CL-LOH (SD = 4.4%) and 17% CN-LOH (SD = 4.6%) across the 15 patients ( Figure 1C and Table S2). Furthermore, a high frequency of copy gain was observed, in decreasing order, on 20q, 13q, 7p/q, and 8q. These arms have copy gain in more than 50% of the patients (Table ...
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... determine whether the recurrent copy gain signals on 18q were specific to pMMR patients, we further analyzed blood samples from 24 patients with dMMR tumors using the same parameters. The result indicated that only four patients (16.7%) had two or more aberrations on 18q, which was significantly lower than pMMR patients (66.7%, P < 0.05). Visual inspection ( Figure S1) indicated that the blood sample of dMMR patients had more wide spread aberrations on chromosome 17, 19, and 22q than pMMR patients. In the pMMR cases, the amount of genetic aberration was much higher in tumor samples than that of normal colon tissue or blood. The highest frequency of LOH was observed on 18q, which had an average of 52% CL-LOH (SD = 4.4%) and 17% CN-LOH (SD = 4.6%) across the 15 patients ( Figure 1C and Table S2). Furthermore, a high frequency of copy gain was observed, in decreasing order, on 20q, 13q, 7p/q, and 8q. These arms have copy gain in more than 50% of the patients (Table ...
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... normal colon tissue, the aberration peaked at 18q22 (61.6-73.1 MB), where seven patients had at least one CN-LOH (mean = 91KB, SD = 71KB) detected. Over the span of the entire 18q arm, 10 patients had at least one CN-LOH, and three patients had at least one copy gain in their normal colon samples ( Figure 1B and Table S1). The enrichment was retained under relatively stringent criteria, which showed that five patients had at least two CN-LOH, and two patients had at least two copy gain regions (Table S1). This was still higher than the frequency of genetic aberration observed on other ...
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... displayed complete copy loss on 1p and complete copy gain on 1q ( Figure 1C). Homozygous deletion was relatively rare and was observed only on 8p of A6-5660 ( Figures 1C and ...
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... displayed complete copy loss on 1p and complete copy gain on 1q ( Figure 1C). Homozygous deletion was relatively rare and was observed only on 8p of A6-5660 ( Figures 1C and ...
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... contrast to what was observed in normal colon tissue and blood, which had relatively short regions with genetic aberrations, most of the LRR and BAF of blood, normal colon tissue, and tumor featured interspersed LOH and copy gain on 10p ( Figures 1C and ...
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... colon tissue samples from the 15 patients showed large variances in the number of LOH and CNV events, compared to blood (Figure 1). This was exemplified by A6-3807 and A6-5660 which have genetic aberrations across whole autosomes, compared to AA-3529 that had only two aberrations (1 CL-LOH and 1 copy gain region). The normal colon tissue samples from A6-3807 and A6-5660 were distant normal (>2 cm away from the corresponding tumor) and had zero percentage of tumor nuclei, therefore their extensive genetic aberrations were unlikely a sign of contamination. Sorting of the patients by tumor TNM stage and gender indicated no association between the amount of genetic aberrations in normal colon tissue with either the tumor stage or sex of the CRC patients. Seventy percent of the CL-LOH and 40% of the copy gain in the normal colon tissues had concurrent genetic aberrations in their matched blood sample (Table ...
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... nine patients had at least one copy gain region (mean = 140 KB, SD = 59 KB), respectively. Over the entire 18q region, 10 patients had at least two putative short regions of copy gain ( Figure 1A and Table S1). These were considered putative since visualization of these regions indicated only slight increase in log R ratio (data not ...
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... determine whether the recurrent copy gain signals on 18q were specific to pMMR patients, we further analyzed blood samples from 24 patients with dMMR tumors using the same parameters. The result indicated that only four patients (16.7%) had two or more aberrations on 18q, which was significantly lower than pMMR patients (66.7%, P < 0.05). Visual inspection ( Figure S1) indicated that the blood sample of dMMR patients had more wide spread aberrations on chromosome 17, 19, and 22q than pMMR patients. In the pMMR cases, the amount of genetic aberration was much higher in tumor samples than that of normal colon tissue or blood. The highest frequency of LOH was observed on 18q, which had an average of 52% CL-LOH (SD = 4.4%) and 17% CN-LOH (SD = 4.6%) across the 15 patients ( Figure 1C and Table S2). Furthermore, a high frequency of copy gain was observed, in decreasing order, on 20q, 13q, 7p/q, and 8q. These arms have copy gain in more than 50% of the patients (Table ...
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... determine whether the recurrent copy gain signals on 18q were specific to pMMR patients, we further analyzed blood samples from 24 patients with dMMR tumors using the same parameters. The result indicated that only four patients (16.7%) had two or more aberrations on 18q, which was significantly lower than pMMR patients (66.7%, P < 0.05). Visual inspection ( Figure S1) indicated that the blood sample of dMMR patients had more wide spread aberrations on chromosome 17, 19, and 22q than pMMR patients. In the pMMR cases, the amount of genetic aberration was much higher in tumor samples than that of normal colon tissue or blood. The highest frequency of LOH was observed on 18q, which had an average of 52% CL-LOH (SD = 4.4%) and 17% CN-LOH (SD = 4.6%) across the 15 patients ( Figure 1C and Table S2). Furthermore, a high frequency of copy gain was observed, in decreasing order, on 20q, 13q, 7p/q, and 8q. These arms have copy gain in more than 50% of the patients (Table ...
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... normal colon tissue, the aberration peaked at 18q22 (61.6-73.1 MB), where seven patients had at least one CN-LOH (mean = 91KB, SD = 71KB) detected. Over the span of the entire 18q arm, 10 patients had at least one CN-LOH, and three patients had at least one copy gain in their normal colon samples ( Figure 1B and Table S1). The enrichment was retained under relatively stringent criteria, which showed that five patients had at least two CN-LOH, and two patients had at least two copy gain regions (Table S1). This was still higher than the frequency of genetic aberration observed on other ...
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... displayed complete copy loss on 1p and complete copy gain on 1q ( Figure 1C). Homozygous deletion was relatively rare and was observed only on 8p of A6-5660 ( Figures 1C and ...
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... displayed complete copy loss on 1p and complete copy gain on 1q ( Figure 1C). Homozygous deletion was relatively rare and was observed only on 8p of A6-5660 ( Figures 1C and ...
Citations
... These results are also consistent with the data showing that a deficiency in the BMP signaling pathway may be strongly involved in sporadic CRC development. Thus, loss of the BMP5 ligand was observed at early stages in the development of sporadic CRC [32], whereas Smad4 mutation was detected at a more advanced stage [33]. Interestingly, inhibition of the BMP pathway combined with simultaneous production of PGE 2 led to the development of gastric tumors in mice, demonstrating the importance of both pathways in gastrointestinal tumorigenesis [34]. ...
Introduction
Recent studies have shown that epithelial-stromal interactions could play a role in the development of colorectal cancer. Here, we investigated the role of fibroblasts in the transformation of normal colonocytes induced by 4-HNE.
Methods
Normal Co colonocytes and nF fibroblasts from the same mouse colon were exposed, in monoculture (m) or coculture (c), to 4-HNE (5 μM) twice weekly for 3 weeks. Gene expression was then analysed and the ability of Co colonocytes to grow in anchorage-independent conditions was tested in soft agar. Fibroblasts previously treated or not with 4-HNE were also seeded in culture inserts positioned above the agar layers to allow paracrine exchanges with colonocytes.
Results
First, 60% of the genes studied were modulated by coculture in Co colonocytes, with notably increased expression of BMP receptors. Furthermore, while 4-HNE increased the ability of monoculture-treated Co colonocytes to form colonies, this effect was not observed in coculture-treated Co colonocytes. Adding a selective BMPR1 inhibitor during the treatment phase abolished the protective effect of coculture. Conversely, addition of a BMP4 agonist to the medium of monoculture-treated Co colonocytes prevented phenotypic transformation by 4-HNE. Second, the presence of nF(m)-HNE fibroblasts during the soft agar assay increased the number and size of Co(m) colonocyte colonies, regardless of whether these cells had been previously treated with 4-HNE in monoculture. For soft agar assays performed with nF(c) and Co(c) cells initially treated in coculture, only the reassociation between Co(c)-HNE and nF(c)-HNE resulted in a small increase in the number of colonies.
Conclusions
During the exposure phase, the epithelial-mesenchymal interaction protected colonocytes from 4-HNE-induced phenotypic transformation via activation of the BMP pathway. This intercellular dialogue also limited the ability of fibroblasts to subsequently promote colonocyte-anchorage-independent growth. In contrast, fibroblasts pre-exposed to 4-HNE in monoculture strongly increased the ability of Co(m) colonocytes to form colonies.
... The human reference cell types we included in each analysis encompassed the entire spectrum of human tissue development: human pre-gastrulation epiblast and hypoblast cells [7]; cells representing the three germ layers, endoderm, mesoderm, and ectoderm in their earliest stages [8]; and tissue-specific foetal [9] and adult cells [10] (Additional file 1: Table S1). We applied this combined reference to a wide spectrum of childhood and adult solid tissue cancers [11][12][13][14][15][16] (Additional file 1: Table S2). We then extended these results using high-resolution atlases of specific tissues together with single-cell cancer transcriptomes for two types of adult epithelial cancers. ...
... We next applied our analytical approach to bulk and single-cell transcriptomes of colorectal cancers (n = 65,362 cells from 23 patients), as well as to adenomas (polyps) [14,16]. Adenomas are low-grade neoplastic lesions of colorectal epithelium that have the potential to progress to carcinomas, via the sequential acquisition of cancer-causing somatic mutations (adenoma-carcinoma sequence). ...
... Each rectangle represents a group of cells (indicated by the label on the y-axis) and shows the distribution of similarity scores for those single cells compared to the reference cell population (indicated by x-axis label)Kildisiute et al. Genome Medicine (2024) 16:See legend on previous page.) ...
Background
As normal cells transform into cancers, their cell state changes, which may drive cancer cells into a stem-like or more primordial, foetal, or embryonic cell state. The transcriptomic profile of this final state may encode information about cancer’s origin and how cancers relate to their normal cell counterparts.
Methods
Here, we used single-cell atlases to study cancer transformation in transcriptional terms. We utilised bulk transcriptomes across a wide spectrum of adult and childhood cancers, using a previously established method to interrogate their relationship to normal cell states. We extend and validate these findings using single-cell cancer transcriptomes and organ-specific atlases of colorectal and liver cancer.
Results
Our bulk transcriptomic data reveals that adult cancers rarely return to an embryonic state, but that a foetal state is a near-universal feature of childhood cancers. This finding was confirmed with single-cell cancer transcriptomes.
Conclusions
Our findings provide a nuanced picture of transformation in human cancer, indicating cancer-specific rather than universal patterns of transformation pervade adult epithelial cancers.
... Lung cancer remains one of the tumors with the highest morbidity and mortality in the world [2]. Chromosomal instability (CIN) can lead to tumor heterogeneity, leading to different responses to treatments among different individuals, resulting in unsatisfactory treatment effects and the inability to customize speci c individualized treatment plans for patients [19]. Centrosome ampli cation is one of the leading causes of CIN [20], excessive centrosomes lead to the nucleation of excessive microtubules, destroying tissue polarity and cellular structure, thus leading to genomic instability [21]. ...
Background
The structure or function of the centrosome can cause abnormal cell proliferation, leading to tumors. There is increasing evidence that the centrosome is closely associated with the occurrence and development of lung adenocarcinoma (LUAD). We aim to construct a new centrosome-related genes (CRGs) prognostic model in this study.
Methods
The gene expression data of LUAD can be downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. We used the R to identify differentially expressed genes between normal and malignant lung tissues, constructed a CRGs risk score, evaluated the prognostic value of clinical data in different subgroups with different CRGs risk score signature to construct a CRGs risk model.
Result
A total of 779 CRGs were detected, and three genes related to prognosis were screened, including ID1, LATS2 and PRKCZ, and CRGs. Risk score was constructed based on these three genes, and its accuracy was verified in the GEO dataset. The prognosis is significantly lower in the high-risk group, and this feature can be used as an independent prognostic factor. In addition, the immune and mutation landscape between the different subgroups were found to be significantly different. We found that the Tumor Immune Dysfunction and Exclusion (TIDE) score of the high-risk group was significantly increased, indicating that the low-risk group is more likely to benefit from immunotherapy.
Conclusion
The research results suggest that the CRGs risk model may be a reliable prognostic model for personalized treatment of LUAD patients.
... The human reference cell types we included in each analysis encompassed the entire spectrum of human tissue development: human pre-gastrulation epiblast and hypoblast cells 7 ; cells representing the three germ layers, endoderm, mesoderm and ectoderm in their earliest stages 8 ; and tissue-specific fetal 9 and adult cells 10 (Table S1). We applied this combined reference to a wide spectrum of childhood and adult solid tissue cancers [11][12][13][14][15][16] (Table S2). We then extended these results using high resolution atlases of specific tissues together with single cell cancer transcriptomes for two types of adult epithelial cancers. ...
... We next applied our analytical approach to bulk and single cell transcriptomes of colorectal cancers, as well as to adenomas (polyps) 14,16 . Adenomas are low grade neoplastic lesions of colorectal epithelium that have the potential to progress to carcinomas, via the sequential acquisition of cancer-causing somatic mutations (adenoma-carcinoma sequence). ...
As normal cells transform into cancers, their cell state changes (or "dedifferentiates"), which may drive cancer cells into a stem-like or more primordial, foetal or embryonic cell state. Here, we used single cell atlases to study dedifferentiation in transcriptional terms across a wide spectrum of adult and childhood cancers. At the level of the whole transcriptome, we find that adult cancers rarely return to an embryonic state, but rather that a foetal state is a near-universal feature of childhood cancers. We extend these bulk transcriptomic findings to a single cell resolution analysis of colorectal and liver cancers, confirming the lack of reversion to a primordial state in adult tumours and the retention of foetal signals in childhood cancers. Our findings provide a nuanced picture of dedifferentiation in these two groups of neoplasms, indicating cancer-specific rather than universal patterns of dedifferentiation pervade adult epithelial cancers.
... Sideris (17) et al. showed that KRAS mutation status may affect the prognosis of ECRC, as this is linked to distant recurrence. However, it is confusing that the relationship of KRAS with staging of CRC is not exactly the same (18). KRAS mutation occurs mostly at the Nterminal codons 12, 13, and 61, and the codon 12 mutation is the most common (19). ...
Background
Early colorectal cancer (ECRC) refers to any size of colorectal cancer (CRC) whose depth of invasion is limited to the mucosa and submucosa. About 10% of patients with ECRC die from cancer after surgery. KRAS, NRAS, and BRAF mutations and microsatellite instability (MSI) are considered diagnostic and prognostic markers in CRC. However, their characteristics in ECRC and whether postoperative chemotherapy based on them will benefit ECRC patients or not remain unknown.
Patients and Methods
Patients with ECRC and 298 patients with advanced colorectal cancer (ACRC) were collected in our hospital from January 2013 to December 2015. The Amplification Refractory Mutation System (ARMS)-PCR was used to perform the KRAS, NRAS, and BRAF mutant tests.
Results
In ECRC patients, 43 cases of KRAS mutation were found, accounting for 69.35%. Interestingly, among KRAS mutations, there were 10 KRAS multi-site mutation patients (16.13% in 62 ECRC patients). Moreover, the NRAS mutation rate was 3.23% but no BRAF mutation was found and only 1 case of MSI-High was detected. KRAS mutation was only related to the depth of tumor invasion whereas KRAS multi-site mutations were related to mucus components and tumor size. As far as NRAS is concerned, mutations were associated with elevated CEA, mucus components, and the depth of tumor invasion. Notably, compared with 2.35% KRAS multi-site mutation in ACRC, the rate of KRAS multi-site mutation in ECRC was much higher. Furthermore, Cox regression analysis revealed that KRAS mutation could be an independent prognostic factor of ECRC in patients who have undergone endoscopic resection or surgery.
Conclusion
Patients with ECRC might benefit from KRAS mutation testing but not from postoperative chemotherapy.
... Some tumors have LOH at many loci in various chromosomes, whereas others have less frequent LOH [14]. A few studies have indicated that different LOH mutation frequencies of loci might be related to the biological behavior of CRC [14,15]. However, this conclusion is still under debate. ...
Background
Microsatellite instability (MSI) is a biomarker for better outcomes in colorectal cancer (CRC). However, this conclusion is controversial. In addition, MSs can be a useful marker for loss of heterozygosity (LOH) of genes, but this finding has not been well studied. Here, we aimed to clarify the predictive value of MSI/LOH within tumor-related genes in CRC.
Methods
We detected MSI/LOH of MSs in tumor-related genes and the Bethesda (B5) panel by STR scanning and cloning/sequencing. We further analyzed the relationship between MSI/LOH status and clinical features or outcomes by Pearson’s Chi-square test, Fisher’s exact test and the Kaplan–Meier method.
Results
The findings indicated that the MSI rates of B5 loci were all higher than those of loci in tumor-related genes. Interestingly, MSI/LOH of 2 loci in the B5 panel and 12 loci in tumor-related genes were associated with poorer outcomes, while MSI/LOH of the B5 panel failed to predict outcomes in CRC. MSI of BAT25, MSI/LOH of BAT26 and MSI of the B5 panel showed closer relationships with mucinous carcinoma. In addition, LOH-H of the B5 panel was associated with increased lymphatic metastasis.
Conclusions
In summary, MSI/LOH of certain loci or the whole panel of B5 is related to clinical features, and several loci within tumor-related genes showed prognostic value in the outcomes of CRC.
... Cancer is a disease caused by the gradual accumulation of genomic variation, primarily by single-nucleotide variations (SNVs) and somatic copy number alterations (SCNAs) 4,5 . Comprehensive analysis of genetic and clinical studies shows that some genes driving SNV or SCNA may be potential biomarkers 6 that play an important role in tumor occurrence and development. ...
Stomach adenocarcinoma (STAD) is a highly heterogeneous disease. Due to the lack of effective molecular markers and personalized treatment, the prognosis of gastric cancer patients is still very poor. The ABSOLUTE algorithm and cancer cell fraction were used to evaluate the clonal and subclonal status of 349 TCGA (The Cancer Genome Cancer Atlas)-STAD patients. Non-negative matrix factorization was used to identify the mutation characteristics of the samples. Univariate Cox regression analysis was used to determine the relationship between clonal/subclonal events and prognosis, and the Spearman correlation was used to evaluate the relationship of clonal/subclonal events to tumor mutation burden (TMB) and neoantigens. The evolution pattern of STAD demonstrated great tumor heterogeneity. TP53, USH2A, and GLI3 appeared earliest in STAD and may drive STAD. CTNNB1, LRP1B, and ERBB4 appeared the latest in STAD, and may be related to STAD's progress. Univariate Cox regression analysis identified four early genes, eight intermediate genes, and seven late genes significantly associated with overall survival. The number of subclonal events in the T stage was significantly different. The N stage, gender, and histological type were significantly different for clonal events, and there was a significant correlation between clonal/subclonal events and TMB/neoantigens. Our results highlight the importance of systematic evaluation of evolutionary models in the clinical management of STAD and personalized gastric cancer treatment.
... Genetic changes in the CDH2 gene have not been studied as extensively in tumors as those of the CDH1 gene. However, studies of chromosomal instability in various tumors, such as colorectal, bladder cancer, or head and neck squamous cell carcinoma have shown deletions of chromosome 18q that contains the N-cadherin gene [37][38][39][40]. The LOH of chromosome 18q has been shown to be involved in tumors with aggressive behavior and reduced survival rates [41]. ...
Simple Summary
Intracranial meningiomas are one of the most common primary brain tumors. Although mostly benign, a small portion may exhibit aggressive and malignant characteristics leading to higher recurrence and mortality rate. Detecting the molecular profiles and genes that are involved in meningioma progression can lead to better stratification of patients and more efficient and targeted treatments. The results of this study reveal the role of main actors of the Wnt signaling pathway (β-catenin) and epithelial to mesenchymal transition (E-cadherin, N-cadherin, TWIST1, SNAIL and SLUG) in progression of these tumors, potentially bringing novel biomarkers in diagnostics and molecular targets for therapeutic interventions.
Abstract
Epithelial to mesenchymal transition (EMT), which is characterized by the reduced expression of E-cadherin and increased expression of N-cadherin, plays an important role in the tumor invasion and metastasis. Classical Wnt signaling pathway has a tight link with EMT and it has been shown that nuclear translocation of β-catenin can induce EMT. This research has showed that genes that are involved in cadherin switch, CDH1 and CDH2, play a role in meningioma progression. Increased N-cadherin expression in relation to E-cadherin was recorded. In meningioma, transcription factors SNAIL, SLUG, and TWIST1 demonstrated strong expression in relation to E- and N-cadherin. The expression of SNAIL and SLUG was significantly associated with higher grades (p = 0.001), indicating their role in meningioma progression. Higher grades also recorded an increased expression of total β-catenin followed by an increased expression of its active form (p = 0.000). This research brings the results of genetic and protein analyzes of important molecules that are involved in Wnt and EMT signaling pathways and reveals their role in intracranial meningioma. The results of this study offer guidelines and new markers of progression for future research and reveal new molecular targets of therapeutic interventions.
... A further paper by Druliner et al. [17] examined the whole genomes, transcriptomes and methylomes of cancer-associated and cancer-free polyps from 31 patients, finding significant genomic, transcriptomic and epigenetic differences in patients who had cancerassociated polyps. In a further paper [18], the group identified recurrent loss of heterozygosity in 18q that was preferentially enriched in patients with sporadic colorectal cancer. ...
Background
Clinical-grade whole-genome sequencing (cWGS) has the potential to become the standard of care within the clinic because of its breadth of coverage and lack of bias towards certain regions of the genome. Colorectal cancer presents a difficult treatment paradigm, with over 40% of patients presenting at diagnosis with metastatic disease. We hypothesised that cWGS coupled with 3′ transcriptome analysis would give new insights into colorectal cancer.
Methods
Patients underwent PCR-free whole-genome sequencing and alignment and variant calling using a standardised pipeline to output SNVs, indels, SVs and CNAs. Additional insights into the mutational signatures and tumour biology were gained by the use of 3′ RNA-seq.
Results
Fifty-four patients were studied in total. Driver analysis identified the Wnt pathway gene APC as the only consistently mutated driver in colorectal cancer. Alterations in the PI3K/mTOR pathways were seen as previously observed in CRC. Multiple private CNAs, SVs and gene fusions were unique to individual tumours. Approximately 30% of patients had a tumour mutational burden of > 10 mutations/Mb of DNA, suggesting suitability for immunotherapy.
Conclusions
Clinical whole-genome sequencing offers a potential avenue for the identification of private genomic variation that may confer sensitivity to targeted agents and offer patients new options for targeted therapies.
... Molecular pathogenesis of CRC is heterogeneous and comprise a range of genomic and epigenomic alterations. 3,4 One of the molecular subtypes (CMS4) of colorectal cancer is characterized by the changes of TGFβ pathway that play an important role in the pathogenesis of many cancers development, being engaged in the regulation of many diverse biological processes within cells of the gastrointestinal epithelium. The TGFβ pathway is responsible for the control of critical cellular processes involved in carcinogenesis, such as cell growth, proliferation, differentiation, or apoptosis. ...
Background
Colon cancer is one of the most common types of malignant tumor worldwide. The molecular mechanism of colorectal carcinogenesis is very complex and not yet fully understood. The TGFβ (transforming growth factor β) signaling pathway plays a significant role in the development of many cancers, including colorectal cancer pathogenesis. Changes in TGFβ pathway are associated with increased colorectal cancer risk, because this pathway participates in the control of important cellular processes such as cell growth, proliferation, differentiation, or apoptosis. The family of SMAD (similar to mother against decapentaplegic) proteins is closely correlated to this pathway. SMADs genes expression affects modulation of the transcription of many genes, which leads to the inhibition of cell-growth and apoptosis in colon epithelial cells. The presence of SNPs (single nucleotide polymorphisms) in SMADs genes encoding proteins involved in the control of biological processes important for the cell may play a significant role in the predisposition to the development of colorectal cancer, or in the regulation of the severity of changes related to tumor growth. Extension of data in this field may provide clinically significant conclusions influencing the implementation of personalized treatment based on specific changes characteristic of a patient with colorectal cancer.
Purpose
The subject of this research was genotyping polymorphisms of SMAD3 (rs6494629) and SMAD4 (rs10502913, rs12968012, rs1057520801) genes in the group of patients with colorectal cancer and in the control group, and comparing the genotypic frequency distributions with clinical-pathological features within the study group and between the groups.
Materials and Methods
SNP genotyping analysis was performed on genomic DNA isolated from 84 frozen tissue sections of colorectal cancer and from 60 peripheral blood samples of patients without cancer. To evaluate the polymorphic variants of SMAD genes, the restricted fragment length of a polymorphism reaction (PCR-RFLP) was used.
Results
The results obtained in the study showed no significant association between the examined polymorphisms and the risk of developing colorectal cancer.
Conclusion
More extensive studies to confirm the results obtained in this study are needed. Further studies on a larger study group divided according to the clinical stage and histological differentiation may allow finding or excluding the significance of the studied SNPs as potential markers of colorectal cancer in relation to the clinico-pathological data.
