Potential driver genes involved in the initiation of CRC
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE228012 | GEO | 2025/02/08
REPOSITORIES: GEO
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Project description:Fecal immunochemical tests (FIT) detecting hemoglobin in stool are widely used for non-invasive colorectal cancer (CRC) screening, but their sensitivity leaves room for improvement. Our aim is to identify novel protein biomarkers in stool that outperform or complement hemoglobin in detecting CRCs and advanced adenomas (AAs). Stool samples (one series of 12 CRCs and 10 controls, and a second series of 81 CRCs, 40 AAs, 43 non-advanced adenomas and 129 controls) were analyzed by mass-spectrometry and searched for human proteins. Classification and regression tree and logistic regression analyses were performed to identify protein combinations that differentiated CRCs and/or AAs from controls. Antibody-based assays for four selected proteins were performed on an independent series of FIT samples (14 CRCs, 16 AAs, 18 non-advanced adenomas and 24 controls) Results: In total, 834 human proteins were identified, of which 29 were significantly enriched in CRCs versus controls in both stool sample series. Combinations of four proteins reached sensitivities of 80% and 45% for detecting CRCs and AAs, at 95% specificity, which was higher than hemoglobin alone.
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Project description:Colorectal adenomas are benign precursor lesions of colorectal cancer (CRC) that arise from normal epithelium1. The prevalence of adenomas in the large intestine is much higher than the incidence of cancer implying that the majority of adenomas will never progress to CRC4. In clinical practice, adenomas detected during colonoscopy are completely removed, and consequently the natural history of disease disrupted. Based on the prevalence of focal cancer in endoscopically removed adenomas, it is estimated that only 5% of adenomas will eventually progress to CRC. The aim of the present study was to characterize adenomas at low and high risk of progressing to cancer by extensive molecular profiling at DNA, RNA, and protein level, allowing to examine the biological processes in which they differ and to discover putative drivers of early colorectal tumor development.
2019-08-22 | PXD012254 | Pride
Project description:RNA sequencing of CRC tumor organoids engineered with key driver mutations
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Project description:Genetic and epigenetic alterations are a fundamental aspect of colorectal cancer formation. There is considerable heterogeneity between colorectal cancers regarding the mutations and methylated genes they carry, and this heterogeneity may arise early in the polyp-cancer sequence. However, our understanding of the epigenetic alterations and gene mutations in colon adenomas and their relation to colorectal cancer is incomplete. Thus, we have assessed the methylome in normal colon mucosa, tubular adenomas, and colorectal adenocarcinomas and have determined the relationship of these findings between adenomas and cancer in the colon. Genome-wide alterations in DNA methylation were found in the normal colon mucosa adjacent to colorectal cancer, tubular adenomas, and colorectal cancer. Three subgroups of CRCs and two subgroups of adenomas were identified on the basis of their DNA methylation patterns. The adenomas separated into a high-frequency methylation class (Adenoma-H) and a low-frequency methylation class. The adenoma-H polyps have a methylated DNA signature similar to non-CIMP CRCs, whereas those of the Adenoma-L class have a similar methylation pattern to normal colon mucosa. The CpGs that account for these signatures are located in intragenic/intergenic regions, which suggests that these two groups of adenomas arise from different stem cell populations.
2014-09-08 | GSE48684 | GEO
Project description:Genetic and epigenetic alterations are a fundamental aspect of colorectal cancer formation. There is considerable heterogeneity between colorectal cancers regarding the mutations and methylated genes they carry, and this heterogeneity may arise early in the polyp-cancer sequence. However, our understanding of the epigenetic alterations and gene mutations in colon adenomas and their relation to colorectal cancer is incomplete. Thus, we have assessed the methylome in normal colon mucosa, tubular adenomas, and colorectal adenocarcinomas and have determined the relationship of these findings between adenomas and cancer in the colon. Genome-wide alterations in DNA methylation were found in the normal colon mucosa adjacent to colorectal cancer, tubular adenomas, and colorectal cancer. Three subgroups of CRCs and two subgroups of adenomas were identified on the basis of their DNA methylation patterns. The adenomas separated into a high-frequency methylation class (Adenoma-H) and a low-frequency methylation class. The adenoma-H polyps have a methylated DNA signature similar to non-CIMP CRCs, whereas those of the Adenoma-L class have a similar methylation pattern to normal colon mucosa. The CpGs that account for these signatures are located in intragenic/intergenic regions, which suggests that these two groups of adenomas arise from different stem cell populations. We conducted genome-wide array-based studies and comprehensive data analyses of aberrantly methylated loci in 41 normal colon samples, 42 colon adenomas, and 64 colorectal cancers. Supplementary file 'GSE48684_Matrix_signal_intensities_1.txt.gz': includes the unmethylated and methylated signal intensities from Samples GSM1183439-GSM1183561. Supplementary file 'GSE48684_Matrix_signal_intensities_2.txt.gz': includes the unmethylated and methylated signal intensities from Samples GSM1235135-GSM1235158.
2014-09-08 | E-GEOD-48684 | biostudies-arrayexpress
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Project description:Clinical Significance: Understanding the differences in colorectal cancer (CRC) aggressiveness and clinical outcomes in relation to tumor stage and different molecular subsets is at most important for designing treatment regimens. However, molecular signatures for specific phenotypic subsets that predict the aggressiveness and clinical outcomes of CRC, specifically in advanced disease stage are lacking. Therefore, for the first time, the current study has identified a set of molecular markers that are associated with aggressive Stage III CRCs that exhibited microsatellite stable and mutant p53 phenotypic features. These findings might aid in designing aggressive treatment regimens and help to provide insights into the development of novel therapeutic targets. Results: Increased incidence of p53 mutations in MSS CRCs (58%) was associated with higher CRC-specific mortality than MSS-p53 wild-type phenotypes (log-rank, P=0.025; and hazard ratio, 2.52; 95% confidence interval, 1.25-5.08). Of 49 down-regulated genes, LPAR6, PDLIM3 and PLAT and of 35 up-regulated genes, TRIM29, FUT3, IQGAP3, and SLC6A8, were confirmed by qNPA, qRT-PCR, and IHC platforms. Conclusions: p53 mutations are associated with poor prognosis of Stage III microsatellite stable CRCs. p53 wild type vs. mutant tumor samples
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Project description:Microsatellite unstable (MSI) colorectal cancers (CRCs) are characterized by Transforming Growth Factor Beta Receptor Type 2 (TGFBR2) deficiency. TGFBR2-deficient CRCs present altered target gene and protein expression. Such cellular alterations modulate the content of CRC-derived extracellular vesicles (EVs). EVs function as couriers of proteins, nucleic acids, and lipids in intercellular communication. At a qualitative level, we have previously shown that TGFBR2 deficiency can cause overall alterations in the EV protein content. To deepen the basic understanding of altered protein dynamics, this work aimed to quantify EV protein signatures in a TGFBR2-dependent manner. Using a SILAC approach for mass spectrometry-based quantification, 48 proteins that appeared to be regulated by cellular TGFBR2 expression were identified in MSI-derived EVs. TGFBR2-primed EVs were enriched in proteasome-associated proteins, whereas TGFBR2 deficiency led to upregulation of EV proteins related to the extracellular matrix and nucleosome. Altogether, the present study emphasizes the general overlap of proteins between EVs and their parental CRC cells and highlights the pathological role of the MSI tumor driver mutation affecting TGFBR2 by altering protein landscapes of EVs. From a clinical perspective, TGFBR2-regulated quantitative differences of protein expression in EVs might nominate novel biomarkers for liquid biopsy-based MSI typing in the future.
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