DEREGULATION OF PRE-mRNA SPLICING IN MISMATCH REPAIR DEFICIENT COLORECTAL CANCER
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PROVIDER: EGAS00001004863 | EGA |
REPOSITORIES: EGA
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Project description:Colorectal cancer (CRC) remains the third most common cancer in the US, with 15% of cases displaying Microsatellite Instability (MSI) secondary to Lynch Syndrome (LS) or somatic hypermethylation of the MLH1 promoter. A cohort of rhesus macaques from our institution developed spontaneous mismatch repair deficient (MMRd) CRC with a notable fraction harboring a pathogenic germline mutation in MLH1. DNA methylation and transcriptome analysis was performed to evaluate the rhesus macaque as a model organism to study carcinogenesis, develop immunotherapies and vaccines, and implement chemoprevention approaches pertinent to sporadic MSI-H and LS CRC in humans. NIH grant(s): Grant ID: 5 P30 CA016672-44 Grant title: Cancer Center Support Grant Affiliation: The University of Texas MD Anderson Cancer Center Grantor: NCI
2022-03-31 | GSE178377 | GEO
Project description:Colorectal cancer (CRC) remains the third most common cancer in the US, with 15% of cases displaying Microsatellite Instability (MSI) secondary to Lynch Syndrome (LS) or somatic hypermethylation of the MLH1 promoter. A cohort of rhesus macaques from our institution developed spontaneous mismatch repair deficient (MMRd) CRC with a notable fraction harboring a pathogenic germline mutation in MLH1. DNA methylation and transcriptome analysis was used to evaluate the rhesus macaque as a model organism to study carcinogenesis, develop immunotherapies and vaccines, and implement chemoprevention approaches pertinent to sporadic MSI-H and LS CRC in humans. NIH grant(s): Grant ID: 5 P30 CA016672-44 Grant title: Cancer Center Support Grant Affiliation: The University of Texas MD Anderson Cancer Center Grantor: NCI
2022-03-31 | GSE178381 | GEO
Project description:DNA mismatch repair-deficient colorectal tumors (CRC) frequently show coding microsatellite frameshift mutations in the MSI tumor driver Transforming Growth Factor Beta Receptor Type 2 (TGFBR2) leading to cellular alteration of MSI tumor cells [Lee, J., Warnken, U., Schnölzer, M., Gebert, J. & Kopitz, J. (2015) Protein Sci. 24, 1686-94; Lee, J., Ballikaya, S., Schonig, K., Ball, C. R., Glimm, H., Kopitz, J. & Gebert, J. (2013) PloS one. 8, e57074]. Whether this receptor expression in MSI tumor cells also impacts the exosomal proteomic cargo of these cells is still unknown.
2017-04-07 | PXD005620 | Pride
Project description:A large proportion of indigenous African (IA) colorectal cancer (CRC) patients in South Africa are young (<50years), with no unique histopathological or molecular characteristics. Anatomical site as well as microsatellite instability (MSI) status have shown to be associated with different clinicopathological and molecular features. This study aimed to ascertain key histopathological and miRNA expression patterns in microsatellite stable (MSS) and low-frequency MSI (MSI-L) patients, to provide insight into the mechanism of the disease. This study revealed distinct histopathological features for Left Colon Cancer (LCC), and suggests BAT25/26, miRNAs let-7a-5p and miRNA-125a/b-5p as negative prognostic markers in African CRC patients.
2023-12-31 | GSE197088 | GEO
Project description:Expression profiling was used to identify genes differentially expressed in MSS (microsatellite stable) and MSI (microsatellite unstable) colon cancer cell lines. Data submitted in support of manuscript entitled Villin expression is frequently lost in poorly differentiated colon cancer, Diego Arango, Sheren Al-Obaidi, David S. Williams, Jose Dopeso, Rocco Mazzolini, Georgia Corner, Do-Sun Byun, Carmel Murone, Lars Tögel, Nikolajs Zeps, Lauri A. Aaltonen, Barry Iacopetta and John M. Mariadason, American Journal of Pathology, 2012. 5 microsatellite stable (MSS) and 5 microsatellite unstable (MSI) colon cancer cell lines profiled. Each cell line grown and arrayed in duplicate, and the duplicates averaged for each cell line before calculating means for MSS and MSI lines.
2012-02-07 | E-GEOD-35566 | biostudies-arrayexpress
Project description:Colorectal cancer (CRC), a malignant tumor worldwide consists of microsatellite instability (MSI) and microsatellite stable (MSS) phenotypes. Although SHP2 is a potential target for cancer therapy, its relationship with innate immunosuppression remains elusive. To address that, single-cell RNA sequencing was performed to explore the role of SHP2 in all cell types of tumor microenvironment (TME) from murine MC38 xenografts.
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Project description:We compared the expression of genes related to inflammatory cytotoxic functions between MSI and MSS (HLA class I negative and positive) gastrointestinal adenocarcinomas (GIACs), seeking evidence of differences in inflammatory mediators and cytotoxic T-cell responses. Twenty-two GIACs were divided into three study groups as a function of HLA class I expression and MSI phenotype. Comparison between eight high-level MSI (MSI-H) and 8 MSS/HLA+ (control) cancers identified 2170 differentially expressed genes (p< 0.05) after microarray analysis on the Affymetrix HG-U133-Plus-PM plate. We grouped genes in Gene Ontology functional categories: apoptotic programme (119 genes, p=5.1·10-7), leukocyte activation (32 genes, p=0.01), T cell activation (20 genes, p= 0.01), and cytokine production (19 genes, p= 0.04). Real-time RT-PCR and immunohistochemical evaluation were used to confirm some microarray data, finding that increased mRNA levels of pro-inflammatory cytokines and cytotoxic mediators were associated with greater infiltration by CD8+ T lymphocytes in the MSI-H group (p<0.001). Finally, tumours with immunohistochemical HLA class I negative pattern were not grouped together but rather in accordance with features of the gene expression profile of MSI or MSS tumours. As expected, genes associated with antigen processing machinery and MHC class I molecules (TAP2, B2m) were downregulated in MSS/HLA-ABC negative CRCs. In conclusion, microarray and immunohistochemical data may be useful to comprehensively assess tumour-host interactions and differentiate MSI from MSS cancers. The two types of tumours, MSI/HLA- and MSS/HLA-, showed marked differences in the composition and intensity of infiltrating leukocytes, suggesting that their immune escape strategies involve distinct pathways. Case-control study. Samples were selected according to immunological criteria: those with total loss of HLA antigens and those without alterations in the expression of HLA molecules. In addition, the microsatellite instability genotype of all the samples was also analyzed, resulting in microsatellite stability (MSS) and microsatellite instability (MSI) samples. Therefore, three groups of samples were selected: MSS/HLA+, MSS/HLA-, and MSI. The MSS/HLA+ group was used as the control.
2011-02-28 | E-GEOD-27544 | biostudies-arrayexpress
Project description:Synthetic lethality is a powerful approach for targeting oncogenic drivers in cancer. Recent studies revealed that cancer cells with microsatellite instability (MSI) require Werner (WRN) helicase for survival; however, the underlying mechanism remains unclear. In this study, we found that WRN depletion strongly induced p53 and its downstream apoptotic target PUMA in MSI colorectal cancer (CRC) cells. p53 or PUMA deletion abolished apoptosis induced by WRN depletion in MSI CRC cells. Importantly, correction of MSI abrogated the activation of p53/PUMA and cell killing, while induction of MSI led to sensitivity in isogenic CRC cells. Rare p53-mutant MSI CRC cells are resistant to WRN depletion due to lack of PUMA induction, which could be restored by wildtype p53 knock-in or reconstitution. WRN depletion or treatment with the RecQ helicase inhibitor ML216 suppressed in vitro and in vivo growth of MSI CRCs in a p53/PUMA_x0002_dependent manner. ML216 treatment was efficacious in MSI CRC patient-derived xenografts (PDX). Interestingly, p53 gene remains wildtype in the majority of MSI CRCs. These results indicate a critical role of p53/PUMA-mediated apoptosis in the vulnerability of MSI CRCs to WRN loss, and support WRN as a promising therapeutic target in p53-wildtype MSI CRCs.
2022-10-26 | GSE216455 | GEO
Project description:Gene expression profiling has discriminated between sporadic microsatellite instable (MSI) and microsatellite stable (MSS) colorectal cancers (CRCs), whereas the expression pattern of familial colorectal cancer type X (FCCTX) and Lynch syndrome (LS) associated CRCs remain largely unknown. The purpose of this study is to use gene expression profiling of formalin-fixed paraffin-embedded (FFPE) tumor specimens from FCCTX, LS and sporadic CRC as a control to detect expression patterns and to identify signaling pathways differing between FCCTX and LS tumors.
2012-03-08 | GSE36335 | GEO
Project description:Background. Colorectal cancer develops through two main genetic instability pathways characterized by distinct pathologic features and clinical outcome. Results. We investigated colon cancer samples (23 characterized by microsatellite stability, MSS, and 16 by high microsatellite instability, MSI-H) for genome-wide expression of microRNA (miRNA) and mRNA. Based on combined miRNA and mRNA gene expression, a molecular signature consisting of twenty seven differentially expressed genes, inclusive of 8 miRNAs, could correctly distinguish MSI-H versus MSS colon cancer samples. Among the differentially expressed miRNAs, various members of the oncogenic miR-17-92 family were significantly up-regulated in MSS cancers. The majority of protein coding genes were also up-regulated in MSS cancers. Their functional classification revealed that they were most frequently associated with cell cycle, DNA replication, recombination, repair, gastrointestinal disease and immune response. Conclusions. This is the first report that indicates the existence of differences in miRNA expression between MSS versus MSI-H colorectal cancers. In addition, the work suggests that the combination of mRNA/miRNA expression signatures may represent a general approach for improving bio-molecular classification of human cancer.
2007-09-07 | E-TABM-326 | biostudies-arrayexpress