Colorectal cancers with microsatellite instability display unique miRNA profiles
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE30454 | GEO | 2011/11/22
SECONDARY ACCESSION(S): PRJNA143541
REPOSITORIES: GEO
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Project description:Analysis of microRNA expression of tumoral and non-tumoral colonic tissues. The aim of this study was to analyze the global miRNA signatures in various groups of well-characterized CRCs based on the presence of microsatellite instability (MSI). Total RNA from formalin-fixed paraffin-embedded tissue blocks from 4 different groups (normal colonic mucosa, Lynch syndrome tumors, sporadic MSI tumors and MSS tumors) was isolated using the RecoverAll Total Nucleic Acid Isolation Kit (Ambion) according to manufacturer instructions. MiRNA expression profiles were analyzed using miRNA microarray platform.
2011-11-22 | E-GEOD-30454 | biostudies-arrayexpress
Project description:Microsatellite instability (MSI), caused by defective mismatch repair, is observed in a subset of colorectal cancers (CRCs). We evaluated somatic mutations in microsatellite repeats of genes chosen based on reduced expression in MSI CRC and existence of a coding mononucleotide repeat. Expression profiling of 34 MSI colorectal cancers and 15 normal colonic mucosas was performed in 2002. Comparison of malignant and healthy tissue.
2011-03-01 | E-GEOD-24514 | biostudies-arrayexpress
Project description:Inflammatory conditions caused by obstruction or perforation are common complications in colorectal cancer (CRC) and play important roles in tumor progression and immunosuppression. However, the significance of inflammatory conditions in the tumor response to immune checkpoint inhibitors (ICIs) remains unclear. We found a high microsatellite instability (MSI-H) CRC patient (Patient 1) whose primary tumor progressed and liver metastasis regressed during PD-1 blockade after having inflammatory conditions. Then, in 73 MSI-H CRCs, inflammatory conditions during ICI treatment were correlated with a poor tumor response, and an elevated NLR was associated with a poor immune status and resistance to ICIs. An organoid-T cell coculture model demonstrated an inhibited local immune response to treatment instead of systemic immunosuppression in Patient 1. Single-cell RNA sequencing suggested that neutrophils suppress the immune microenvironment mostly through CTLA-4-associated pathways. Therefore, inflammatory conditions in MSI-H CRCs correlate with resistance to ICIs through neutrophil-associated immunosuppression. Additional CTLA-4 blockade may improve the sensitivity to PD-1 blockade.
2021-07-09 | GSE179784 | GEO
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.
2019-09-04 | PXD013980 | Pride
Project description:The three main pathways of colorectal carcinogenesis are chromosomal instability, microsatellite instability (MSI) (15% of colorectal cancers =CRCs) and CpG island methylator phenotype (CIMP). MSI CRCs are associated with a better prognosis after curative surgery than CRCs without microsatellite instability (MSS). In contrast, MSI CRCs do not appear to benefit from adjuvant 5-FU chemotherapy, unlike patients with MSS CRCs. Nevertheless, the benefit of adjuvant chemotherapy with FOLFOX seems to be retained. The identification of prognostic markers in this subgroup of patients is therefore essential to decide on adjuvant chemotherapy, the efficacy of which is currently debated in MSI CRC.
To date, there are very few data concerning metastatic MSI CRC. Metastatic forms are rare (about 5% of metastatic CRCs), but are thought to be associated with chemoresistance and poor prognosis. Nevertheless, data are very sparse and there are no data regarding the use of modern chemotherapies and targeted therapies in metastatic MSI CRC. Thus, it is important to characterize the chemosensitivity of metastatic forms.
Clinical predictors of recurrence after curative CRC surgery are known but have only been studied in MSI CRC retrospectively. Similarly, many molecular and immunohistochemical factors, prognostic or predictive of response to adjuvant chemotherapy, have been recently identified in CRC (KRAS, BRAF, TP53, PI3KCA mutations, CIMP phenotype, SMAD4, immune response...). Most of these markers have been studied in all CRCs, but not specifically in the MSI CRC subgroup. All these prognostic and/or predictive biomarkers need to be better characterized in a large cohort of MSI CRCs.
| 2746047 | ecrin-mdr-crc
Project description:microRNAs (miRNA) are small noncoding transcripts that play an important role in carcinogenesis. miRNA expression profiles have been shown to discriminate between different types of cancers. The aim of this study was to analyze global miRNA signatures in various groups of colorectal cancers (CRC) based on the presence of microsatellite instability (MSI).We analyzed genome-wide miRNA expression profiles in 54 CRC tissues [22 with Lynch syndrome, 13 with sporadic MSI due to MLH1 methylation, 19 without MSI (or microsatellite stable, MSS)] and 20 normal colonic tissues by miRNA microarrays. Using an independent set of MSI-positive samples (13 with Lynch syndrome and 20 with sporadic MSI), we developed a miRNA-based predictor to differentiate both types of MSI by quantitative reverse transcriptase PCR.We found that the expression of a subset of nine miRNAs significantly discriminated between tumor and normal colonic mucosa tissues (overall error rate = 0.04). More importantly, Lynch syndrome tumors displayed a unique miRNA profile compared with sporadic MSI tumors; miR-622, miR-1238, and miR-192 were the most differentially expressed miRNAs between these two groups. We developed a miRNA-based predictor capable of differentiating between types of MSI in an independent sample set.CRC tissues show distinct miRNA expression profiles compared with normal colonic mucosa. The discovery of unique miRNA expression profiles that can successfully discriminate between Lynch syndrome, sporadic MSI, and sporadic MSS colorectal cancers provides novel insights into the role of miRNAs in colorectal carcinogenesis, which may contribute to the diagnosis, prognosis, and treatment of this disease.
| S-EPMC3186834 | biostudies-literature
Project description:As part of a genomic profiling study of CRCs with MSI, we have performed genome-wide expression analyses of a consecutive patient series.
2017-04-24 | GSE79959 | 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
Project description:Microsatellite instability (MSI) leads to accumulation of an excessive number of mutations in the genome, mostly small insertions and deletions. MSI CRCs, however, also contain more point mutations than microsatellite stable (MSS) tumors, yet they have not been as comprehensively studied. To identify candidate driver genes affected by point mutations in MSI CRC, we ranked genes based on mutation significance while correcting for replication timing and gene expression utilizing an algorithm, MutSigCV. Somatic point mutation data from the exome kit-targeted area from 24 exome sequenced sporadic MSI CRCs and respective normals, and 12 whole genome sequenced sporadic MSI CRCs and respective normals were utilized. The top 73 genes were validated in 93 additional MSI CRCs.
| EGAS00001003101 | EGA
Project description:Loss of WRN, a DNA repair helicase, was identified as a strong vulnerability of microsatellite instable(MSI) cancers, making WRN a promising drug target. We show that ATP binding and hydrolysis are required for genome integrity and viability of MSI cancer cells. We report a 2.2 Å crystal structure of the WRN helicase core (517-1093), comprising the two helicase subdomains and winged helix domain but not the HRDC domain or nuclease domains. The structure highlights unusual features: First, an atypical mode of nucleotide binding that results in unusual relative positioning of the two helicase subdomains. Second, an additional β-hairpin in the second helicase subdomain and an unusual helical hairpin in the Zn2+ binding domain. Modelling of the WRN helicase in complex with DNA suggests roles for these features in the binding of alternative DNA structures. NMR analysis of shows a weak interaction between the HRDC domain and the helicase core, indicating a possible biological role for this association. Together, this study will facilitate the structure-based development of inhibitors against WRN helicase.
2020-11-11 | PXD018910 | Pride