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Predictive Value of DNA Mismatch Repair System in Colorectal Cancers

ABSTRACT: * Microsatellite instable (MSI) tumors represent almost the 15% of all sporadic colorectal cancers (CRCs). * Literature data show that this unique tumor population appears to be poorly responsive to conventional chemotherapy and conversely reveals excellent results to immunotherapy. * Our data, as demonstrated by propensity score-matched and win ratio analysis, show that there are no substantial differences between MSI and MSS tumors in early CRC stages treated with surgery alone. * On the contrary, stable tumors (MSS) did much better than MSI tumors in advanced CRC stages undergoing conventional adjuvant treatment. * Determination of status of DNA mismatch repair system is crucial in high-risk CRCs to optimize treatment.

DISEASE(S): Colorectal Neoplasms,Msi-h Colorectal Cancer

PROVIDER: 61019 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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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.

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Predictive Value of DNA Mismatch Repair System in Colorectal Cancers

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