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Expression Profiles in Stage II Colon Cancer According to APC Gene Status.

ABSTRACT: Colorectal cancer is one of the most common cancers in the world. Histoclinical staging is efficient, but combination with molecular markers may improve the classification of stage II cancers. Several tumor-suppressor genes have been associated with colorectal cancer, and the most frequent allelic losses have been extensively studied for their prognosis effect, but the results remain controversial. In a previous study, we found a possible influence of the chromosome 5 status in the development of liver metastases in stage II colon cancers. We have here investigated the role of the APC gene, located in chromosome arm 5q, in a series of 183 colon adenocarcinomas through a combined analysis of gene expression, mutation, allelic loss and promoter methylation, and metastasis occurrence. Point mutations were found in 73% of cases and allelic losses were found in 39%; 59% of tumors presented with a biallelic inactivation, with a very strong interdependence of the two APC hits (P = 2.1 x 10(-9)). No association was found between expression, number and type of APC alterations, and metastatic evolution. Our results show that the determination of APC status cannot help in the prediction of metastasis and cannot be used to subclassify stage II colon cancers.

SUBMITTER: Birnbaum DJ

PROVIDER: S-EPMC3323927 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThough colon cancer (CC) is one of the most malignant tumors across the world, CC patients with microsatellite instability-high (MSI-H) in stage II seem to have a better prognosis. However, the molecular mechanisms underlying the phenomena haven't been elucidated yet.MethodsThis study enrolled 322 CCs with known microsatellite status from GSE143985, GSE39582 and GSE92921 in the Gene Expression Omnibus (GEO) database. Robust rank aggregation (RRA) analysis, univariate Cox regression analysis and multivariate Cox stepwise regression analysis were performed to identify genes and construct risk score signature. Kaplan-Meier and receiver operating characteristic (ROC) curves analyses were used to evaluate the prognostic value of the signature. The potential mechanisms underlying this signature were assessed in the Metascape database, gene set enrichment analysis (GSEA) and immune infiltration analysis.ResultsRRA analysis identified 40 differently expressed genes (DEGs). A 3-gene risk score signature (MKQ signature) associated with disease-free survival (DFS) was generated. DFS was significantly longer in CC patients with lower than higher scores (P=0.0046). The areas under curves (AUCs) of the time-dependent ROC curves of MKQ signature at 1-, 3- and 5-year DFS were 1, 0.963 and 0.961 respectively. Recurrence-free survival (RFS) was significantly longer in patients in GSE39582 with lower than higher risk scores (P=0.032). The AUCs for 1-, 3- and 5-year RFS in GSE39582 were 0.63, 0.618 and 0.583, respectively, validating the value of the MKQ signature. Functional annotation and GSEA revealed that the MKQ signature was associated with multiple immune-related pathways. Immune cell infiltration was found to differ in patients differing in the MKQ signature.ConclusionsGene expression and microsatellite status identified a 3-gene signature (MKQ signature) that could facilitate risk-stratified management in patients with stage II CC. Dysregulation of MSMB, KRT23, and QPRT can serve as prognostic markers in stage II CC.

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Expression Profiles in Stage II Colon Cancer According to APC Gene Status.

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