Abstract
577 Background: We examined if KRAS somatic mutation in colorectal carcinoma (CRC) is associated with differential tumor DNA methylation. Methods: We did a genome-wide methylation assay (450K) for a total of 250 paired samples from 125 CRC patients (m = 72, f = 53) at different stages (stage 1: 25, stage II: 33 and stage III: 67). Of them 101 had left-sided CRC (descending colon to rectum); 30 had MSI, and 34 had somatic mutation in KRAS (rs112445441). Results: Frequency of KRAS mutation was not different between right and left-sided CRC (29% vs. 27%). But, like other series, MSI was more frequent in the right-sided tumor (54% vs. 17%, p = 0.003). In patients with wild type KRAS tumor (n = 91), paired comparison between tumor and corresponding normal tissue identified a total of 1244 tumor-specific differential methylation loci (DML) covering 532 genes that were significant at FDR 0.001 and magnitude of difference ≥ 20%; But similar analysis in patients with KRAS mutation (n = 34) revealed 7612 tumor-specific DML covering 2357 genes - suggesting an association of KRAS mutation and DNA methylation. We also found that MSI in tumor tissue was associated with DNA methylation change too. Next, we identified 726 genes that are markedly differentially methylated in tumor compared to corresponding normal tissue only in presence of KRAS mutation, irrespective of MSI status, staging, and location of tumor (KRAS mutation associated tumor-specific genes – list enriched in GO ontology “developmental process”, “biological regulation”). We also identified 241 genes that are differentially methylated in tumor compared to normal tissue irrespective of KRAS mutation, MSI status, staging, and location of tumor. (common tumor-specific genes) Conclusions: KRAS somatic mutation is independently associated with methylation changes in a number of genes related to carcinogenesis in CRC.
Published Version
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