Effect of classification based on combination of mutation and methylation in colorectal cancer prognosis

Abstract

Colorectal cancer (CRC) is caused by an accumulation of genetic alterations and epigenetic alterations. The molecular classification of CRCs based on genetic alterations and epigenetic alterations is evolving. Here, we examined mutations and methylation status in CRCs to determine if the combination of genetic and epigenetic alterations predicts prognosis. We examined 134 sporadic CRCs. We used the direct sequencing method to identify mutations in BRAF and AKT1, which are downstream of KRAS and PIK3CA, respectively, in the EGFR pathway. We used the Methylight method to determine the methylation status of hMLH1, p16, MINT1, MINT2 and MINT31. Both BRAF and AKT1 mutations were found in only one case (0.75%). Aberrant methylation of hMLH1, p16, MINT1, MINT2 and MINT31 was detected in 22.4, 35.1, 32.8, 59.7 and 41.0% of cases, respectively. The clinicopathological factors were not significantly correlated to mutation or methylation. Among the patients who had no mutation in the EGFR pathway, the overall survival was significantly shorter in the patients with methylation compared to the patients with no methylation in hMLH1 and p16 (p=0.0318). Methylation could play a key role in the prognosis of patients without mutations in the EGFR pathway. The combination of genetic and epigenetic alterations may be a good marker for the prognosis of CRC patients.