Mutations of BRAF are associated with extensive hMLH1 promoter methylation in sporadic colorectal carcinomas.

Activating mutations of BRAF have been frequently observed in microsatellite unstable (MSI+) colorectal carcinomas (CRCs), in which mutations of BRAF and KRAS are mutually exclusive. Previously, we reported that hypermethylation of hMLH1 might play an important role in the tumorigenesis of right-sided sporadic CRCs with MSI showing less frequency of KRAS/TP53 alteration. Therefore, we have assumed that BRAF mutations might be highly associated with hMLH1 methylation status rather than MSI status. In this study, mutations of BRAF and KRAS and their relationship with MSI and hMLH1 methylation status were examined in 140 resected specimens of CRC. The methylation status was classified into 3 types: full methylation (FM), partial methylation (PM) and nonmethylation (NM). Only FM closely linked to reduced expression of hMLH1 protein. BRAF mutations were found in 16 cases (11%), all leading to the production of BRAF(V599E). As for MSI status, BRAF mutations were found in 43% of MSI+ and 4% of MSI- cases (p < 0.0001). Among the MSI+ individuals, BRAF mutations were more frequent in cases with hMLH1 deficiency (58%) than those with hMSH2 deficiency (0%; p=0.02). Moreover, they were found in 69% of FM, 4% of PM and 4% of NM, revealing a striking difference between FM and the other 2 groups (FM vs. PM or NM; p < 0.0001). These findings suggest that BRAF activation may participate in the carcinogenesis of sporadic CRCs with hMLH1 hypermethylation in the proximal colon, independently of KRAS activation.

Koinuma K ，Shitoh K ，Miyakura Y ，Furukawa T ，Yamashita Y ，Ota J ，Ohki R ，Choi YL ，Wada T ，Konishi F ，Nagai H ，Mano H ... -  《INTERNATIONAL JOURNAL OF CANCER》

BRAF mutations in colorectal carcinoma suggest two entities of microsatellite-unstable tumors.

Lubomierski N ，Plotz G ，Wormek M ，Engels K ，Kriener S ，Trojan J ，Jungling B ，Zeuzem S ，Raedle J ... -  《-》

Distinct patterns of KRAS mutations in colorectal carcinomas according to germline mismatch repair defects and hMLH1 methylation status.

Oliveira C ，Westra JL ，Arango D ，Ollikainen M ，Domingo E ，Ferreira A ，Velho S ，Niessen R ，Lagerstedt K ，Alhopuro P ，Laiho P ，Veiga I ，Teixeira MR ，Ligtenberg M ，Kleibeuker JH ，Sijmons RH ，Plukker JT ，Imai K ，Lage P ，Hamelin R ，Albuquerque C ，Schwartz S Jr ，Lindblom A ，Peltomaki P ，Yamamoto H ，Aaltonen LA ，Seruca R ，Hofstra RM ... -  《HUMAN MOLECULAR GENETICS》

Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability.

Cunningham JM ，Christensen ER ，Tester DJ ，Kim CY ，Roche PC ，Burgart LJ ，Thibodeau SN ... -  《CANCER RESEARCH》

hMLH1 and hMSH2 expression in human hepatocellular carcinoma.

Wang L ，Bani-Hani A ，Montoya DP ，Roche PC ，Thibodeau SN ，Burgart LJ ，Roberts LR ... -  《INTERNATIONAL JOURNAL OF ONCOLOGY》