Journal Article

Distinct patterns of <i>KRAS</i> mutations in colorectal carcinomas according to germline mismatch repair defects and h<i>MLH1</i> methylation status

Carla Oliveira, Jantine L. Westra, Diego Arango, Miina Ollikainen, Enric Domingo, Ana Ferreira, Sérgia Velho, Renee Niessen, Kristina Lagerstedt, Pia Alhopuro, Paivi Laiho, Isabel Veiga, Manuel R. Teixeira, Marjolijn Ligtenberg, Jan H. Kleibeuker, Rolf H. Sijmons, John T. Plukker, Kohzoh Imai, Pedro Lage, Richard Hamelin, Cristina Albuquerque, Simo Schwartz, Annika Lindblom, Päivi Peltomaki, Hiroyuki Yamamoto, Lauri A. Aaltonen, Raquel Seruca and Robert M.W. Hofstra

in Human Molecular Genetics

Volume 13, issue 19, pages 2303-2311
Published in print October 2004 | ISSN: 0964-6906
Published online August 2004 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddh238
Distinct patterns of KRAS mutations in colorectal carcinomas according to germline mismatch repair defects and hMLH1 methylation status

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In sporadic colorectal tumours the BRAFV600E is associated with microsatellite instability (MSI-H) and inversely associated to KRAS mutations. Tumours from hereditary non-polyposis colorectal cancer (HNPCC) patients carrying germline mutations in hMSH2 or hMLH1 do not show BRAFV600E, however no consistent data exist regarding KRAS mutation frequency and spectrum in HNPCC tumours. We investigated KRAS in 158 HNPCC tumours from patients with germline hMLH1, hMSH2 or hMSH6 mutations, 166 MSI-H and 688 microsatellite stable (MSS) sporadic carcinomas. All tumours were characterized for MSI and 81 of 166 sporadic MSI-H colorectal cancer (CRCs) were analysed for hMLH1 promoter hypermethylation. KRAS mutations were observed in 40% of HNPCC tumours, and the mutation frequency varied upon the mismatch repair gene affected: 48% (29/61) in hMSH2, 32% (29/91) in hMLH1 and 83% (5/6) in hMSH6 (P=0.01). KRAS mutation frequency was different between HNPCC, MSS and MSI-H CRCs (P=0.002), and MSI-H with hMLH1 hypermethylation (P=0.005). Furthermore, HNPCC CRCs had more G13D mutations than MSS (P<0.0001), MSI-H (P=0.02) or MSI-H tumours with hMLH1 hypermethylation (P=0.03). HNPCC colorectal and sporadic MSI-H tumours without hMLH1 hypermethylation shared similar KRAS mutation frequency, in particular G13D. In conclusion, we show that depending on the genetic/epigenetic mechanism leading to MSI-H, the outcome in terms of oncogenic activation may be different, reinforcing the idea that HNPCC, sporadic MSI-H (depending on the hMLH1 status) and MSS CRCs, may target distinct kinases within the RAS/RAF/MAPK pathway.

Journal Article.  6242 words.  Illustrated.

Subjects: Genetics and Genomics

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