Human Molecular Genetics Advance Access originally published online on August 4, 2004
Human Molecular Genetics 2004 13(19):2303-2311; doi:10.1093/hmg/ddh238
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Human Molecular Genetics, Vol. 13, No. 19 © Oxford University Press 2004; all rights reserved
Distinct patterns of KRAS mutations in colorectal carcinomas according to germline mismatch repair defects and hMLH1 methylation status
1Institute of Molecular Pathology and Immunology, The University of Porto, IPATIMUP, 4200-465 Porto, Portugal, 2Department of Medical Genetics, University of Groningen, 9713 AW Groningen, The Netherlands, 3Department of Medical Genetics, Haartman Institute, 4Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland, 5Centre d'Investigacions en Bioquimica i Biologia Molecular (CIBBIM), Hospital Universitari Vall d'Hebron, Barcelona 08035, Spain, 6Department of Clinical Genetics, Karolinska University Hospital, S 171 76 Stockholm, Sweden, 7Department of Genetics, Portuguese Institute of Oncology (IPO), 4200-072 Porto, Portugal, 8Department of Human Genetics, UMC Nijmegen, 6500 HB Nijmegen, The Netherlands, 9Department of Gastroenterology, and 10Department of Surgery, University Hospital Groningen, 9713 AW Groningen, The Netherlands, 11First Department of Internal Medicine, Sapporo Medical University, Sapporo 060-8543, Japan and 12Serviço de Gastroenterologia, and 13Centro de Investigacao de Patobiologia Molecular-CIPM, Instituto Portugues de Oncologia Francisco Gentil, 1093 Lisbon, Portugal and 14INSERM U434 CEPH, 75010 Paris, France
Received May 17, 2004; Accepted July 22, 2004
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.
* To whom correspondence should be address at: IPATIMUP, Rua Roberto Frias S/N, 4200-465 Porto, Portugal. Tel: +351 225570700; Fax: +351 225570799; Email: rseruca{at}ipatimup.pt
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