Human Molecular Genetics Advance Access published online on August 4, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh238
© 2004 by Oxford University Press
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1 Institute of Molecular Pathology and Immunology of the University of Porto, IPATIMUP, 4200-465 Porto, Portugal
* To whom correspondence should be addressed. E-mail: rseruca{at}ipatimup.pt.
In sporadic colorectal tumours the BRAFV600E is associated with microsatellite instability (MSI-H) and inversely associated to KRAS mutations. Tumours from HNPCC patients carrying germline mutations in hMSH2 or hMLH1, do not show BRAFV600E, however no consistent data exists 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 MSS sporadic carcinomas. All tumours were characterised for MSI and 81 of 166 sporadic MSI-H CRCs were analysed for hMLH1 promoter hypermethylation. KRAS mutations were observed in 40% of HNPCC tumours, and the mutation frequency varied upon the MMR 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.
Article
Distinct patterns of KRAS mutations in colorectal carcinomas according to germline Mismatch Repair defects and hMLH1 methylation status
2 Department of Medical Genetics, University of Groningen, 9713 AW Groningen, The Netherlands
3 Department of Medical Genetics, Haartman Institute, FIN-00014 University of Helsinki, Finland
4 Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland
5 Centre d'Investigacions en Bioquimica i Biologia Molecular (CIBBIM), Hospital Universitari Vall d'Hebron, Barcelona 08035, Spain
6 Dept Clinical Genetics, Karolinska University Hospital, S 71 76 Stockholm, Sweden
7 Department of Genetics, Portuguese Institute of Oncology (IPO), 4200-072 Porto, Portugal
8 Department of Human Genetics, UMC Nijmegen, 6500 HB Nijmegen, The Netherlands
9 Department of Gastroenterology, University Hospital Groningen, 9713 AW Groningen, The Netherlands
10 Department of Surgery, University Hospital Groningen, 9713 AW Groningen, The Netherlands
11 First Department of Internal Medicine, Sapporo Medical University, Sapporo 060-8543, Japan
12 Serviço de Gastroenterologia, Instituto Portugues de Oncologia Francisco Gentil, 1093 Lisbon, Portugal
13 INSERM U434 CEPH, 75010 Paris, France
14 Centro de Investigacao de Patobiologia Molecular-CIPM, Instituto Portugues de Oncologia Francisco Gentil, 1093 Lisbon, Portugal
15 Institute of Molecular Pathology and Immunology of the University of Porto, IPATIMUP, Rua Roberto Frias S/N, 4200-465 Porto, Portugal
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