Carcinogenesis Advance Access originally published online on December 19, 2003
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Carcinogenesis, Vol. 25, No. 4, 527-533,
April 2004
Carcinogenesis vol.25 no.4 © Oxford University Press 2004; all rights reserved.
CANCER BIOLOGY |
Mutation analysis of the BRAF, ARAF and RAF-1 genes in human colorectal adenocarcinomas
1 Division of Cell Biology, Floor 9, Department of Biomedicine and Surgery, Faculty of Health Sciences, Linköping University, SE-581 85 Linköping, Sweden, 2 Department of Natural Science and Biomedicine, University College of Health Sciences, Jönköping, Sweden and 3 Molecular Biology Laboratory, Strategic Development-LMÖ/IBK, University Hospital, Linköping, Sweden
Colorectal cancer is a multi-step process characterized by a sequence of genetic alterations in cell growth regulatory genes, such as the adenomatous polyposis coli, KRAS, p53 and DCC genes. In the present study mutation analysis was performed with SSCA/direct sequencing of the hot-spot regions in exons 11 and 15 for the BRAF gene and exons 1–2 for the KRAS gene in 130 primary colorectal cancer tumors and correlated with clinico-pathological and mutational data. We also performed mutation analysis of the corresponding conserved regions in the ARAF and RAF-1 genes. Mutations in the BRAF and KRAS genes were found in 11.5 and 40% of the tumors, respectively. One germline exonic and nine germline intronic genetic variants were found in the ARAF and RAF-1 genes. All of the BRAF mutations were located in the kinase domain of the conserved region 3 in exon 15 of the BRAF gene. One novel somatic mutation was also identified in the BRAF gene. The majority of the BRAF mutations were found in colon compared with rectal tumors (P = 0.014). In agreement with others, a statistically significant correlation between BRAF mutations and microsatellite instability could be found. A negative correlation was also evident between mutations in the BRAF and KRAS genes, which supports earlier studies where somatic mutations in these genes are mutually exclusive. Collectively, our results provide support for the idea that activation of the MAP kinase pathway, especially via BRAF and KRAS mutations, is of critical importance for the development of colorectal cancer.
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