Journal Article

Mutation analysis of the <i>BRAF</i>, <i>ARAF</i> and <i>RAF-1</i> genes in human colorectal adenocarcinomas

Karin Fransén, Maria Klintenäs, Anna Österström, Jan Dimberg, Hans-Jürg Monstein and Peter Söderkvist

in Carcinogenesis

Volume 25, issue 4, pages 527-533
Published in print April 2004 | ISSN: 0143-3334
Published online April 2004 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgh049
Mutation analysis of the BRAF, ARAF and RAF-1 genes in human colorectal adenocarcinomas

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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.

Keywords: APC, adenomatous polyposis coli; CRC, colorectal cancer; DCC, deleted in colorectal cancer; ERK-1/-2, extracellular regulated kinases; MAPK, mitogen-activated protein kinase; MAPKKs, MAP kinase kinases; MAPKKKs, MAP kinase kinase kinases; MCR, mutation cluster region; MDE, mutation detection enhancement; MEK-1/-2, Map or Erk kinases; MSI, microsatellite instability; SSCA, single strand conformation analysis

Journal Article.  5248 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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