BRAF mutations in colorectal cancer are linked to loss of hMLH1 expression and proximal location, while independent of K-RAS activation

Anna Colomer 1, Nadina Erill 1, August Vidal 2, Ruth Román 1, Montse Verdú 2, Carlos Cordon-Cardo 3, Xavier Puig 1,2.

1BIOPAT, Grup Assistència, Barcelona, Spain; 2HISTOPAT Laboratoris, Barcelona, Spain; 3Division of Molecular Pathology, Memorial Sloan-Kettering Cancer Center, New York.

The RAF gene family encodes RAS-regulated kinases that mediate cellular responses to growth signals. Mutations within the BRAF gene occur in about 10% of colorectal cancers, and are significantly associated to defective mismatch repair (MMR) due to gene silencing of hMLH1 promoter by methylation. The V599E mutant accounts for most BRAF point mutations. It leads to constitutive ERK activation, allowing evasion of apoptosis by induced survival. In this study, we evaluated the frequency of BRAF mutations in a series of 244 primary colorectal cancers previously assessed for microsatellite instability (MSI) by testing a panel of 11 markers. MMR status was studied by immunohistochemistry, while both BRAF and K-RAS mutations were studied by direct sequencing. Twenty-five cases (10%) had the MSI phenotype. Within this group, 19 cases were found to exhibit loss of hMLH1 expression (hMLH1-). Fourteen of those cases were proximal tumors that harbored V599E in the absence of K-RAS mutation, while 2 lesions carried K-RAS mutations, and 2 cases were suspected HNPCC based on the early age of presentation. Two additional cases were respectively hMSH2- and hMSH6-, but lacked BRAF mutations. These results support the hypothesis that BRAF and K-RAS mutations are alternative genetic events associated with sporadic MSI colorectal cancer. This, in turn, could be used as a strategy for the detection of HNPCC families. More studies should be performed in order to clarify the role of BRAF in colorectal tumorigenesis, since this gene is a candidate therapeutic target which could provide novel strategies for clinical management.

Texto completo

Abstract in J Mol Diagn 2004; 6: 429 (ST15).

 

2004-07-23T17:02:21+00:00