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BRAF mutations in colorectal carcinoma suggest two entities of microsatellite‐unstable tumors
Author(s) -
Lubomierski Nikolaus,
Plotz Guido,
Wormek Marc,
Engels Knut,
Kriener Susanne,
Trojan Jorg,
Jungling Bernd,
Zeuzem Stefan,
Raedle Jochen
Publication year - 2005
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.21266
Subject(s) - microsatellite instability , dna mismatch repair , kras , cancer research , medicine , colorectal cancer , carcinogenesis , germline mutation , germline , dna methylation , mutation , methylation , carcinoma , oncology , microsatellite , cancer , biology , gene , genetics , gene expression , allele
Abstract BACKGROUND Alterations of BRAF have been implicated in the carcinogenesis of colorectal tumors with microsatellite instability (MSI). These alterations were attributed to defective DNA mismatch repair, which underlies MSI. It was the objective of this study to clarify the role of BRAF in colorectal carcinoma with MSI. METHODS After sequencing for BRAF and KRAS in 82 colorectal tumor samples with or without MSI, mismatch repair protein expression was analyzed by immunohistochemistry, and promoter methylation of h MLH1 was analyzed with a methylation‐specific polymerase chain reaction. Results were correlated with the germline status of h MLH1 or h MSH2 and clinical characteristics. RESULTS BRAF was mutated more often in tumors with MSI than in tumors without MSI (27% vs. 5%; P = 0.016). The most prevalent BRAF alteration, V599E, occurred only in tumors with MSI. BRAF V599E was associated with more frequent h MLH1 promoter methylation ( P = 0.07) and loss of hMLH1 ( P = 0.02). The median age of patients with BRAF V599E was older compared with the median age of patients without this mutation ( P = 0.001; 78 vs. 49 yrs). No BRAF alterations occurred in patients with germline mutations of mismatch repair genes. Five novel BRAF mutations were identified. CONCLUSIONS Although BRAF V599E was common in colorectal carcinomas with MSI, it was not a consequence of deficient mismatch repair. The current data showed instead that the BRAF V599E mutation was associated only with a subgroup of colorectal carcinomas with MSI that were obtained from older patients without hereditary nonpolyposis colorectal carcinoma and showed epigenetic silencing of hMLH1. These results indicated that tumors with MSI caused by epigenetic MLH1 silencing have a distinct mutational background from that of tumors with genetic loss of mismatch repair, suggesting that there are two genetically distinct entities of microsatellite‐instable tumors. Cancer 2005. © 2005 American Cancer Society.