The first two authors contributed equally to this work.
BRAF mutations in colorectal carcinoma suggest two entities of microsatellite-unstable tumors
Version of Record online: 13 JUL 2005
Copyright © 2005 American Cancer Society
Volume 104, Issue 5, pages 952–961, 1 September 2005
How to Cite
Lubomierski, N., Plotz, G., Wormek, M., Engels, K., Kriener, S., Trojan, J., Jungling, B., Zeuzem, S. and Raedle, J. (2005), BRAF mutations in colorectal carcinoma suggest two entities of microsatellite-unstable tumors. Cancer, 104: 952–961. doi: 10.1002/cncr.21266
- Issue online: 17 AUG 2005
- Version of Record online: 13 JUL 2005
- Manuscript Accepted: 20 APR 2005
- Manuscript Revised: 21 MAR 2005
- Manuscript Received: 3 NOV 2004
- University of the Saarland. Grant Number: A/2003/46
- colorectal carcinomas;
- colorectal neoplasms;
- hereditary nonpolyposis;
- DNA repair
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.
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 hMLH1 was analyzed with a methylation-specific polymerase chain reaction. Results were correlated with the germline status of hMLH1 or hMSH2 and clinical characteristics.
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 hMLH1 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.
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.