The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer

Steven M. Lipkin, Laura S. Rozek, Gad Rennert, Wei Yang, Peng Chieh Chen, Joseph Hacia, Nathan Hunt, Brian Shin, Steve Fodor, Mark Kokoris, Joel K. Greenson, Eric Fearon, Henry Lynch, Francis Collins, Stephen B. Gruber

研究成果: Article

88 引文 斯高帕斯(Scopus)

摘要

Most susceptibility to colorectal cancer (CRC) is not accounted for by known risk factors. Because MLH1, MSH2 and MSH6 mutations underlie high-penetrance CRC susceptibility in hereditary nonpolyposis colon cancer (HNPCC), we hypothesized that attenuated alleles might also underlie susceptibility to sporadic CRC. We looked for gene variants associated with HNPCC in Israeli probands with familial CRC unstratified with respect to the microsatellite instability (MSI) phenotype. Association studies identified a new MLH1 variant (415G→C, resulting in the amino acid substitution D132H) in ∼1.3% of Israeli individuals with CRC self-described as Jewish, Christian and Muslim. MLH1 415C confers clinically significant susceptibility to CRC. In contrast to classic HNPCC, CRCs associated with MLHI 415C usually do not have the MSI defect, which is important for clinical mutation screening. Structural and functional analyses showed that the normal ATPase function of MLH1 is attenuated, but not eliminated, by the MLH1 415G→C mutation. The new MLH1 variant confers a high risk of CRC and identifies a previously unrecognized mechanism in microsatellite-stable tumors. These studies suggest that variants of mismatch repair proteins with attenuated function may account for a higher proportion of susceptibility to sporadic microsatellite-stable CRC than previously assumed.

原文English
頁(從 - 到)694-699
頁數6
期刊Nature Genetics
36
發行號7
DOIs
出版狀態Published - 2004 七月 1

All Science Journal Classification (ASJC) codes

  • Genetics

指紋 深入研究「The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer」主題。共同形成了獨特的指紋。

  • 引用此

    Lipkin, S. M., Rozek, L. S., Rennert, G., Yang, W., Chen, P. C., Hacia, J., Hunt, N., Shin, B., Fodor, S., Kokoris, M., Greenson, J. K., Fearon, E., Lynch, H., Collins, F., & Gruber, S. B. (2004). The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer. Nature Genetics, 36(7), 694-699. https://doi.org/10.1038/ng1374