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 T. Lynch, Francis Collins, Stephen B. Gruber

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)694-699
Number of pages6
JournalNature Genetics
Volume36
Issue number7
DOIs
StatePublished - Jul 2004

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Colorectal Neoplasms
Hereditary Nonpolyposis Colorectal Neoplasms
Microsatellite Instability
Microsatellite Repeats
Mutation
Islam
DNA Mismatch Repair
Penetrance
Amino Acid Substitution
Adenosine Triphosphatases
Alleles
Phenotype
Genes
Neoplasms
Proteins

All Science Journal Classification (ASJC) codes

  • Genetics(clinical)
  • Genetics

Cite this

Lipkin, S. M., Rozek, L. S., Rennert, G., Yang, W., Chen, P. C., Hacia, J., ... 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

The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer. / Lipkin, Steven M.; Rozek, Laura S.; Rennert, Gad; Yang, Wei; Chen, Peng Chieh; Hacia, Joseph; Hunt, Nathan; Shin, Brian; Fodor, Steve; Kokoris, Mark; Greenson, Joel K.; Fearon, Eric; Lynch, Henry T.; Collins, Francis; Gruber, Stephen B.

In: Nature Genetics, Vol. 36, No. 7, 07.2004, p. 694-699.

Research output: Contribution to journalArticle

Lipkin, SM, Rozek, LS, Rennert, G, Yang, W, Chen, PC, Hacia, J, Hunt, N, Shin, B, Fodor, S, Kokoris, M, Greenson, JK, Fearon, E, Lynch, HT, Collins, F & Gruber, SB 2004, 'The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer', Nature Genetics, vol. 36, no. 7, pp. 694-699. https://doi.org/10.1038/ng1374
Lipkin SM, Rozek LS, Rennert G, Yang W, Chen PC, Hacia J et al. The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer. Nature Genetics. 2004 Jul;36(7):694-699. https://doi.org/10.1038/ng1374
Lipkin, Steven M. ; Rozek, Laura S. ; Rennert, Gad ; Yang, Wei ; Chen, Peng Chieh ; Hacia, Joseph ; Hunt, Nathan ; Shin, Brian ; Fodor, Steve ; Kokoris, Mark ; Greenson, Joel K. ; Fearon, Eric ; Lynch, Henry T. ; Collins, Francis ; Gruber, Stephen B. / The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer. In: Nature Genetics. 2004 ; Vol. 36, No. 7. pp. 694-699.
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