title: The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer.
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 approximately 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 MLH1 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.
authors.affiliation: Division of Oncology, Department of Medicine, University of California, Irvine, Irvine, California 92697, USA. slipkin@uci.edu
authors.forename: Steven M
authors.initials: SM
authors.lastname: Lipkin
authors.forename: Laura S
authors.initials: LS
authors.lastname: Rozek
authors.forename: Gad
authors.initials: G
authors.lastname: Rennert
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.forename: Peng-Chieh
authors.initials: PC
authors.lastname: Chen
authors.forename: Joseph
authors.initials: J
authors.lastname: Hacia
authors.forename: Nathan
authors.initials: N
authors.lastname: Hunt
authors.forename: Brian
authors.initials: B
authors.lastname: Shin
authors.forename: Steve
authors.initials: S
authors.lastname: Fodor
authors.forename: Mark
authors.initials: M
authors.lastname: Kokoris
authors.forename: Joel K
authors.initials: JK
authors.lastname: Greenson
authors.forename: Eric
authors.initials: E
authors.lastname: Fearon
authors.forename: Henry
authors.initials: H
authors.lastname: Lynch
authors.forename: Francis
authors.initials: F
authors.lastname: Collins
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gruber
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D002352:Carrier Proteins; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D009687:Nuclear Proteins; D010375:Pedigree; D017386:Sequence Homology, Amino Acid
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1