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

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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 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.

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Figure 1: Variant allele detection by the HNPCC Chip resequencing array.
Figure 2: Pedigrees of selected carriers of MLH1 415C.
Figure 3: Structural and functional analyses of MLH1 D132H.

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Acknowledgements

We would like to thank J. Nguyen and L. Paxton for technical assistance. This work was supported by an American Cancer Society Research Scholar Grant (to S.M.L.), Public Health Service grants (to S.B.G. and L.S.R.) and the Ravitz Foundation (S.B.G.).

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Correspondence to Steven M Lipkin or Stephen B Gruber.

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Competing interests

S.F. is the CEO of Affymetrix Corporation.

Supplementary information

Supplementary Table 1

MLH1, MSH2 and MSH6 exon and peri-exonic variant allels identified in Israeli familial CRC probands. (PDF 8 kb)

Supplementary Table 2

Israeli population based CRC allele frequencies of MLH1, MSH2 and MSH6 variants. (PDF 3 kb)

Supplementary Table 3

Pathological characteristics of CRCs from MLH1 D132H carriers. (PDF 2 kb)

Supplementary Table 4

Microsatellite instability results for subjects carrying the MLH1 D132H variant allele with available tumors. (PDF 2 kb)

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