Journal of the National Cancer Institute Advance Access originally published online on September 25, 2007
JNCI Journal of the National Cancer Institute 2007 99(19):1490; doi:10.1093/jnci/djm137
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Published by Oxford University Press 2007.
CORRESPONDENCE |
Re: MLH1 –93G>A Promoter Polymorphism and the Risk of Microsatellite-Unstable Colorectal Cancer
Affiliations of authors: Section of Cancer Genetics, Institute of Cancer Research, Sutton, UK
Correspondence to: Richard A. Hubner, MA, BM, BCh, Institute of Cancer Research, Section of Cancer Genetics, 15 Cotswold Rd, Sutton, SM2 5NG, UK. (e-mail: richard.hubner{at}icr.ac.uk).
Raptis et al. (1) propose an association between the MLH1 –93G>A polymorphism and colorectal cancers with high microsatellite instability (MSI-H) status and suggest that this variant is a low-penetrance allele for colorectal cancer susceptibility. Although it is plausible that, in addition to highly penetrant truncating mutations, common variants of DNA mismatch repair genes such as MLH1 may contribute to colorectal cancer susceptibility, demonstrating causality is not straightforward.
In the study of Raptis et al. (1), case patients with colorectal cancer were ascertained from the Ontario and Newfoundland Familial Colorectal Cancer Registries. Patients captured by these registries have previously been demonstrated to be enriched for familial colorectal cancer (2). A recent study (3) of familial colorectal cancer has shown that pathogenic germline MLH1 mutations can be identified in approximately 50% of MSI-H tumor-carrying families that fulfill the Amsterdam criteria and in approximately 30% of MSI-H tumor-carrying families that do not fulfill those criteria. On this basis, it is possible that a high proportion of case patients with MSI-H colorectal cancer in the study by Raptis et al. (1) might be carriers of germline MLH1 mutations. If this is the case, then linkage disequilibrium between such mutations and the –93A allele is a potential confounder. Such linkage disequilibrium has already been demonstrated for the MLH1 IVS14-19A>G polymorphism (4), and it is entirely plausible that other polymorphisms may similarly be over- or underrepresented in mutation carriers. In this regard, it is interesting to note that the same group recently reported that the –42C>T sequence change in the MLH1 promoter, which is only 51 bases from the –93G>A variant, cosegregates with colorectal cancer in a Newfoundland kindred (5). Although 929 and 430 case patients were initially recruited from the two different registries, information on MSI status was unavailable for 163 (18%) and 136 (32%), respectively, raising the possibility of selection bias, and the analyses of case patients with MSI-H tumors were based on only 117 and 33 case patients, respectively.
However attractive the hypothesis that polymorphisms in MLH1 confer susceptibility to colorectal cancer may be, validation of the association reported by Raptis et al. (1) is required in multiple independent outbred populations that are analogous to those stipulated for large-scale genome-wide studies (6) before it can be unambiguously asserted that –93G>A is a low-penetrance susceptibility allele.
REFERENCES
(1) Raptis S, Mrkonjic M, Green RC, Pethe VV, Monga N, Chan YM, et al. MLH1 –93G>A promoter polymorphism and the risk of microsatellite-unstable colorectal cancer. J Natl Cancer Inst (2007) 99:463–74.
(2) Green RC, Green JS, Buehler SK, Robb JD, Daftary D, Gallinger S, et al. Very high incidence of familial colorectal cancer in Newfoundland: a comparison with Ontario and 13 other population-based studies. Fam Cancer (2007) 6:53–62.[CrossRef][Web of Science][Medline]
(3) Lagerstedt Robinson K, Liu T, Vandrovcova J, Halvarsson B, Clendenning M, Frebourg T, et al. Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics. J Natl Cancer Inst (2007) 99:291–9.
(4) Hutter P, Wijnen J, Rey-Berthod C, Thiffault I, Verkuijlen P, Farber D, et al. An MLH1 haplotype is over-represented on chromosomes carrying an HNPCC predisposing mutation in MLH1. J Med Genet (2002) 39:323–7.
(5) Green RC, Green AG, Simms M, Pater A, Robb JD, Green JS. Germline hMLH1 promoter mutation in a Newfoundland HNPCC kindred. Clin Genet (2003) 64:220–7.[CrossRef][Web of Science][Medline]
(6) Hirschhorn JN, Daly MJ. Genome-wide association studies for common diseases and complex traits. Nat Rev Genet (2005) 6:95–108.[Web of Science][Medline]
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J Natl Cancer Inst 2007 99: 463-474.
J Natl Cancer Inst 2007 99: 1490-1491.
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