Re: MLH1 93G>A Promoter Polymorphism and the Risk of Microsatellite-Unstable Colorectal Cancer

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.

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