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We thank Drs Hubner and Houlston for their interest in our study. Linkage disequilibrium with a mutation or another single-nucleotide polymorphism is a possibility that we considered and discussed in our article. In Ontario and Newfoundland, all case patients with a high-frequency microsatellite instability status (MSI-H) and/or mismatch repair immunohistochemical deficiency undergo germline mutation screening for the MLH1, MSH2, and MSH6 genes. This screening includes exon-by-exon genomic DNA sequencing and the detection of large genomic insertions–deletions with a multiplex ligation-dependent probe amplification assay. Among the 117 patients with colorectal cancers who had MSI-H tumors in the Ontario Familial Cancer Registry, 27 met Amsterdam I criteria—eight (30%) of whom carried germline MLH1 gene mutations. Of these eight case patients, five were homozygous wild type for the MLH1 polymorphism -93G>A, two were heterozygous for it, and one was homozygous for the variant. In the remaining 90 non-Amsterdam MSI-H colorectal cancer patients, we identified three (3.3%) with MLH1 germline mutations (one for each of the MLH1 -93 respective genotypes). For the Newfoundland MSI-H colorectal cancer patients, no germline MLH1 mutations were detected. Thus, the sample of MSI-H MLH1 germline mutation carriers in our populations (whether meeting Amsterdam criteria or not) was small and did not demonstrate evidence for linkage of MLH1 -93G>A with germline MLH1 mutations. Moreover, although enriched with familial colorectal cancers, a large proportion of case patients in our study did not in fact have familial colorectal cancers and, therefore, our results should not be compared with those from the study by Lagerstedt Robinson et al. ( 1 ), which clearly focuses on high-risk colorectal cancer families.

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