A novel germline 1.8-kb deletion of hMLH1 mimicking alternative splicing: a founder mutation in the Chinese population

We have previously reported that there is a high incidence of microsatellit e instability (MSI) and germline mismatch repair gene mutation in colorecta l cancer arising from young Hong Kong Chinese, Most of the germline mutatio ns involve hMSH2, which is different from the mutation spectrum in the West ern population. It is well known that alternative splicing is common in hML H1, which complicates RNA based mutation detection methods. In contrast, la rge deletions in hMLH1, commonly observed in some ethnic groups, tend to es cape detection by exon-by-exon direct DNA sequencing. Here we report the de tection of a novel germline 1.8 kb deletion involving exon 11 of hMLH1 in a local hereditary non-polyposis colorectal cancer family. This mutation gen erates a mRNA transcript with deletion of exons 10-11, which is indistingui shable from one of the most common and predominant hMLH1 splice variants, A diagnostic test based on PCR of the breakpoint region led to the identific ation of an additional young colorectal cancer patient with this mutation. Haplotype analysis suggests that they may share a common ancestral mutation . Our results caution investigators in the interpretation of alternative sp licing and have important implications for the design of hMLH1 mutation det ection strategy in the Chinese population. Oncogene (2001) 20, 2976-2981.