Abstract
We have previously reported that there is a high incidence of microsatellite instability (MSI) and germline mismatch repair gene mutation in colorectal cancer arising from young Hong Kong Chinese. Most of the germline mutations involve hMSH2, which is different from the mutation spectrum in the Western population. It is well known that alternative splicing is common in hMLH1, which complicates RNA based mutation detection methods. In contrast, large deletions in hMLH1, commonly observed in some ethnic groups, tend to escape detection by exon-by-exon direct DNA sequencing. Here we report the detection of a novel germline 1.8 kb deletion involving exon 11 of hMLH1 in a local hereditary non-polyposis colorectal cancer family. This mutation generates a mRNA transcript with deletion of exons 10–11, which is indistinguishable from one of the most common and predominant hMLH1 splice variants. A diagnostic test based on PCR of the breakpoint region led to the identification 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 splicing and have important implications for the design of hMLH1 mutation detection strategy in the Chinese population.
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Acknowledgements
We thank Professor Andrew H Wyllie for useful discussions and comments. We also thank Professor John Wong, Professor JST Sham, Dr David Higgins and Dr RJ Collins for their support, Mr Ivan SH Ho for his technical assistance, and Dr N Trendell-Smith for his help in the preparation of this manuscript. This work was supported by a grant from the Research Grants Council of the Hong Kong Special Administrative Region (HKU 7330/00M), a donation from the Hong Kong Cancer Fund and a donation from the Hong Kong Society of Gastroenterology.
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Chan, T., Yuen, S., Ho, J. et al. A novel germline 1.8-kb deletion of hMLH1 mimicking alternative splicing: a founder mutation in the Chinese population. Oncogene 20, 2976–2981 (2001). https://doi.org/10.1038/sj.onc.1204376
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DOI: https://doi.org/10.1038/sj.onc.1204376
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