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Discovery of Novel Hypermethylation Mechanism in Heritable MSH2 Mutations Linked to HNPCC

This study explores a novel mutational mechanism involving hypermethylation that leads to gene silencing in MSH2 representative of hereditary non-polyposis colorectal cancer (HNPCC). Notably, cases from Dutch and Chinese families reveal a deletion upstream of MSH2 in the TACSTD1 gene, which leads to aberrant transcription and hypermethylation of the MSH2 promoter. While hypermethylation typically undergoes erasure during gametogenesis, unknown mechanisms perpetuate this alteration, contributing to HNPCC phenotype. Insights into this mechanism may provide implications for understanding similar occurrences in other genes.

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Discovery of Novel Hypermethylation Mechanism in Heritable MSH2 Mutations Linked to HNPCC

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  1. A novel mutational mechanism

  2. Hypermethylation • Methylation is known as a method of gene silencing • Hypermethylation can occur somatically in MLH1 and MSH2 tumours • Some v. rare cases of heritable MSH2 hypermethylation described, cause unknown • Thought that any hypermethylation imprint would normally be erased during gametogenesis – mechanism currently unknown

  3. The initial cases • Dutch family with MSI high colorectal cancer and loss of MSH2/MSH6 on IHC • No mutation identified despite comprehensive mutation scanning • Routine MLPA identified a deletion 16kb upstream of MSH2 in exon 9 of the TACSTD1 gene • The deletion leaves the MSH2 promoter intact • Screening of further Dutch families with unexplained HNPCC revealed four further cases with the same deletion • Haplotype analysis indicate a founder mutation • Mosaic promoter hypermethylation present

  4. Further cases • A Chinese family previously reported with heritable methylation of MSH2 also showed a deletion of exons 6-9 at the 3’ end of TACSTD1 • Screening of further Chinese HNPCC cases showed a further family with a TACSTD1 deletion and MSH2 methylation • The 2 Chinese families had the same deletion but haplotype analysis indicated different origins

  5. Conclusions • TACSTD1 deletion removes the TACSTD1 polyadenylation signal • Normally the TACSTD1 transcript terminates no more than 35bp 3’ of the polyadenylation signal • Transcripts from Dutch and Chinese families show hybrid TACSTD1/MSH2 mRNA • Transcript read through then causes the MSH2 CpG island to become hypermethylated • This inactivates MSH2 leading to a phenotype of HNPCC • A novel mutational mechanism • This effect may occur in other genes and also from transcript read through on opposite DNA strand

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