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Recurrent germline mutation in MSH2 arises frequently de novo
D C Desai1, J C Lockman, R B Chadwick
1Division of Surgical Oncology, The Ohio State University, 410 W 10th Avenue, N-924 Doan Hall, Columbus, OH 43210, USA.
Journal of Medical Genetics
|September 9, 2000
Summary
The common MSH2 gene mutation (A-->T at nt942+3) causing hereditary non-polyposis colorectal cancer (HNPCC) arises frequently de novo, not from a recent founder. This finding highlights a significant predisposition to HNPCC.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- A specific intronic germline mutation in the MSH2 gene (A-->T at nt942+3) disrupts splicing, leading to exon 5 skipping and causing hereditary non-polyposis colorectal cancer (HNPCC).
- Previous studies suggested a founder effect for this mutation in Newfoundland, but not in England, indicating potential for frequent de novo occurrences.
- Understanding the origin of recurrent mutations is crucial for assessing genetic predisposition and cancer risk.
Purpose of the Study:
- To investigate the origin of the recurrent MSH2 A-->T nt942+3 mutation.
- To determine whether the mutation arose from a recent founder event or occurs frequently de novo across diverse populations.
Main Methods:
- Genomic DNA analysis of 10 families from England, Italy, Hong Kong, and Japan.
- Utilized a panel of intragenic and flanking polymorphic single nucleotide and microsatellite markers to assess haplotype sharing.
Main Results:
- No significant haplotype sharing was observed among families, even within continental groups (European and Asian).
- The marker panel was sufficiently powered to detect mutations originating within the last several thousand generations.
- The absence of shared haplotypes strongly argues against a recent common ancestor for this mutation.
Conclusions:
- The MSH2 A-->T nt942+3 mutation occurs de novo with a relatively high frequency, as a more ancient founder effect is implausible.
- The mutation likely arises from replication or recombination errors at a polyadenine tract (26 adenines), with the mutated A being the first.
- This represents the most common recurrent de novo germline mutation identified in a human mismatch repair gene, accounting for 11% of known pathogenic MSH2 mutations.