Recurrent germline mutation in MSH2 arises frequently de novo

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.