Health Information

Defects in mismatch repair cause hereditary nonpolyposis colon cancer (HNPCC) and probably are important in other cancers. This was initially suggested by the finding that some colon tumors showed frequent mutations in microsatellites (short repeating sequences, particularly mono- and dinucleotides), a phenotype called microsatellite instability.

HNPCC is an autosomal dominant disease. A gene contributing dominant to the risk for HNPCC was mapped to a region that contains a mismatch repair gene. This led to studies that demonstrated the primary defect to be a mutation in one of the mismatch repair genes. Defects in MLH1, MSH2, or PMS2 lead to HNPCC.

Why does the inheritance of a single defective allele in a mismatch repair gene lead to HNPCC? Cells lining the intestinal tract actively divide throughout a person’s life. There is a high probability that at some time in one’s life, a somatic mutation will occur in one allele of a mismatch repair gene in at least one colon cell. Cell in which one of the alleles at any of these loci is inactive can still carry out mismatch repair, so this does not generally lead to a tumor. However, in an individual who inherits one inactive allele, a somatic mutation that inactivates the single active copy leads to defective mismatch repair. Mutation rates can be elevated 100 to 1000 fold in cells when inactivated mismatch repair. The result is the accumulation of mutations that eventually lead to tumor formation through mutations in growth- regulating genes.