DNA Mismatch Repair in Prostate Cancer

Abstract

Identification of germline mutations associated with cancer susceptibility has led to the rational development of screening protocols and prevention strategies for patients with heritable syndromes or those at increased risk for developing cancer. As reported in Journal of Clinical Oncology, Raymond et al investigated several generations of a large cohort of DNA mismatch repair (MMR) mutation–positive Lynch syndrome families and discovered an increased risk of prostate cancer in the 4,127 male carriers evaluated, at a rate two-fold higher than that in the general population and slightly higher in those younger than 60 years of age. These findings not only have important clinical implications for screening but also highlight the role of DNA MMR in tumorigenesis. Normal cells rely on DNA repair processes to correct biosynthetic errors that occur during replication. Six MMR proteins are required for proper nucleotide mismatch repair: MSH2, MLH1, PMS1, PMS2, MSH6, and MLH3. These proteins function coordinately within biochemical complexes to recognize and repair single base-base mismatches or defective insertion-deletion loops (Fig 1A). Lynch syndrome is an autosomal-dominant disorder characterized by single-allele germline mutations of an MMR gene, most commonly MLH1, MSH2, MSH6, or PMS2. By definition, these germline mutations are present in all cells of affected patients; however, a second allelic hit in somatic cells within a particular tissue type (through mutation, loss of heterozygosity, or epigenetic