DNA Mismatch Repair Genes

HNPCC has been linked to multiple genetic mutations in the DNA mismatch repair (MMR) genes (134,135). One function of the MMR genes is to detect and correct mismatched nucleotides in DNA strands. Loss-of-function of these genes leads to error-prone DNA replication and microsatellite instability. Eventually, buildup of genetic replication errors in oncogenes and tumor suppressor genes leads to carcinogenesis. Indeed, Risinger et al. (136) detected microsatellite instability in 75% of endometrial carcinomas associated with HNPCC vs only 17% of sporadic cancers.

Five mutations in the MMR genes have been linked to HNPCC (Table 3). Two of these, MLH1 on chromosome 3 and MSH2 on chromosome 2, account for the vast majority of cases, 45 and 49%, respectively (137). Most of the remainder occurs in PMS2 on chromosome 7, whereas mutations in PSM1 and MSH6 are noted only sporadically. Little is known about the prevalence of MMR gene mutations, but prevalence appears to vary widely. Carrier frequencies are usually calculated by screening individuals with colon cancer for mutations in various MMR genes. Samowitz et al. (138) conducted a population-based study of 1066 individuals from Utah and California with colon cancer and identified seven pathogenical mutations in MSH2 and MLH1. Thus, leading to a prevalence of 0.86% after adjustment for availability of germline DNA. Percesepe et al. examined 336 consecutive cases of colon cancer in Italy and noted only one germline mutation (in MSH2), yielding a prevalence of 0.3% (139). In the largest study to date, Salovaara et al. (140) examined 1044 consecutive cases of colon cancer in Finland and noted 28 cases of mutation-positive HNPCC, predicting a rate of 2.7%, more than three times that found in the United States study.

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