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Some cases of hereditary nonpolyposis colorectal cancer (HNPCC) are due to alterations in a mutS-related mismatch repair gene. A search of a large database of expressed sequence tags derived from random complementary DNA clones revealed three additional human mismatch repair genes, all related to the bacterial mutL gene. One of these genes (hMLH1) resides on chromosome 3p21, within 1 centimorgan of markers previously linked to cancer susceptibility in HNPCC kindreds. Mutations of hMLH1 that would disrupt the gene product were identified in such kindreds, demonstrating that this gene is responsible for the disease. These results suggest that defects in any of several mismatch repair genes can cause HNPCC.

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disorder characterized by the early onset of colorectal cancer and linked to germline defects in at least four mismatch repair genes. Although much has been learned about the molecular pathogenesis of this disease, questions related to effective presymptomatic diagnosis are largely unanswered because of its genetic complexity. In this study, we evaluated tumors from 74 HNPCC kindreds for genomic instability characteristic of a mismatch repair deficiency and found such instability in 92% of the kindreds. The entire coding regions of the five known human mismatch repair genes were evaluated in 48 kindreds with instability, and mutations were identified in 70%. This study demonstrates that a combination of techniques can be used to genetically diagnose tumor susceptibility in the majority of HNPCC kindreds and lays the foundation for genetic testing of this relatively common disease.

Persons with the Lynch syndrome (LS) are at high risk for cancer, including cancers of the small bowel, stomach, upper urologic tract (renal pelvis and ureter), ovary, biliary tract, and brain tumors, in addition to the more commonly observed colorectal and endometrial cancers. Cancer prevention strategies for these less-common cancers require accurate, age-specific risk estimation. We pooled data from four LS research centers in a retrospective cohort study, to produce absolute incidence estimates for these cancer types, and to evaluate several potential risk modifiers. After elimination of 135 persons missing crucial information, cohort included 6041 members of 261 families with LSassociated MLH1 or MSH2 mutations. All were either mutation carriers by test, probable mutation carriers (endometrial/colorectal cancer-affected), or first-degree relatives of these. Among mutation carriers and probable carriers, urologic tract cancer (N=98) had an overall lifetime risk (to age 70) of 8.4% (95%CI: 6.6-10.8); risks were higher in males (p<0.02) and members of MSH2 families (p<0.0001). Ovarian cancer (N=72) had an lifetime risk of 6.7% (95%CI: 5.3-9.1); risks were higher in women born after the median year of birth (p<0.008) and in members of MSH2 families (p<0.006). Brain tumors and cancers of the small bowel, stomach, breast, and biliary tract were less common. Urologic tract cancer and ovarian cancer occur frequently enough in some LS subgroups to justify trials to evaluate promising prevention interventions. Other cancer types studied occur too infrequently to justify strenuous cancer control interventions. NIH Public Access