Gene-environment interaction in hereditary nonpolyposis colorectal cancer with implications for diagnosis and genetic testing

Hereditary nonpolyposis colorectal cancer (Lynch syndrome) is an autosomal dominant disease caused by mutations in the mismatch repair genes in partic ular in MLH1, MSH2 and MSH6. The disease is characterized by the developmen t of colorectal, endometrial cancer and several other cancers, There is evi dence that the clinical expression of the disease varies from one country t o another. This variation might affect not only the application of criteria proposed to identify families but also clinical risk factors reported to p redict the outcome of genetic testing. Data on site of the cancer, age at diagnosis and pathology were collected f rom 155 families with suspected HNPCC known at the Korean and Dutch HNPCC r egistries. DGGE, SSCP and DNA-sequencing were performed to identify MSH2, M LH1 and MSH6 mutations. A total of 33 Korean and 42 Dutch families met the clinical criteria for HN PCC. Germline mutations in the MMR-genes were found in 23 Korean and 24 Dut ch families. In families that met the Amsterdam criteria, and also in those associated with MLH1 mutations, more cancers of the stomach and pancreas w ere observed in the Korean families than in the Dutch HNPCC families; in re lative terms, the incidence of cancers of the endometrium in the Korean fam ilies was lower. Multivariate analysis showed that an early age at diagnosi s, and the occurrence of pancreatic cancer were independent predictive fact ors of germline mutations in MLH1, MSH2 and MSH6 in the Korean subset of fa milies, (C) 1999 Wiley-Liss, Inc.