Mutation screening of mismatch repair gene Mlh3 in familial esophageal cancer

摘要

AIM: To shed light on the possible role of mismatch repair gene Mlh3 in familial esophageal cancer (FEC). METHODS: A total of 66 members from 10 families suggestive of a genetic predisposition to hereditary esophageal cancer were screened for germline muta-tions in Mlh3 with denaturing high performance liquid chromatography (DHPLC), a newly developed method of comparative sequencing based on heteroduplex detec-tion. For all samples exhibiting abnormal DHPLC profi les, sequence changes were evaluated by cycle sequencing. For any mutation in family members, we conducted a segregation study to compare its prevalence in sporadic esophageal cancer patients and normal controls. RESULTS: Exons of Mlh3 in all samples were successful-ly examined. Overall, 4 missense mutations and 3 poly-morphisms were identifi ed in 4 families. Mlh3 missense mutations in families 9 and 10 might be pathogenic, but had a reduced penetrance. While in families 1 and 7, there was no suffi cient evidence supporting the mono-genic explanations of esophageal cancers in families. The mutations were found in 33% of high-risk families and 50% of low-risk families. CONCLUSION: Mlh3 is a high risk gene with a reduced penetrance in some families. However, it acts as a low risk gene for esophageal cancer in most families. Muta-tions of Mlh3 may work together with other genes in anaccumulated manner and result in an increased risk ofesophageal tumor. DHPLC is a robust and sensitive tech-nique for screening gene mutations.