AIM： To shed light on the possible role of mismatch repair gene MIh3 in familial esophageal cancer （FEC）. METHODS： A total of 66 members from 10 families suggestive of a genetic predisposition to hereditary esopha...AIM： To shed light on the possible role of mismatch repair gene MIh3 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 mutations in MIh3 with denaturing high performance liquid chromatography （DHPLC）, a newly developed method of comparative sequencing based on heteroduplex detection. For all samples exhibiting abnormal DHPLC profiles, 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 MIh3 in all samples were successfully examined. Overall, 4 missense mutations and 3 polymorphisms were identified in 4 families. MIh3 missense mutations in families 9 and 10 might be pathogenic, but had a reduced penetrance. While in families 1 and 7, there was no sufficient evidence supporting the monogenic explanations of esophageal cancers in families. The mutations were found in 33% of high-risk families and 50% of low-risk families.CONCLUSION： MIh3 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. Mutations of MIh3 may work together with other genes in an accumulated manner and result in an increased risk of esophageal tumor. DHPLC is a robust and sensitive technique for screening gene mutations.展开更多
基金Supported by the National Natural Science Foundation of China,No. 30070850 grant from Ministry of Education of China, No.(2004) 527 and grant from Armed Police Logistics ScientificResearch Project, No. WKH2004010
文摘AIM： To shed light on the possible role of mismatch repair gene MIh3 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 mutations in MIh3 with denaturing high performance liquid chromatography （DHPLC）, a newly developed method of comparative sequencing based on heteroduplex detection. For all samples exhibiting abnormal DHPLC profiles, 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 MIh3 in all samples were successfully examined. Overall, 4 missense mutations and 3 polymorphisms were identified in 4 families. MIh3 missense mutations in families 9 and 10 might be pathogenic, but had a reduced penetrance. While in families 1 and 7, there was no sufficient evidence supporting the monogenic explanations of esophageal cancers in families. The mutations were found in 33% of high-risk families and 50% of low-risk families.CONCLUSION： MIh3 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. Mutations of MIh3 may work together with other genes in an accumulated manner and result in an increased risk of esophageal tumor. DHPLC is a robust and sensitive technique for screening gene mutations.
