【摘要】 目的探讨错配修复基因hMLH3在家族性食管癌发生与发展中的作用。方法应用聚合酶链反应(PCR)、变性高效液相色谱分析(DHPLC)和直接测序法对10个有遗传背景的食管癌家族(66名成员),检测hMLH3基因所有外显子(共12个)的突变。对发现的基因改变,在家系内进行分离分析,并与在96例散发性食管癌患者和96例正常对照中发生的频率相比较。结果在4个家系中共发现了4个错义突变和3个碱基多态性,而4个错义突变在各自家系中的发生频率均高于散发性食管癌患者和正常对照中的频率。在家系9(A2173C)和10(C2825T)中,hMLH3的突变可能具有致病性,但外显率下降;而在家系1(T3826C)和7(T3826C)的结果不支持它是单一的高风险基因。结论hM-LH3基因在某些家族性食管癌中可能为高风险基因,但外显率下降,而在某些家系中可能仅为一低风险的基因,它诱导肿瘤的产生可能通过与其他基因相互叠加、共同起作用。更多还原

【Abstract】 OBJECTIVE:To investigate the possible role of the mismatch repair gene hMLH3 in familial esophageal cancer. METHODS: A total of 66 members from 10 families suggestive of a genetic predisposition for hereditary esophageal cancer,were screened for germline mutations in a total of 12 exons of hMLH3, with PCR, denaturing high performance liquid chromatography (DHPLC) and cycle sequencing. For any mutation in family members, the segregation study within families was conducted, and compared its prevalence was compared with that of 96 sporadic esophageal cancers and as well as in 96 normal controls. RESULTS: Overall, 4 missense mutations and 3 polymorphisms were identified in 4 families. The prevalence in families was higher than that in patients with sporadic esophageal cancers and normal controls. Missense mutations A2173C in family 9 and C2825T in family 10 may be pathogenic, but with reduced penetrance. As for T3826C in family 1 and T3826C in 7, there was not sufficient evidence supporting the monogenic explanations of esophageal cancers in families. CONCLUSION: In some families, hMLH3 could be a high risk gene with reduced penetrance. While in most families, it acts as a low risk gene for esophageal cancer. The mutations of hMLH3 could work together with other genes in an additive manner and result in an elevated risk of esophageal tumors in the family.更多还原