遗传性非息肉病性结直肠癌家系临床及分子遗传学分析

目的探讨总结遗传性非息肉病性结直肠癌(hereditary nonpolyposis colorectal cancer,HNPCC)的临床和分子生物学特征,提高临床诊断和治疗水平。方法分析总结温州地区12个HNPCC家系临床病理特征。用显微切割、微卫星不稳定性分析、免疫组织化学、直接DNA测序法,检测HNPCC患者肿瘤组织微卫星不稳定性状态,错配修复基因hMHL1和hMSH2蛋白水平表达及hMHL1和hMSH2基因种系突变。结果12个家系32例患者中,患第1癌的中位年龄45．2岁;75．0％的患者在50岁以前发病;51．1％的肿瘤位于脾曲近侧结肠,34．4％为多原发结直肠癌,53．1％为组织分化差的癌,68．8％为Dukes A、B期。12个家系中6个家系伴有7例肠外肿瘤患者;19例健在患者生存1～28年,13例死亡患者平均生存期6．4年。9例患者肿瘤组织均表现高度微卫星不稳定性,其中5例患者表现hMSH2或hMLH1蛋白失表达(5／9);5个家系中3个家系存在hMH;1或hMSH2突变(3／5),其中有2个新发现的突变。结论HNPCC有特定的临床病理特征;检测错配修复基因hMHL1和hMSH2序列对HNPCC家系的成员具有指导价值;微卫星不稳定性和错配修复蛋白失表达是HNPCC的重要特征,可作为测序前的筛选手段。

Clinical analysis and molecular genetic study of hereditary nonpolyposis colorectal cancer kindreds

OBJECTIVE: To study the clinicopathological and molecular genetic characteristics of hereditary nonpolyposis colorectal cancer (HNPCC), to enable the early diagnosis and to evaluate the treatment. METHODS: We analyzed 12 families of HNPCC from Wenzhou, Zhejiang province, China. Mismatch repair genes hMSH2 and hMLH1 expression and microsatellite instability of tumor tissue were studied using microdissection, microsatellite analysis, immunohistochemical staining and Gene Scan analysis. Direct DNA sequencing of hMSH2 and hMLH1 were performed subsequently. RESULTS: Altogether 32 patients with colorectal cancer were recognized in 12 HNPCC families, with the median age of 45.2 years (75.0% before the age of 50 years). The proximal tumors accounted for 51.1%, while multiple colorectal cancers accounted for 34.4%. Poor differentiation cancers occupied half of the patients (53.1%). And 68.8% of the patients had the tumor of Dukes A and B. Among 12 HNPCC families, 7 cases in 6 HNPCC families developed extracolonic cancer. 13 cases died during follow up of 1 - 23 years. The median survival time was 6.4 years. 19 alive cases followed up from 1 to 28 years. All tumors (9/9) displayed microsatellite instability, with the half losing hMSH2 or hMLH1 expression. In the 5 genetic analyzed kindreds 3 possessed germline mutation. Two of three mutations have not been reported in the worldwide database previously. CONCLUSION: HNPCC showed distinct clinicopathological characteristics. Microsatellite instability analysis and immunohistochemical staining might be the effective screening methods before direct DNA sequencing for the detection of mutation in mismatch repair genes. It is important to analyze the members of affected families.