Ponz de Leon M, Benatti P, Di Gregorio C, Pedroni M, Losi L, Genuardi M, Viel A, Fornasarig M, Lucci-Cordisco E, Anti M, Ponti G, Borghi F, Lamberti I, Roncucci L
Dipartimento di Medicine e Specialità Mediche, Medicina I, Università di Modena e Reggio Emilia, Policlinico, Via del Pozzo 71, Modena 41100, Italy.
Br J Cancer. 2004 Feb 23;90(4):882-7. doi: 10.1038/sj.bjc.6601529.
Hereditary nonpolyposis colorectal cancer (HNPCC) is frequently associated with constitutional mutations in a class of genes involved in DNA mismatch repair. We identified 32 kindreds, with germline mutations in one of three genes hMSH2, hMLH1 or hMSH6. In this study, we purposed to evaluate how many high-risk individuals in each family underwent genetic testing: moreover, we assessed how many mutation-positive unaffected individuals accepted colonoscopic surveillance and the main findings of the recommended follow-up. Families were identified through a population-based registry, or referred from other centres. Members of the families were invited for an education session with two members of the staff. When a kindred was consistent with HNPCC, neoplastic tissues were examined for microsatellite instability (MSI) and immunohistochemical expression of MSH2, MLH1 and MSH6 proteins. Moreover, constitutional mutations were searched by SSCP or direct sequencing of the whole genomic region. Of the 164 subjects assessed by genetic testing, 89 were gene carriers (66 affected - that is, with HNPCC-related cancer diagnosis - and 23 unaffected) and 75 tested negative. Among the 23 unaffected gene carriers, 18 (78.3%) underwent colonoscopy and four declined. On a total of 292 first degree at risk of cancer, 194 (66.4%) did not undergo genetic testing. The main reasons for this were: (a) difficulty to reach family members at risk, (b) lack of collaboration, (c) lack of interest in preventive medicine or 'fatalistic' attitude towards cancer occurrence. The number of colorectal lesions detected at endoscopy in gene carriers was significantly (P<0.01) higher than in controls (noncarriers). We conclude that a large fraction of high-risk individuals in mutation-positive HNPCC families does not undergo genetic testing, despite the benefits of molecular screening and endoscopic surveillance. This clearly indicates that there are still barriers to genetic testing in HNPCC, and that we are unable to provide adequate protection against cancer development in these families.
遗传性非息肉病性结直肠癌（HNPCC）常与一类参与DNA错配修复的基因的先天性突变相关。我们鉴定出32个家系，其种系突变存在于hMSH2、hMLH1或hMSH6这三个基因之一中。在本研究中，我们旨在评估每个家族中有多少高危个体接受了基因检测；此外，我们评估了有多少未受影响的突变阳性个体接受了结肠镜监测以及推荐随访的主要结果。这些家系是通过基于人群的登记处识别出来的，或者是由其他中心转诊而来的。邀请这些家系的成员参加由两名工作人员组织的教育活动。当一个家系符合HNPCC时，对肿瘤组织进行微卫星不稳定性（MSI）检测以及MSH2、MLH1和MSH6蛋白的免疫组化表达检测。此外，通过单链构象多态性（SSCP）或对整个基因组区域进行直接测序来寻找先天性突变。在接受基因检测的164名受试者中，89名是基因携带者（66名受影响，即被诊断患有与HNPCC相关的癌症，23名未受影响），75名检测结果为阴性。在23名未受影响的基因携带者中，18名（78.3%）接受了结肠镜检查，4名拒绝了。在总共292名有患癌风险的一级亲属中，194名（66.4%）未接受基因检测。主要原因如下：（a）难以联系到有风险的家庭成员；（b）缺乏合作；（c）对预防医学缺乏兴趣或对癌症发生持“宿命论”态度。基因携带者在内镜检查中检测到的结直肠病变数量显著高于对照组（非携带者）（P<0.01）。我们得出结论，尽管分子筛查和内镜监测有益，但突变阳性的HNPCC家系中仍有很大一部分高危个体未接受基因检测。这清楚地表明，HNPCC的基因检测仍然存在障碍，而且我们无法为这些家系提供足够的癌症发生预防保护。
