Pensotti V, Radice P, Presciuttini S, Calistri D, Gazzoli I, Grimalt Perez A, Mondini P, Buonsanti G, Sala P, Rossetti C, Ranzani G N, Bertario L, Pierotti M A
Division of Experimental Oncology A, Istituto Nazionale Tumori, Milano, Italy.
Genes Chromosomes Cancer. 1997 Jul;19(3):135-42.
Fourteen Italian families affected with hereditary nonpolyposis colorectal cancer (HNPCC) were screened for germline mutations at three DNA mismatch repair (MMR) genes, MSH2, MLHI, and GTBP, by using a combination of different methods that included an in vitro synthesized protein assay, single-strand conformation polymorphism analysis, and direct sequencing. DNA alterations were observed in six instances, including a single base deletion in MSH2 exon 14, an A-to-G transition in the splice donor site of MLHI exon 6, and two missense mutations in MLHI exons 5 and 9. A previously reported common mutation affecting the splice donor site of MSH2 exon 5 was identified in two families. No mutations were detected in the GTBP gene. In total, eight of 16 Italian HNPCC families (50%), including two previously reported kindreds, were found to carry a mutation in MMR genes. We compared the mean age of colorectal cancer onset in the index cases (three patients for each family) between the two groups of kindreds, those with identified mutation vs. those without, and found that the first had a significantly lower value (43.0 vs. 53.7 years, P = 0.014). This finding suggests that HNPCC families with a more advanced age of tumor onset are less likely to be associated with known MMR genes.
通过使用包括体外合成蛋白检测、单链构象多态性分析和直接测序在内的多种不同方法，对14个患有遗传性非息肉病性结直肠癌（HNPCC）的意大利家庭进行了3个DNA错配修复（MMR）基因（MSH2、MLH1和GTBP）的种系突变筛查。在6例中观察到DNA改变，包括MSH2外显子14中的单个碱基缺失、MLH1外显子6剪接供体位点的A到G转换以及MLH1外显子5和9中的两个错义突变。在两个家庭中鉴定出先前报道的影响MSH2外显子5剪接供体位点的常见突变。在GTBP基因中未检测到突变。总共16个意大利HNPCC家庭中有8个（50%），包括两个先前报道的家族，被发现携带MMR基因中的突变。我们比较了两组家族（有已鉴定突变的家族与无突变的家族）中索引病例（每个家族3名患者）结直肠癌发病的平均年龄，发现前者的值显著更低（43.0岁对53.7岁，P = 0.014）。这一发现表明，肿瘤发病年龄较大的HNPCC家庭与已知MMR基因相关的可能性较小。
