中国汉族和韩国朝鲜族非息肉性结直肠癌家系临床及遗传学表型的比较分析

Comparison of clinical and genetic phenotypes between Chinese and Korean hereditary nonpolyposis colorectal cancer families

目的分析和比较汉族和朝鲜族遗传性非息肉性结直肠癌（hereditary nonpolyposis colorectal cancer，HNPCC）家系的临床及遗传学表型的异同点。方法收集31个中国的汉族家系和63个韩国的朝鲜族家系先证者和家系成员的各项临床资料，对先证者外周血DNA进行相关基因hMLH1和hMSH2的种系突变检测。应用聚合酶链反应-单链构象多态性分析或变性高效液相色谱法筛查突变，对结果异常的样本进行DNA测序。结果31个汉族家系中共发生136例次恶性肿瘤，其中结直肠癌106例次，占所有肿瘤患者的77．9％，诊断年龄平均为（48．6±29．0）岁；其次为胃癌共14例。经突变检测，31例汉族先证者中有7例被检出含有hMLH1（3个）或hMSH2（4个）基因的病理性突变，总突变率为22．6％。其中错义突变2个、无义突变2个、移码突变2个、大片段缺失1个。63个朝鲜族家系中共发生293例次恶性肿瘤，其中结直肠癌242例次，占所有肿瘤患者的82．6％，诊断年龄平均为（45．9±11．0）岁；胃癌同样也是第2大常见肿瘤类型，共发生21例。63例朝鲜族先证者中有19例被检测出含有hMLH1（17个）或hMSH2（2个）基因的突变，总突变率为30．2％。其中12个为移码突变，5个为错义突变，1个为无义突变，1个为剪接位点的碱基改变导致异常剪接。结论（1）汉族与朝鲜族HNPCC家系在临床表现上相似，均有发病年龄轻、以远端结肠癌和直肠癌多见、多原发大肠癌发生率较西方国家低、肠外肿瘤以胃癌最多见等特点。（2）遗传表型方面，汉族与朝鲜族HNPCC家系的总突变率相似，但均低于西方国家的报道。两个种族的家系中的突变基因、突变类型和突变分布上存在差异及各自的特征。

Objective To compare the clinical and genetic features between Chinese and Korean hereditary nonpolyposis colorectal cancer （HNPCC） families. Methods Thirty-one Chinese HNPCC families and 63 HNPCC Korean families were involved in this study. The clinical data of the probands and families were collected. Genomic DNAs were prepared from peripheral blood samples of probands for DNA test. PCR and DHPLC were employed to screen the mutations. Sequencing analysis was followed to find out the exact mutation site and feature in samples showing abnormahties in SSCP or DHPLC analysis. Results In a total, there were 136 malignant neoplasms diagnosed in the 31 Chinese families, about 77.9% of them were colorectal cancer. The mean age of colorectal cancer at diagnosis was （48.6 ± 29.0） years. Gastric cancer was the second most common cancer in these families. Seven pathogenic mutations （ 3 in hMLH1 gene and 4 in hMSH2 gene） were detected in the 31 probands, including 2 missense mutations, 2 nonsense mutations, 2 frameshift mutations and 1 large-fragment deletion. The total mutation rate was 22.6%. In the 63 Korean families, 293 malignant neoplasms were documented, 82.6% of them were diagnosed as colorectal cancer. The mean age of colorectal cancer at diagnosis was （45.9 ± 11.0） years. Gastric cancer was also the most common extracolonic cancer in these Korean families. Nineteen pathogenic mutations （ 17 in hMLH1 gene and 2 in hMSH2 genes） were detected in the 63 probands, including 12 frarneshift mutations, 5 missense mutations, 1 nonsense mutation and 1 base-change at the splicing site. The total mutation rate was 30.2%. Conclsuion （1） Chinese and Korean HNPCC families had many similar clinical features, such as early-onset of colorectal cancer, predominance in distal colon and rectum, lower incidence of synchronous or metachronous colorectal cancers as compared with Western countries, and a frequent occurrence of gastric cancer in the families. （2） The total mutation rate of hMLH1 and hMSH2 gene in Chinese and Korean HNPCC families was similar and lower than that reported in Western countries. But the mutation characteristics, such as predominant gene, mutation type and mutation distribution, were different in the two populations.