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目的分析中国人遗传性非息肉病性结直肠癌(hereditary nonpolyposis colorectal cancer,HNPCC)家系的临床及遗传性突变特点。方法收集整理符合中国人HNPCC诊断标准的31个家系资料,应用PCR及变性高效液相色谱分析(denaturing high-performance liquid chromatography,DHPLC)筛查hMLH1和hMSH2基因的突变,对DHPLC图形异常的样本进行测序。结果31个家系中共发生136例次恶性肿瘤(多原发肿瘤14例),其中结直肠癌106例次,占所有肿瘤患者的77．9%,诊断年龄均数为48．6±29．0岁；胃癌14例。肿瘤先证者中共检出分属于17个不同家系的23个碱基变异位点,经DNA序列分析,证实10个家系存在10个不同的碱基突变(10/31,32．9%),其中3个为同义突变未引起蛋白质序列的改变,另外7个为病理性改变,分别为错义突变、无义突变、移码突变。这10个突变中7个位点为首次报道。外显子区检测到5个已知SNP,内含子区检测到8个碱基改变。结论(1)符合中国人HNPCC标准家系约有1/3可检出hMLH1、hMSH2基因遗传性种系突变。(2)中国人HNPCC家系以左半结肠癌和直肠癌多见。
Objective To analyze the clinical and genetic characteristics of Chinese hereditary nonpolyposis colorectal cancer (HNPCC) pedigrees. Methods A total of 31 pedigrees matched with Chinese HNPCC diagnostic criteria were collected. The mutations of hMLH1 and hMSH2 genes were screened by PCR and denaturing high-performance liquid chromatography (DHPLC) Sequencing. Results A total of 136 malignancies (multiple primary tumors, 14 cases) occurred in 31 pedigrees, of which 106 cases were colorectal cancer, accounting for 77.9% of all cancer patients, the mean age at diagnosis was 48.6 ± 29.0 Years old; gastric cancer in 14 cases. Twenty-two base loci belonging to 17 different families were detected in the tumor probands, and 10 different base mutations (10/31, 32.9%) were confirmed in 10 families by DNA sequence analysis. Three of them were synonymous mutations did not cause changes in protein sequence, the other seven pathological changes were missense mutations, nonsense mutations, frameshift mutations. Seven of the ten mutations were reported for the first time. Five known SNPs were detected in the exon region and eight bases were detected in the intron region. Conclusions (1) About one third of HNPCC pedigrees in China can detect the genetic germline mutations of hMLH1 and hMSH2 genes. (2) Chinese HNPCC family is more common in left and right colon cancer and rectal cancer.