Cai Qi, Sun Meng-hong, Fu Gang, Ding Chun-wei, Mo Shan-jing, Cai San-jun, Ren Shuang-xi, Min Da-liu, Xu Xiao-li, Zhu Wei-ping, Zhang Tai-ming, Shi Da-ren
Department of Pathology, Cancer Hospital/Cancer Institute, Fudan University, Shanghai 200032, China.
Zhonghua Bing Li Xue Za Zhi. 2003 Aug;32(4):323-8.
To determine the germ-line mutations of hMSH2 and hMLH1 genes in Chinese hereditary nonpolyposis colorectal cancer (HNPCC) families' probands or in patients fulfilling different clinical criteria or guidelines; to clarify the nature and distribution of the mutations; to evaluate the sensitivity of different clinical criteria in mutation prediction.
The entire coding regions (35 exons including exon-intron boundaries) of hMSH2 and hMLH1 genes were directly sequenced in 24 Amsterdam criteria (AC) probands, 15 Japanese criteria (JC) probands (except AC kindreds) and 19 Bethesda guidelines (BG) patients (except two former groups). All available affected and unaffected members from families of those with mutations were screened for mutation.
In 16 unrelated families selected by the different clinical criteria, 17 germ-line mutations were found with 11 (64.7%) of hMLH1 and 6 (35.3%) of hMSH2. Two mutations were identified in one of the families. Among the 17 germ-line mutations, 12 had not been reported previously. A diversified mutation spectrum was found, but 6 hMLH1 mutations were found to be concentrated in the region encompassing exon 14, 15 and 16. There was a wide spectrum of mutation type including frame shift, nonsense, splice site mutation, in frame insertion or deletion and missense mutations. The mutation detection rate of hMSH2 and hMLH1 in the AC group was significantly higher than that in the JC group (12/24 vs. 3/15). On the other hand, a low mutation rate (1/19) was detected in 19 BG patients. The mutation cosegregated with disease. Besides, three different genotypes in tumors from probands of mutation-positive families were found.
hMSH2 and hMLH1 mutations in Chinese HNPCC families show a wide spectrum. It seems that hMLH1 gene is involved more frequently than hMSH2 gene in Chinese HNPCC families. Different clinical criteria predict mutations with different sensitivities. The Amsterdam Criteria are most sensitive, while Japanese Criteria are highly practical and the Bethesda Guidelines are also practical to some extent. Gene mutations cosegregate with the disease phenotype. Carriers with no symptom in HNPCC families are most vulnerable groups, follow-ups are required for this group to get early diagnosis and to prevent the development of CRCs.
确定中国遗传性非息肉病性结直肠癌（HNPCC）家系先证者或符合不同临床标准或指南的患者中hMSH2和hMLH1基因的种系突变；阐明突变的性质和分布；评估不同临床标准在突变预测中的敏感性。
对24例符合阿姆斯特丹标准（AC）的先证者、15例符合日本标准（JC）的先证者（不包括符合AC标准的家系）以及19例符合贝塞斯达指南（BG）的患者（不包括前两组）的hMSH2和hMLH1基因的整个编码区（35个外显子，包括外显子-内含子边界）进行直接测序。对那些有突变者的家系中所有可获得的患病和未患病成员进行突变筛查。
在根据不同临床标准选择的16个无关家系中，发现了17个种系突变，其中hMLH1基因11个（64.7%），hMSH2基因6个（35.3%）。在其中一个家系中鉴定出两个突变。在这17个种系突变中，有12个此前未被报道。发现了多样化的突变谱，但发现6个hMLH1突变集中在外显子14、15和16区域。突变类型广泛，包括移码突变、无义突变、剪接位点突变、框内插入或缺失以及错义突变。AC组中hMSH2和hMLH1的突变检出率显著高于JC组（12/24对3/15）。另一方面，在19例BG患者中检测到低突变率（1/19）。突变与疾病共分离。此外，在突变阳性家系先证者的肿瘤中发现了三种不同的基因型。
中国HNPCC家系中的hMSH2和hMLH1突变显示出广泛的谱。在中国HNPCC家系中，hMLH1基因似乎比hMSH2基因更频繁地受累。不同的临床标准对突变的预测敏感性不同。阿姆斯特丹标准最敏感，而日本标准实用性高，贝塞斯达指南在一定程度上也实用。基因突变与疾病表型共分离。HNPCC家系中无症状的携带者是最脆弱的群体，该群体需要进行随访以早期诊断并预防结直肠癌的发生。
