Tanyi Miklós, Olasz Judith, Lukács Géza, Csuka Orsolya, Tóth László, Szentirmay Zoltán, Ress Zsuzsa, Barta Zsolt, Tanyi János L, Damjanovich László
1st Department of Surgery, Medical and Health Sciences Center, University of Debrecen, H-4012 Debrecen, Nagyerdei krt. 98, PO Box 27, Hungary.
World J Gastroenterol. 2006 Feb 28;12(8):1192-7. doi: 10.3748/wjg.v12.i8.1192.
To screen a suspected Hungarian HNPCC family to find specific mutations and to evaluate their effect on the presentation of the disease.
The family was identified by applying the Amsterdam and Bethesda Criteria. Immunohistochemistry was performed, and DNA samples isolated from tumor tissue were evaluated for microsatellite instability. The identification of possible mutations was carried out by sequencing the hMLH1 and hMSH2 genes.
Two different mutations were observed in the index patient and in his family members. The first mutation was located in exon 7, codon 422 of hMSH2, and caused a change from Glu to STOP codon. No other report of such a mutation has been published, as far as we could find in the international databases. The second mutation was found in exon 3 codon 127 of the hMSH2 gene, resulting in Asp-->Ser substitution. The second mutation was already published, as a non-pathogenic allelic variation.
The pedigree analysis suggested that the newly detected nonsense mutation in exon 7 of the hMSH2 gene might be responsible for the development of colon cancers. In family members where the exon 7 mutation is not coupled with this missense mutation, colon cancer appears after the age of 40. The association of these two mutations seems to decrease the age of manifestation of the disease into the early thirties.
对一个疑似匈牙利遗传性非息肉病性结直肠癌（HNPCC）家族进行筛查，以寻找特定突变并评估其对疾病表现的影响。
应用阿姆斯特丹标准和贝塞斯达标准对该家族进行鉴定。进行免疫组织化学检测，并对从肿瘤组织中分离的DNA样本进行微卫星不稳定性评估。通过对hMLH1和hMSH2基因进行测序来鉴定可能的突变。
在索引患者及其家族成员中观察到两种不同的突变。第一种突变位于hMSH2基因的第7外显子，密码子422处，导致从谷氨酸（Glu）变为终止密码子。据我们在国际数据库中所能查到的，尚未有关于这种突变的其他报道。第二种突变在hMSH2基因的第3外显子密码子127处被发现，导致天冬氨酸（Asp）替换为丝氨酸（Ser）。第二种突变已作为一种非致病性等位基因变异发表过。
系谱分析表明，新检测到的hMSH2基因第7外显子的无义突变可能是结肠癌发生的原因。在第7外显子突变未与这种错义突变同时出现的家族成员中，结肠癌在40岁以后出现。这两种突变的关联似乎将疾病的发病年龄降低到了三十出头。
