Plaschke Jens, Krüger Stefan, Dietmaier Wolfgang, Gebert Johannes, Sutter Christian, Mangold Elisabeth, Pagenstecher Constanze, Holinski-Feder Elke, Schulmann Karsten, Möslein Gabriela, Rüschoff Josef, Engel Christoph, Evans Gareth, Schackert Hans K
Department of Surgical Research, Dresden University of Technology, Germany.
Hum Mutat. 2004 Mar;23(3):285. doi: 10.1002/humu.9217.
Germline mutations in mismatch repair (MMR) genes, predominantly in MLH1 and MSH2, are responsible for hereditary nonpolyposis colorectal cancer (HNPCC), a cancer-susceptibility syndrome with high penetrance. In addition, MSH6 mutations have been reported to account for about 10% of all germline mismatch repair (MMR) gene mutations in HNPCC patients, and have been associated with a later age of onset of the disease compared to MLH1 and MSH2 mutations. Here, we report eight novel germline mutations in MSH6. The patients were selected by having developed tumors with loss of MSH6 protein expression. All tumors showed high-level microsatellite instability (MSI-H). Seven mutations resulted in premature stop codons, comprised of two nonsense mutations (c.426G>A [p.W142X], c.2105C>A [p.S702X]), two insertions (c.2611_2614dupATTA [p.I872fsX10], c.3324dupT [p.I1109fsX3]) and three deletions (c.1190_1191delAT [p.Y397fsX3], c.1632_1635delAAAA [p.E544fsX26], c.3513_3514delTA [p.1171fsX5]). In addition, an amino acid substitution of an arginine residue (c.2314C>T [p.R772W]) conserved throughout a wide variety of mutS homologs has been found in a patient not fulfilling the Bethesda criteria for HNPCC. Our results emphasize the suitability of IHC as a pre-selection tool for MSH6 mutation analysis and the high frequency of germline mutation detection in patients with MSH6-deficient tumors. In addition, our findings point towards a broad variability regarding penetrance associated with MSH6 germline mutations.
错配修复（MMR）基因的种系突变，主要是MLH1和MSH2基因的突变，是遗传性非息肉病性结直肠癌（HNPCC）的病因，HNPCC是一种具有高外显率的癌症易感性综合征。此外，据报道，MSH6突变约占HNPCC患者所有种系错配修复（MMR）基因突变的10%，与MLH1和MSH2突变相比，其发病年龄较晚。在此，我们报告了MSH6基因的8个新的种系突变。这些患者是通过患有MSH6蛋白表达缺失的肿瘤而被挑选出来的。所有肿瘤均显示高水平微卫星不稳定性（MSI-H）。7个突变导致过早出现终止密码子，包括2个无义突变（c.426G>A [p.W142X]，c.2105C>A [p.S702X]）、两个插入突变（c.2611_2614dupATTA [p.I872fsX10]，c.3324dupT [p.I1109fsX3]）和3个缺失突变（c.1190_1191delAT [p.Y397fsX3]，c.1632_1635delAAAA [p.E544fsX26]，c.3513_3514delTA [p.1171fsX5]）。此外，在一名不符合HNPCC贝塞斯达标准的患者中发现了一个精氨酸残基的氨基酸替代（c.2314C>T [p.R772W]），该残基在多种mutS同源物中保守。我们的结果强调了免疫组化作为MSH6突变分析的预筛选工具的适用性，以及在MSH6缺陷肿瘤患者中种系突变检测的高频率。此外，我们的发现表明与MSH6种系突变相关的外显率存在广泛差异。
