Buttin Barbara M, Powell Matthew A, Mutch David G, Babb Sheri A, Huettner Phyllis C, Edmonston Tina Bocker, Herzog Thomas J, Rader Janet S, Gibb Randall K, Whelan Alison J, Goodfellow Paul J
Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Am J Hum Genet. 2004 Jun;74(6):1262-9. doi: 10.1086/421332. Epub 2004 Apr 19.
Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by inherited mutations in DNA mismatch-repair genes, most commonly MLH1 or MSH2. The role MSH6 plays in inherited cancer susceptibility is less well defined. The aim of this study was to investigate the penetrance and expressivity of MSH6 mutations in kindreds ascertained through endometrial cancer probands unselected for family history. Detailed pedigrees were constructed for six MSH6 mutation carriers. All reported cancers and precancers were confirmed, and tissues were obtained when available. Tumors were analyzed for microsatellite instability (MSI) and for expression of MSH2, MLH1, and MSH6. MSH6 mutation status was determined for 59 family members. Of these 59 individuals, 19 (32%) had confirmed cancers and precancers. There was an excess of mutation carriers among the 19 affected family members (11 [58%] of 19) compared with those among the 40 unaffecteds (8 [20%] of 40, P=.0065, odds ratio = 5.5, 95% CI = 1.66-18.19). In four of the seven tumors analyzed from mutation carriers other than the probands, MSI and/or MMR protein expression was consistent with the involvement of MSH6. Overall estimated penetrance of the MHS6 mutations was 57.7%. Of the tumors in mutation carriers, 78% were part of the extended HNPCC spectrum. This study demonstrates that MSH6 germline mutations are, indeed, associated with increased cancer risk and that the penetrance of mutations may be higher than appreciated elsewhere. A combination of MSI and immunohistochemistry analyses may be helpful in screening for MSH6 mutation carriers.
遗传性非息肉病性结直肠癌（HNPCC）由DNA错配修复基因的遗传性突变引起，最常见的是MLH1或MSH2。MSH6在遗传性癌症易感性中所起的作用尚不太明确。本研究的目的是调查通过未根据家族史进行选择的子宫内膜癌先证者确定的家系中MSH6突变的外显率和表现度。为6名MSH6突变携带者构建了详细的家系图谱。所有报告的癌症和癌前病变均得到确认，如有可能则获取组织样本。对肿瘤进行微卫星不稳定性（MSI）分析以及MSH2、MLH1和MSH6的表达分析。确定了59名家庭成员的MSH6突变状态。在这59名个体中，19名（32%）患有确诊的癌症和癌前病变。与40名未受影响的家庭成员相比，19名受影响的家庭成员中突变携带者过多（19名中的11名[58%]，而40名未受影响者中的8名[20%]，P = 0.0065，优势比 = 5.5，95%可信区间 = 1.66 - 18.19）。在除先证者之外的突变携带者所分析的7个肿瘤中，有4个肿瘤的MSI和/或错配修复蛋白表达与MSH6的参与情况一致。MSH6突变的总体估计外显率为57.7%。在突变携带者的肿瘤中，78%属于广义的HNPCC谱系。本研究表明，MSH6种系突变确实与癌症风险增加相关，且突变的外显率可能高于其他地方的认识。MSI和免疫组织化学分析相结合可能有助于筛查MSH6突变携带者。
