Peterlongo Paolo, Nafa Khedoudja, Lerman Gabriel S, Glogowski Emily, Shia Jinru, Ye Tian Z, Markowitz Arnold J, Guillem José G, Kolachana Prema, Boyd Jeffrey A, Offit Kenneth, Ellis Nathan A
Cell Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Int J Cancer. 2003 Nov 20;107(4):571-9. doi: 10.1002/ijc.11415.
Germline mutations in MSH6 can cause HNPCC, which is associated with a tumor phenotype featuring MSI. However, tumors arising in persons with disease-causing mutations of MSH6 may or may not exhibit MSI. We used D-HPLC to screen for germline mutations in the promoter region, the coding region and the 3'-UTR of MSH6. Eighty-four families, enrolled on the basis of Amsterdam I and II criteria (HNPCC families) and less stringent criteria (HNPCC-like families), were tested for MMR gene mutations; 27 families had a disease-causing mutation in MLH1 or MSH2, and the remaining 57 families were tested for mutations in MSH6. Two protein-truncating mutations were identified in each of 2 families fulfilling the Amsterdam I criteria, being present in persons affected with early-onset colorectal cancers exhibiting MSI. Immunohistochemical analysis showed that expression of both MSH2 and MSH6 proteins was lost in the cancer cells of the 2 mutation carriers but only MSH6 protein expression was lost in 2 adenomatous polyps. A third possibly disease-causing mutation was found in a person affected with a tumor that did not exhibit MSI. In addition, we found 4 new polymorphisms and determined that neither of the 2 studied by association analysis conferred susceptibility to colorectal or endometrial cancer. Altogether, our results indicate that disease-causing germline mutations of MSH6 are rare in HNPCC and HNPCC-like families.
MSH6基因的种系突变可导致遗传性非息肉病性结直肠癌（HNPCC），这与一种具有微卫星不稳定性（MSI）的肿瘤表型相关。然而，由MSH6致病突变的个体所患肿瘤可能表现出MSI，也可能不表现出MSI。我们使用变性高效液相色谱法（D-HPLC）来筛查MSH6启动子区域、编码区和3'-非翻译区的种系突变。根据阿姆斯特丹I和II标准（HNPCC家系）以及不太严格的标准（类HNPCC家系）招募了84个家系，对其进行错配修复（MMR）基因突变检测；27个家系在MLH1或MSH2中有致病突变，其余57个家系检测MSH6突变。在符合阿姆斯特丹I标准的2个家系中，各发现了2个蛋白质截短突变，这些突变存在于患有表现出MSI的早发性结直肠癌的个体中。免疫组织化学分析显示，2名突变携带者癌细胞中MSH2和MSH6蛋白的表达均缺失，但在2个腺瘤性息肉中仅MSH6蛋白表达缺失。在一名患有未表现出MSI的肿瘤的个体中发现了第三个可能致病的突变。此外，我们发现了4个新的多态性，并确定关联分析所研究的2个多态性均未赋予结直肠癌或子宫内膜癌易感性。总之，我们的结果表明，MSH6致病种系突变在HNPCC和类HNPCC家系中很少见。
