INHERITED MSH6 MUTATIONS IN DIVERSE COLORECTAL CANCERS

错配修复基因的种系突变是最常见的 遗传性结肠癌的病因四个错配修复基因的突变 (MSH2，MLH 1，PMS 1和PMS 2）主要在患有 遗传性非息肉病性结直肠癌（HNPCC）具有高转移率， 诊断时年龄小，右半结肠占优势。这些患者多 显示复制错误（DNA重复序列中微卫星不稳定性（MSI 肿瘤细胞的序列。最近，第五种遗传性突变 错配修复基因MSH 6已经在结直肠癌患者中被鉴定。 同时，我们的初步研究共发现了9个生殖系MSH 6 198例结直肠癌患者和不同的家族史。 令人惊讶的是，我们的MSH 6携带者中没有一个有符合 HNPCC的经典阿姆斯特丹标准;相反，他们通常只有一个 一级或二级相关的癌症。此外，MSH 6载体 诊断结直肠癌的中位年龄为62.5岁，与 即散发病例。家庭成员受到各种其他影响， 癌症，包括乳腺癌、子宫内膜癌和卵巢癌。追求这些 出乎意料的观察，我们建议分析700例CRC病例中的MSH 6基因 家族史不符合HNPCC的经典标准案件将 按诊断时的年龄分层。具有生殖系MSH 6突变的病例和 同样数量的无MSH 6突变的结直肠癌病例对照将 分析MSI。此外，MSH 6携带者的家庭成员将被 评估生殖系突变，并将其可用的肿瘤块 检查MSI。将分析结果以确定1。的频率和 所有700例结直肠癌中生殖系MSH 6突变的临床表现 患者; 2. MSI的类型和频率在相应的肿瘤组织中， MSH 6载体与一系列匹配的非载体相比;以及3. MSH6 MSH 6携带者的受影响和未受影响亲属的状态，以及MSH 6携带者的MSI。 受影响的家庭成员的肿瘤。我们的初步数据表明，MSH 6可能 与MSH 2、MLH 1、PMS 1和PMS 2相比， 加起来有证据表明MSH 6是一种中度渗透性、迟发型遗传性 结直肠癌基因的存在意味着其他类似基因的存在。 等待发现的常见癌症

Germline mutations in mismatch repair genes are the most common cause of hereditary colon cancer. Mutations in four mismatch repair genes (MSH2, MLH1, PMS1 and PMS2) have been identified primarily in families with hereditary nonpolyposis colorectal cancer (HNPCC) featuring high penetrance, early age at diagnosis, and right colon predominance. These patients tend to show replication errors (microsatellite instability (MSI) in DNA repeat sequences of their neoplastic cells. Recently, inherited mutations in a fifth mismatch repair gene, MSH6, have been identified in colorectal cancer patients. Concurrently, our preliminary studies have found a total of 9 germline MSH6 mutations in 198 patients with colorectal cancer and diverse family histories. Surprisingly, none of our MSH6 carriers have family histories that fulfill the classic Amsterdam criteria for HNPCC; instead, they generally have only one first- or second degree relative with cancer. In addition, the MSH6 carriers have a median age of diagnosis of colorectal cancer of 62.5 years, similar to that of sporadic cases. Family members are affected by a variety of other cancers, including breast, endometrial and ovarian tumors. To pursue these unexpected observations, we propose to analyze the MSH6 gene in 700 CRC cases with family histories that do no fulfill classic criteria for HNPCC. Cases will be stratified by age at diagnosis. Cases with germline MSH6 mutations and an equal number of controls of colorectal cancer cases without MSH6 mutations will be analyzed for MSI. Additionally, family members of MSH6 carriers will be evaluated for the germline mutation, and their available tumor blocks will be examined for MSI. Results will be analyzed to determine 1. the frequency and clinical manifestations of germline MSH6 mutations in all 700 colorectal cancer patients; 2. types and frequencies of MSI in the corresponding tumor tissues of MSH6 carriers as compared with a matched series of non-carriers; and 3. MSH6 status of affected and unaffected relatives of MSH6 carriers, as well as MSI in tumors of affected family members. Our preliminary data suggest that MSH6 may be responsible for more colorectal cancer cases than MSH2, MLH1, PMS1 and PMS2 combined. Evidence that MSH6 is a moderately penetrant, later-onset hereditary colorectal cancer gene would imply the existence of similar genes for other common cancers that await discovery.