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、MLH1、PMS1和PMS2)主要在患有 遗传性非息肉病性结直肠癌(HNPCC)具有高外显性， 确诊时年龄较早，且右半结肠占优势。这些患者倾向于 显示复制错误(DNA重复中的微卫星不稳定性(MSI) 它们的肿瘤细胞的序列。最近，五分之一的遗传突变 错配修复基因MSH6已在结直肠癌患者中被发现。 同时，我们的初步研究共发现了9个种系MSH6 198例有不同家族史的结直肠癌患者的突变。 令人惊讶的是，我们的MSH6携带者中没有一人有符合 HNPCC的经典阿姆斯特丹标准；相反，它们通常只有一个 与癌症有一级或二级亲属关系。此外，MSH6携带者 被诊断为结直肠癌的年龄中值为62.5岁，与 散发性病例。家庭成员会受到各种其他疾病的影响 癌症，包括乳腺癌、子宫内膜癌和卵巢癌。为了追求这些 意想不到的发现，我们建议分析700例结直肠癌患者的MSH6基因 家族史不符合HNPCC的经典标准。案件将会 确诊时按年龄分层。患有生殖系MSH6突变和AN的病例 无MSH6突变的结直肠癌病例的同等数量的对照将 被分析是否有MSI。此外，MSH6携带者的家属将是 对生殖系突变进行评估，他们可用的肿瘤块将是 已检查MSI。将对结果进行分析以确定1.频率和 700例结直肠癌胚系MSH6突变的临床表现 相应肿瘤组织中MSI的类型和频率。 MSH6携带者与匹配的一系列非携带者的比较；以及3.MSH6 MSH6携带者的患病亲属和未患病亲属的状况，以及MSI在 受影响家庭成员的肿瘤。我们的初步数据表明，MSH6可能 比MSH2、MLH1、PMS1和PMS2更多的结直肠癌病例 加在一起。MSH6是一种中等渗透性、发病较晚的遗传性疾病的证据 结直肠癌基因可能暗示存在其他类似基因。 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.