MOLECULAR GENETICS OF HNPCC

描述：这是一个修改后的应用程序，将研究遗传 非息肉病性结直肠癌（HNPCC）。 HNPCC的大多数被认为是 是由于生殖细胞突变和DNA错配修复（MMR）基因， 包括hMSH2、hMlH1、hPMS1、hPMS2和GTBP。 作者以及其他 研究人员已经注意到HNPCC是以常染色体显性遗传的， 占所有结直肠癌病例的5 - 10%。 MMR突变导致DNA错配修复缺陷，随后 导致突变的积累，这些突变是由缺陷检测到的， DNA的串联重复序列。 微卫星中出现复制错误（RERs） 重复片段。 申请人提出研究来检验假设 HNPCC家族之间和家族内的显著差异导致 在HNPCC中观察到的年龄和肿瘤谱的差异。 她有 召集了一些调查人员和家庭， 四个具体目标。 一是考联想 MMR基因的特定突变与肿瘤谱的变异之间的关系 与年龄相关的癌症风险。 第二个具体目标是确定 MMR基因的突变或碱基变化是否会导致HNPCC， 不符合严格的阿姆斯特丹标准的家族中的相关癌 的搜索. 第三个具体目标是确定是否多态性在 与散发性结直肠癌风险增加相关的基因 谷胱甘肽S-转移酶M1（GSTM1）或N-乙酰转移酶2 （NAT2）影响MMR携带者的癌症风险。 第四个具体目标是 确定符合阿姆斯特丹标准但RER-的家庭。

DESCRIPTION: This is a revised application that will study hereditary nonpolyposis colorectal cancer (HNPCC). The majority of HNPCC is considered to be due to germline mutations and DNA mismatch repair (MMR) genes which include hMSH2, hMlH1, hPMS1, hPMS2, and GTBP. The author, as well as other investigators, have noticed that HNPCC is inherited in an autosomal dominant fashion and accounts for 5-10% of all cases of colorectal carcinoma. Mutation in MMR leads to deficient DNA mismatch repair, which subsequently leads to the accumulation of mutations that are detected by defects in tandem repeats of DNA. Replication errors (RERs) appear in microsatellite repeat fragments. The applicant proposes studies to test the hypothesis that significant variation among and within HNPCC families leads to the differences in age and spectrum of tumors observed in HNPCC. She has assembled a number of investigators and families and will approach this problem through four specific aims. The first is to test for associations between specific mutations in MMR genes and variations of the tumor spectrum and age-associated risk for cancer. The second specific aim is to determine whether mutations or base changes in MMR genes cause HNPCC with its associated carcinomas in families that do not meet the rigid Amsterdam criteria. The third specific aim is to determine whether polymorphisms in genes that are associated with increased risk of sporadic colorectal carcinomas in glutathione S-transferase M1 (GSTM1) or N-acetyltransferase 2 (NAT2) affect risk for cancer in MMR carriers. The fourth specific aim is to identify families that meet the Amsterdam criteria but are RER-.