Germline epimutation of hMLH1 as a factor in HNPCC

描述（由申请人提供）：本项目旨在研究DNA错配修复（MMR）基因hMLH1的表观遗传沉默（“epimutation”）在MMR缺陷肿瘤发展中的作用。遗传性非息肉病性结直肠癌（HNPCC）是一种家族性综合征，患者因MMR基因突变而发生多种癌症。但许多似乎患有HNPCC的患者并没有可识别的突变。上皮化可以通过使基因失活来模拟基因突变。生殖系细胞可能会发生突变，因此是可遗传的，但它不像DNA序列的变化那样遗传下去。我们发现一些明显的HNPCC患者在hMLH1中携带这样的突变，这可以通过评估hMLH1启动子中的胞嘧啶甲基化来鉴定。我们建议通过筛选缺乏MMR基因突变的疑似HNPCC病例来确定更多此类病例。这个策略可以确定

DESCRIPTION (provided by applicant): This project aims to investigate the role that epigenetic silencing ("epimutation") of the DNA mismatch repair (MMR) gene hMLH1 plays in the development of tumors that are deficient in MMR. Hereditary non-polyposis colorectal cancer (HNPCC) is a familial syndrome in which patients develop multiple cancers due to genetic mutation of a MMR gene. But many patients who appear to have HNPCC do not have an identifiable mutation. Epimutation can mimic genetic mutation by inactivating a gene. An epimutation may be present in germline cells, and so be heritable, but it is not passed on in the same way as a change in DNA sequence. We have found that some people with apparent HNPCC carry such an epimutation in hMLH1, which can be identified by assessing cytosine methylation in the hMLH1 promoter. We propose to identify more such cases by screening suspected HNPCC cases who lack mutation in an MMR gene. This strategy may identify kindreds in which the epimutation has been inherited, explaining why in some families cancer predisposition does not behave as a Mendelian trait. We will also ask if epimutation of hMLH1 is more likely to occur on certain genotypes at the hMLH1 locus, which would suggest that something about the genetic architecture of the locus can predispose it to silencing. Many sporadic (non-familial) cases of cancer exhibit deficiency in MMR. We hypothesize that some individuals have an increased risk of developing a cancer because they carry the hMLH1 epimutation in only a small proportion of their cells, i.e., they are mosaic. We will measure the proportion of the hMLH1 epimutation in peripheral blood of 2000 normal blood donors, thus establishing a normal range. We will also assess the proportion of hMLH1 epimutation in patients with sporadic MMRdeficient tumors. These studies have the potential to uncover evidence that epimutation of a tumor suppressor gene is an underlying cause of sporadic cancers. They may also produce the first clear evidence that epigenetic silencing can be inherited to produce a familial disorder such as HNPCC.