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（“表突变”）在MMR缺陷肿瘤发生中的作用。遗传性非息肉病性结直肠癌（HNPCC）是一种家族性综合征，患者由于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。表突变可以通过使基因失活来模拟基因突变。表突变可能存在于生殖细胞中，因此是可遗传的，但它并不以与DNA序列变化相同的方式传递。我们已经发现，一些人与明显HNPCC进行这样的表突变hMLH1，这可以通过评估胞嘧啶甲基化hMLH1启动子。我们建议通过筛查缺乏MMR基因突变的疑似HNPCC病例来识别更多此类病例。这一战略可以确定 这种表位突变是遗传的，解释了为什么在某些家族中癌症易感性不表现为孟德尔特征。我们还将询问hMLH1的表位突变是否更可能发生在hMLH1基因座的某些基因型上，这表明该基因座的遗传结构可能使其易于沉默。许多散发性（非家族性）癌症病例表现出MMR缺陷。我们假设一些个体患癌症的风险增加，因为他们只在一小部分细胞中携带hMLH1表型突变，即，它们是马赛克。我们将测量2000名正常献血员外周血中hMLH1表型突变的比例，从而建立正常范围。我们还将评估散发性MMR缺陷型肿瘤患者中hMLH1表型突变的比例。这些研究有可能揭示肿瘤抑制基因的表型突变是散发性癌症的潜在原因的证据。他们也可能产生第一个明确的证据表明，表观遗传沉默可以遗传产生家族性疾病，如HNPCC。

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.