Germline epimutation of hMLH1 as a factor in HNPCC

hMLH1 种系表突变作为 HNPCC 的一个因素

• 批准号: 6856870
• 负责人: David Ian Kingston Martin
• 金额: $ 13.77万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-13 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6856870
• 关键词: DNA repair; cancer risk; colorectal neoplasms; family genetics; gene induction /repression; gene mutation; genetic promoter element; genetic screening; genetic susceptibility; genotype; human subject; neoplasm /cancer genetics; patient oriented research

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.

描述（由申请人提供）：该项目旨在研究 DNA 错配修复 (MMR) 基因 hMLH1 的表观遗传沉默（“表观突变”）在 MMR 缺陷肿瘤的发展中所起的作用。遗传性非息肉病性结直肠癌 (HNPCC) 是一种家族综合征，患者由于 MMR 基因的基因突变而患上多种癌症。但许多看似患有 HNPCC 的患者并没有可识别的突变。表观突变可以通过灭活基因来模拟基因突变。表观突变可能存在于种系细胞中，因此是可遗传的，但它不会以与 DNA 序列变化相同的方式传递。我们发现一些患有明显 HNPCC 的人在 hMLH1 中携带这种表突变，这可以通过评估 hMLH1 启动子中的胞嘧啶甲基化来识别。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。该策略可能会识别 表突变已被遗传的亲属，这解释了为什么在一些家庭中癌症易感性并不表现为孟德尔特征。我们还将询问 hMLH1 基因座的某些基因型是否更有可能发生 hMLH1 表突变，这表明该基因座的遗传结构中的某些因素可能使其易于沉默。许多散发（非家族性）癌症病例表现出 MMR 缺陷。我们假设某些个体患癌症的风险增加，因为他们仅在一小部分细胞中携带 hMLH1 表突变，即它们是嵌合体。我们将测量2000名正常献血者外周血中hMLH1表突变的比例，从而建立一个正常范围。我们还将评估散发性 MMR 缺陷肿瘤患者中 hMLH1 表突变的比例。这些研究有可能发现证据，证明肿瘤抑制基因的表突变是散发性癌症的根本原因。他们还可能提供第一个明确的证据，证明表观遗传沉默可以遗传，从而产生 HNPCC 等家族性疾病。