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在不足MMR的肿瘤发展中发挥的DNA不匹配修复（MMR）基因的表观遗传沉默（“ epimotim”）的作用。遗传性非型物结节癌（HNPCC）是一种家族综合征，由于MMR基因的基因突变，患者会出现多种癌症。但是许多似乎患有HNPCC的患者没有可识别的突变。取代可以通过失活基因模仿遗传突变。种系细胞中可能存在一个夸张，因此可以遗传，但并不像DNA序列的变化一样传递。我们发现，有些具有明显HNPCC的人在HMLH1中具有如此夸张，可以通过评估HMLH1启动子中的胞嘧啶甲基化来识别。我们建议通过筛选MMR基因中缺乏突变的可疑HNPCC病例来识别更多此类病例。该策略可以确定 遗传了spimimutim的亲属，解释了为什么在某些家庭中，癌症的易感性并不是孟德尔的特征。我们还将询问HMLH1在HMLH1基因座的某些基因型上是否更可能发生HMLH1的夸张，这表明有关该基因座的遗传结构的某些东西可以使其易于沉默。许多零星（非家庭）癌症病例在MMR中表现出缺乏。我们假设某些人患癌症的风险增加，因为他们仅在一小部分细胞中携带HMLH1 epimimunt，即他们是镶嵌的。我们将测量2000个正常献血者的外周血中HMLH1释放的比例，从而建立正常范围。我们还将评估零星MMRDECOINIC肿瘤患者中HMLH1释放的比例。这些研究可能会发现证据表明抑制肿瘤抑制基因是零星癌症的根本原因。他们还可能产生第一个明确的证据，表明表观遗传沉默可以遗传以产生HNPCC等家族疾病。