ANALYSIS OF COMMON CANCER ASSOCIATED MUTATIONS IN ASHKENAZI JEWS

德系犹太人常见癌症相关突变分析

• 批准号: 6109025
• 负责人: Lawrence C Brody
• 金额: --
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6109025
• 关键词: Bloom syndrome; Jewish; adenomatous polyps; alleles; brca gene; breast neoplasms; cancer risk; clinical research; colon polyp; congenital aplastic anemia; dihydrofolate reductase; gene mutation; genetic carriers; human genetic material tag; human subject; neoplasm /cancer genetics; nucleic acid sequence; polymerase chain reaction

Over the past decade many successes in identifying mutations responsible for human illness have been for relatively uncommon diseases which are inherited in simple mendelian patterns. More recent years have seen attention turn to attempts to elucidate genetic alterations associated with common diseases such as cancer, diabetes and a variety of neurodegenerative disorders. Several lines of evidence suggest that such mutations might be present at high frequencies, have low penetrance and involve distinct genes in different individuals with similar phenotypes. Further, it is likely, that epistatic interactions between multiple genetic and environmental factors will be required before disease develops. As a practical matter, it is often easiest to identify these types of mutations in genetically homogeneous populations. Once such group are Ashkenazi Jews of eastern and middle European origin. Although there is no evidence that they have an overall greater burden of genetic illness than other groups, common mutations most likely due to founder effect and genetic drift have been detected at a comparatively high frequency. A recent study examining the penetrance of common founder mutations in BRCA1 and BRCA2, two genes associated with inherited forms of breast cancer, resulted in the collection of DNA samples and family histories of cancer from a sample of approximately 5000 Ashkenazi Jews from the Baltimore-Washington area. These valuable resources provide powerful tools for the characterization of common DNA sequence variations potentially associated with the development of cancer. Mutations in four genes with common, potentially disease- associated alleles will be investigated for increased cancer risk in the above-mentioned cohort of Ashkenazim. A multiplex PCR assay has been developed that will allow simultaneous amplification of DNA products from portions of APC, the gene mutated in familial adenomatosis (6% carrier frequency), BLM, which is mutated in Bloom syndrome (1% carrier frequency), FACC, which is mut ated in Fanconi anemia, complementation group C (1% carrier frequency) and MTHFR, methylene tetrahydrofolate reductase, an enzyme involved in intracellular folate metabolism (approximately 40% carrier frequency). The relative risk of cancer (in particular colon cancer in the cases of APC and MTHFR) among relatives of carriers and non-carriers will allow estimation of penetrance of each mutation. The APC portion of this project was completed in 1998.

在过去的十年中，在识别方面取得了许多成功 导致人类疾病的突变已经相对 简单的孟德尔（Mendelian）继承的罕见疾病 模式。近年来，注意力转向尝试 阐明与常见疾病有关的遗传改变 作为癌症，糖尿病和各种神经退行性疾病。 几条证据表明，这种突变可能是 高频出现，具有较低的渗透率，涉及 具有相似表型的不同个体的不同基因。 此外，很可能是多个多个的上皮相互作用 疾病之前需要遗传和环境因素 发展。实际上，识别这些通常是最容易的 遗传均质种群中的突变类型。一次 这样的群体是东欧和中欧的Ashkenazi犹太人 起源。尽管没有证据表明他们总体 遗传疾病的负担比其他群体更大，常见 突变最有可能是由于创始人效应和遗传漂移而引起的 以相对较高的频率检测到。最近的研究 检查BRCA1中常见创始人突变的渗透率 和BRCA2，两个与遗传形式的乳房相关的基因 癌症，导致收集DNA样品和家族 大约5000个Ashkenazi样本的癌症历史 巴尔的摩 - 华盛顿地区的犹太人。这些有价值 资源为表征提供了强大的工具 常见的DNA序列变化可能与 癌症的发展。四个具有常见基因的突变， 可能会研究潜在的疾病 - 相关等位基因 上述队列中的癌症风险增加 Ashkenazim。已经开发了一种多重PCR分析 允许同时放大DNA产品的部分 APC，在家族性腺瘤病中突变的基因（6％载体 频率），BLM，该BLM在Bloom综合征中突变（1％载体 频率），FACC，在Fanconi贫血中拟合， 互补组C（1％载体频率）和MTHFR， 亚甲基四氢叶酸还原酶，一种参与的酶 细胞内叶酸代谢（约40％载体 频率）。癌症的相对风险（尤其是结肠癌 APC和MTHFR的案件）和 非载体将允许估计每个突变的渗透率。 该项目的APC部分于1998年完成。