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: 6162606
• 负责人: L 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/6162606
• 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 is being 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 mutated 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. Furthermore, this dataset will be able to be examined for epistatic interactions in individuals who are carriers of multiple mutations.

在过去的十年中，许多成功的鉴定突变负责 对于人类疾病来说， 以简单的孟德尔模式遗传。近年来， 人们的注意力转向试图阐明与基因突变相关的 与常见疾病如癌症、糖尿病和各种 神经退行性疾病一些证据表明， 突变可能以高频率存在，具有低突变率， 涉及具有相似表型的不同个体的不同基因。 此外，可能的是，多个之间的上位相互作用 遗传和环境因素将需要在疾病之前 发展起来的作为一个实际问题， 基因同质群体中的突变类型。一旦这样 他们是东欧和中欧血统的德系犹太人。虽然 没有证据表明他们有更大的遗传负担， 疾病比其他群体，常见的突变最有可能是由于创始人 影响和遗传漂变已被检测到在一个相对较高的 频率.最近一项研究调查了共同创始人的智力水平， BRCA 1和BRCA 2的突变，这两个基因与遗传形式有关 乳腺癌，导致收集DNA样本和家庭 从大约5000名德系犹太人的样本中， 巴尔的摩-华盛顿地区这些宝贵的资源提供 用于表征常见DNA序列变异的强大工具 可能与癌症的发展有关。四个突变 具有共同的、潜在的疾病相关等位基因的基因将被 研究了上述队列中癌症风险的增加， 德系犹太人正在开发一种多重PCR检测方法， 同时扩增来自APC部分的DNA产物， 突变的家族性腺瘤病（6%的携带者频率），BLM，这是 在Bloom综合征（1%携带者频率）中突变，FACC， 在范可尼贫血中，互补组C（1%载波频率）和 MTHFR，亚甲基四氢叶酸还原酶，一种参与 细胞内叶酸代谢（约40%的载波频率）。 癌症的相对风险（特别是结肠癌， APC和MTHFR）将允许携带者和非携带者的亲属之间 估计每个突变的突变率。此外，该数据集将 能够检查上位相互作用的个人谁是 多个突变的携带者