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: 6290311
• 负责人: LAWRENCE 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/6290311
• 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 understandgenetic 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 interactions between multiple genetic and environmental factors are 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. We recently determined the risk of colon and breast cancer associated with a particular mutation in the APC gene (I1307K). Mutations in other genes with common, potentially disease-associated alleles will be investigated for increased cancer risk in the above-mentioned cohort of Ashkenazim. This will include genes related to folate and carcinogen metabolism. A second series of experiments aimed at identifying genes which modify the risk of cancer are currently being designed. In these studies individuals known to carry mutation in their BRCA1, BRCA2 or APC genes will be collected. The DNA from persons with a mutation and affected with cancer will be compared to the DNA from older individuals who carry mutations and have remained cancer free. Regions of the genome that differ between these individuals should correlate to the location of genes that act to increase or decrease cancer risk. - breast cancer, BRCA1/2, carcinogen, ovarian cancer, genetics, Womens's Health Research - Human Subjects

在过去的十年中，在识别导致人类疾病的突变方面取得的许多成功都是针对以简单孟德尔模式遗传的相对罕见的疾病。近年来，人们的注意力转向了解与癌症、糖尿病和各种神经退行性疾病等常见疾病相关的基因改变。多项证据表明，此类突变可能出现频率较高、外显率较低，并且涉及具有相似表型的不同个体中的不同基因。此外，在疾病发生之前，多种遗传因素和环境因素之间可能需要相互作用。实际上，在遗传同质群体中识别这些类型的突变通常是最容易的。曾经这样的群体是东欧和中欧血统的德系犹太人。尽管没有证据表明他们比其他群体总体上有更大的遗传疾病负担，但很可能由于创始人效应和遗传漂变而导致的常见突变以相对较高的频率被发现。最近的一项研究检查了 BRCA1 和 BRCA2（两种与乳腺癌遗传形式相关的基因）常见创始人突变的外显率，结果从巴尔的摩-华盛顿地区约 5000 名德系犹太人的样本中收集了 DNA 样本和癌症家族史。这些宝贵的资源为表征可能与癌症发展相关的常见 DNA 序列变异提供了强大的工具。我们最近确定了与 APC 基因 (I1307K) 的特定突变相关的结肠癌和乳腺癌风险。将研究具有常见的、可能与疾病相关的等位基因的其他基因的突变，以了解上述德系犹太人队列中癌症风险的增加。这将包括与叶酸和致癌物代谢相关的基因。目前正在设计第二系列实验，旨在识别改变癌症风险的基因。在这些研究中，将收集已知携带 BRCA1、BRCA2 或 APC 基因突变的个体。来自携带突变且患有癌症的人的 DNA 将与来自携带突变且未患癌症的老年人的 DNA 进行比较。这些个体之间不同的基因组区域应该与增加或减少癌症风险的基因位置相关。 - 乳腺癌、BRCA1/2、致癌物、卵巢癌、遗传学、女性健康研究 - 人类受试者