Genetic Susceptibility And The Environment In Cancer Ris

癌症风险的遗传易感性和环境

• 批准号: 6838352
• 负责人: JACK A TAYLOR
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 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/6838352
• 关键词: DNA damage; DNA repair; antioxidants; bladder neoplasm; cancer risk; carcinogenesis; clinical research; environment related neoplasm /cancer; flow cytometry; gel electrophoresis; gene environment interaction; gene expression; gene interaction; genetic polymorphism; genetic susceptibility; green fluorescent proteins; hormone metabolism; human subject; neoplasm /cancer genetics; oxidative stress; polymerase chain reaction; population genetics; prostate neoplasms; restriction fragment length polymorphism; vitamin D receptors

Summary: We have an established program of research on genetic susceptibility in relation to disease risk. I collaborate with a number of PIs within the Epidemiology Branch to add measures of genetic susceptibility to their studies of reproductive, autoimmune, and neurologic diseases, while my own research continues to center primarily on bladder and prostate cancers. During the last few years my group has focused on DNA repair gene polymorphisms as we try to understand the risks and phenotypic consequences of the DNA repair gene polymorphisms that are being discovered by the NIEHS Environmental Genome Project. The large number of DNA repair genes (>200), coupled with the large number of polymorphisms (averaging >85 per gene) presents an increasingly daunting problem given that we have little or no information about the functional consequences of the polymorphisms, and do not yet have the technology to cheaply genotype thousands of polymorphisms in case-control studies. We are taking two approaches to simplify this problem: 1) we have been working to describe gene haplotypes (the specific combination of variant alleles) for DNA repair genes and 2) In order to find repair genotype-phenotype associations we are using single cell gel electrophoresis (the Comet assay) to measure rates of DNA repair phenotype in cells from a large sample of people where we have complete genotype (and now haplotype) information. We have started to apply our newly discovered haplotype information in our existing case-control studies, and are planning a new large study of prostate cancer. In addition, we are beginning to explore the use of SELDI proteomic profiling as a new molecular epidemiologic tool for understanding disease susceptibility. Last year's progress: Haplotype discovery: We characterized haplotypes in 107 genes using genotype data generated by the EGP from an ethnically diverse sample of 90 people. We find that although genes have many polymorphisms, most have only a few haplotypes and show surprisingly little evidence of recombination. The haplotypes of most genes have mutually exclusive sets of alleles and are shared across ethnic groups, suggesting that they are the consequence of ancient evolutionary bottlenecks prior to human migration out of Africa 100,000 years ago. These ancient haplotypes represent a simple organization to gene diversity that provides a 30-fold reduction in the genotyping requirements for studies of gene-disease association. Phenotypic measure of DNA repair in human populations: We have established the Comet assay in my laboratory to be able to measure levels of DNA damage in individual cells. We have adapted and extended this assay to measure rates of DNA repair in populations of cells. Using immortalized lymphocytes from the 90 people being resequenced as part of the EGP we are characterizing repair rates following damage with H2O2 and with MMS. Both exposures produce damage predominantly repaired via the base excision repair pathway. We have completed characterization of the first 65 individuals, and are working to finish the remaining 25. In addition, working in collaboration with David Dunson, we have developed new statistical methods for the analysis of Comet data and have one paper published, one submitted, and one in preparation on these methods. Prostate cancer study: I have obtained funding, as part of a $10M DOD Consortium with UNC and LSU to study DNA repair and hormone metabolism gene polymorphisms in relation ethnicity and prostate cancer aggressiveness. The Consortium project plans to enroll 2000 men with prostate cancer, half white, half black over the next 3 years. I am PI of the genetic susceptibility project and am a co-investigator, along with Alex Merrick and Ken Tomer from NIEHS, and others, on the SELDI proteomics project. Enrollment of patients should start in February 2004.

概括： 我们有一个关于与疾病风险相关的遗传易感性的既定研究计划。我与流行病学部门的许多 PI 合作，在他们的生殖、自身免疫和神经系统疾病研究中添加遗传易感性的测量方法，而我自己的研究仍然主要集中在膀胱癌和前列腺癌。在过去的几年里，我的团队一直专注于 DNA 修复基因多态性，因为我们试图了解 NIEHS 环境基因组计划发现的 DNA 修复基因多态性的风险和表型后果。大量的 DNA 修复基因 (>200) 加上大量的多态性 (平均每个基因 >85) 提出了一个日益令人畏惧的问题，因为我们对多态性的功能后果知之甚少或根本没有，并且不了解然而，我们拥有在病例对照研究中廉价地对数千种多态性进行基因分型的技术。我们正在采取两种方法来简化这个问题：1）我们一直致力于描述 DNA 修复基因的基因单倍型（变异等位基因的特定组合）；2）为了找到修复基因型-表型关联，我们使用单细胞凝胶电泳（彗星测定）来测量大量人群样本细胞中 DNA 修复表型的速率，我们拥有完整的基因型（现在是单倍型）信息。我们已开始将新发现的单倍型信息应用到现有的病例对照研究中，并计划开展一项新的前列腺癌大型研究。此外，我们开始探索使用 SELDI 蛋白质组分析作为了解疾病易感性的新分子流行病学工具。 去年的进展： 单倍型发现：我们使用 EGP 从 90 人的不同种族样本中生成的基因型数据来表征 107 个基因的单倍型。我们发现，虽然基因有许多多态性，但大多数只有少数单倍型，并且几乎没有重组的证据。大多数基因的单倍型具有相互排斥的等位基因组，并且在不同种族群体中共享，这表明它们是10万年前人类迁出非洲之前古代进化瓶颈的结果。这些古老的单倍型代表了基因多样性的简单组织，使基因-疾病关联研究的基因分型要求减少了 30 倍。 人类 DNA 修复的表型测量：我们在实验室建立了彗星测定法，能够测量单个细胞中 DNA 损伤的水平。我们已经调整并扩展了该测定法，以测量细胞群中 DNA 修复的速率。作为 EGP 的一部分，我们使用来自 90 人的永生化淋巴细胞进行重新测序，描述了 H2O2 和 MMS 损伤后的修复率。两种暴露都会产生主要通过碱基切除修复途径修复的损伤。我们已经完成了前 65 个个体的特征描述，并正在努力完成剩余 25 个个体的特征描述。此外，与 David Dunson 合作，我们开发了用于分析彗星数据的新统计方法，并发表了一篇论文，提交了一篇论文，以及一个正在准备这些方法的人。 前列腺癌研究：我已获得资助，作为与北卡罗来纳大学和路易斯安那州立大学合作的 1000 万美元国防部联盟的一部分，研究 DNA 修复和激素代谢基因多态性与种族和前列腺癌侵袭性的关系。该联盟项目计划在未来 3 年内招募 2000 名患有前列腺癌的男性，其中一半是白人，一半是黑人。我是遗传易感性项目的 PI，并且与来自 NIEHS 的 Alex Merrick 和 Ken Tomer 以及其他人一起参与 SELDI 蛋白质组学项目。患者招募应于 2004 年 2 月开始。