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.

总结： 我们有一个关于遗传易感性与疾病风险的既定研究计划。我与流行病学分支内的一些PI合作，在他们对生殖、自身免疫和神经系统疾病的研究中增加了遗传易感性的测量，而我自己的研究继续主要集中在膀胱癌和前列腺癌上。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个），加上大量的多态性（平均每个基因>85个），提出了一个越来越令人生畏的问题，因为我们对多态性的功能后果知之甚少或一无所知，而且还没有在病例对照研究中廉价地对数千个多态性进行基因分型的技术。我们采取两种方法来简化这个问题：1）我们一直致力于描述基因单倍型2）为了发现修复基因型-表型之间的联系，我们使用单细胞凝胶电泳技术，（彗星试验）来测量细胞中DNA修复表型的速率，这些细胞来自我们具有完整基因型的大样本人群。（现在是单体型）信息。我们已经开始将我们新发现的单倍型信息应用于我们现有的病例对照研究中，并正在计划一项新的前列腺癌大型研究。此外，我们开始探索使用SELDI蛋白质组分析作为一种新的分子流行病学工具，了解疾病的易感性。 去年的进展： 单倍型发现：我们使用EGP从90人的种族多样性样本中产生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，大多数只有几个单倍型，并显示令人惊讶的重组的证据很少。大多数基因的单倍型都有相互排斥的等位基因组，并且在不同种族之间共享，这表明它们是10万年前人类迁移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，为基因-疾病关联研究的基因分型要求提供了30倍的减少。 人类群体中DNA修复的表型测量：我们在实验室建立了彗星试验，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这种测定法，以测量细胞群体中的DNA修复率。使用来自90人的永生化淋巴细胞作为EGP的一部分，我们正在表征H2 O2和MMS损伤后的修复率。两种暴露均产生主要通过碱基切除修复途径修复的损伤。我们已经完成了对前65个个体的定性，并正在努力完成其余25个个体的定性。此外，与大卫邓森合作，我们开发了新的统计方法来分析彗星数据，并发表了一篇论文，一篇提交了一篇，还有一篇正在准备这些方法。 前列腺癌研究：我已经获得了资金，作为一个1000万美元的国防部联盟的一部分，与密歇根大学和路易斯安那州立大学研究DNA修复和激素代谢基因多态性与种族和前列腺癌的侵略性。该联盟项目计划在未来3年内招募2000名前列腺癌男性，一半是白色，一半是黑人。我是遗传易感性项目的PI，也是SELDI蛋白质组学项目的共同研究者，沿着的还有来自NIEHS的Alex梅里克和Ken Tomer，以及其他人。应于2004年2月开始招募患者。