Variation in Hormone and xenobiotic metabolizing enzyme genes and breast cancer

激素和外源性代谢酶基因的变异与乳腺癌

• 批准号: 7198295
• 负责人: OLUFUNMILAYO F. OLOPADE
• 金额: $ 21.12万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-11-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7198295
• 关键词: breast neoplasms; clinical research; enzymes; genes; genetics

Of all racial/ethnic groups, African Americans and Africans experience a disproportionate burden of premenopausal breast cancer for reasons that remain unknown and understudied. The vast majority of African-Americans originated from West Africa, a region currently estimated to have a population of 200 million persons, of whom more than 120 million is concentrated in Nigeria. In the post genome age, research focused on racial or ethnic group differences is less relevant in view of the dynamic interplay between genes and the environment. Rather, we believe studies should be focused on the individual, each with her unique genetic constitution and history of environmental exposures. We are in a unique position to fill the huge knowledge gaps in the causes of breast cancer in populations of African ancestry by examining a large cohort of African American and Nigerian breast cancer cases. In ongoing work funded through separate R01s, we are collecting comprehensive family and exposure history and have established a large bio-specimen repository of cases and controls from Nigeria that will be invaluable for assessing the reasons why women of African ancestry develop earlier onset and pathologically more aggressive breast cancer. This project aims at testing whether sequence variation in genes involved in the metabolism of sex hormones and xenobiotics (including drugs) influences the risk to breast cancer. We will build on our previous efforts in this area that include large-scale SNP discovery studies guided by comparative genomics analyses involving the UGT1A gene cluster and the CYP3A gene cluster. The goal of this SPORE proposal is to extend our studies and determine whether sequence variation in the UDP-glucuronosyltransferases 2B (UGT2B) family of genes influence the risk to breast cancer. Constructing genetic profiles that could be used to assess risk could also be used to individualize therapy and will increase our understanding of the role of gene environment interactions in breast cancer etiology and treatment. Moreover, because these enzymes are important in the metabolism of anticancer agents, the information obtained through these studies may help in dissecting the genetic bases of inter-individual variability in response to anticancer treatment and, ultimately, lead to individualized therapy. This should ultimately lead to reduced breast cancer morbidity and mortality and improved clinical outcomes for all women with breast cancer. Our specific aims are:1) Perform a re-sequencing survey of the UGT2B gene cluster based on comparative genomics analyses in ethnically diverse population samples to select tag SNPs for association study; 2) Examine whether polymorphic variants of UGT2B genes are associated with breast cancer risk in women of African descent and 3) Examine whether UGT2B genes and environmental factors are associated with age at diagnosis, tumor grade, and ER/PR staining.

在所有种族/民族群体中，非洲裔美国人和非洲人经历了不成比例的绝经前负担。 乳腺癌的原因仍然未知和研究不足。绝大多数 非洲裔美国人起源于西非，该地区目前估计有200人口 2000万人，其中1.2亿多人集中在尼日利亚。在后基因组时代， 鉴于种族或族裔群体之间的动态相互作用， 基因和环境之间的关系。相反，我们认为研究应该关注个人， 每个人都有独特的基因结构和环境暴露史。我们正处在一个独特的 填补非洲血统人群中乳腺癌原因的巨大知识空白 通过研究大量的非裔美国人和尼日利亚乳腺癌病例。在正在进行的工作中 通过单独的R 01资助，我们正在收集全面的家族和暴露史， 建立了一个大型的生物标本库，储存了来自尼日利亚的病例和对照，这将对 评估非洲血统的妇女发病较早和病理上更多的原因， 侵袭性乳腺癌。这个项目的目的是测试是否在基因序列变异参与 性激素和异生物质（包括药物）的代谢影响患乳腺癌的风险。 我们将建立在我们以前在这一领域的努力，包括大规模的SNP发现研究指导 通过涉及UGT 1A基因簇和CYP 3A基因簇的比较基因组学分析。 这个SPORE提案的目标是扩展我们的研究，并确定序列变异是否 在UDP-葡萄糖醛酸转移酶2B（UGT 2B）基因家族中，影响乳腺癌的风险。 构建可用于评估风险的遗传图谱也可用于个体化 治疗，并将增加我们对乳腺癌基因环境相互作用的作用的理解， 癌症病因学和治疗。此外，由于这些酶在代谢中很重要， 抗癌药物，通过这些研究获得的信息可能有助于解剖遗传 个体间对抗癌治疗反应的变异性基础，并最终导致 个体化治疗这将最终导致乳腺癌发病率和死亡率的降低 并改善所有乳腺癌患者的临床结果。我们的具体目标是：1）执行一个 基于比较基因组学分析的UGT 2B基因簇的重新测序调查， 种族多样性的人群样本，以选择标签SNP进行关联研究; 2）检查是否 UGT 2B基因多态性变异与非洲女性乳腺癌风险相关 3）检查UGT 2B基因和环境因素是否与年龄相关， 诊断、肿瘤分级和ER/PR染色。