Genes, Hormones and Breast Cancer Risk

描述（由申请人提供）：Wendy Setiawan博士于2002年在加州大学洛杉矶分校获得流行病学博士学位。她在哈佛大学完成了一年的博士后培训，目前在南加州大学预防医学系，在那里她是Brian E. Henderson博士领导的高度互动的人口/癌症遗传学小组的一员。这个职业发展奖项的目标是为Setiawan博士提供知识和必要的技能，成为一名独立的癌症研究人员。研究项目、结构化课程、研讨会、讲习班和指导的组合已经被设计来实现这一目标。Henderson博士（癌症流行病学）和Duncan Thomas博士（生物统计学和遗传学）这两位具有相关专业知识的高素质和经验丰富的导师将监督她的培训。该系的科学文化和合作研究氛围为候选人的学术生涯发展提供了理想的环境。Setiawan博士的研究项目的目的是确定循环内源性性类固醇激素水平的环境和遗传决定因素，因为循环激素水平存在实质性的个体间差异，绝经后雌激素和雄激素升高的妇女患乳腺癌的风险增加。将对来自多民族队列研究（MEC）的健康绝经后妇女进行横断研究，以1)确定已知/潜在的乳腺癌危险因素是否与血浆激素水平相关，2)使用双管方法（假定的功能变异和推断的单倍型）描述雌激素生物合成基因（CYP11A、CYP17、CYP19、HSD3B1、HSD3B2、HSD17B1、HSD17B2和SHBG）的遗传变异，并评估这些基因与激素水平的关系；3)开发并实现贝叶斯分层统计模型，该模型允许对影响激素水平的多个基因-基因和先天基因-环境相互作用进行有效的、途径驱动的检查。该研究的独特之处在于，它整合了一项基于多民族人群的大型研究，前沿的基因组资源和新的统计方法，以确定内源性激素水平的个体间差异的遗传和环境因素。确定这些因素对于了解它们可能影响乳腺癌风险的机制以及最终确定高危妇女以实施预防战略非常重要。

DESCRIPTION (provided by applicant): Dr. Wendy Setiawan received her Ph.D. in epidemiology from UCLA in 2002. She completed a year of postdoctoral training at Harvard and is currently at the Department of Preventive Medicine at USC where she is part of the highly interactive population/cancer genetics group headed by Dr. Brian E. Henderson. The goal of this career development award is to provide Dr. Setiawan with the knowledge and necessary skills to become an independent cancer researcher. A combination of research project, structured courses, seminars, workshops, and mentoring has been designed to accomplish this goal. Two highly qualified and experienced mentors with relevant expertise, Dr. Henderson (cancer epidemiology) and Dr. Duncan Thomas (biostatistics and genetics), will supervise her training. The scientific culture and collaborative research atmosphere in the department provide an ideal environment for the candidate's academic career development. The objective of Dr. Setiawan's research project is to identify environmental and genetic determinants of circulating endogenous sex-steroid hormone levels, because there are substantial inter-individual variations in circulating hormone levels and postmenopausal women with elevated estrogens and androgens are at an increased risk of breast cancer. A cross-sectional study of healthy postmenopausal women from the Multiethnic Cohort Study (MEC) will be conducted to 1) determine whether known/potential breast cancer risk factors are associated with plasma hormone levels, 2) characterize genetic variation of estrogen biosynthesis genes (CYP11A, CYP17, CYP19, HSD3B1, HSD3B2, HSD17B1, HSD17B2, and SHBG) using a two-pronged approach (putative functional variants and inferred haplotypes) and evaluate these in relation to hormone levels; 3) develop and implement a Bayesian hierarchical statistical model that allows for an efficient and pathway-driven examination of multiple gene-gene and a priori gene-environment interactions in influencing hormone levels. The unique feature of the proposed study is that it integrates a large multiethnic population-based study, cutting edge genomic resources, and novel statistical approaches to identify genetic and environmental factors responsible for inter-individual variations in endogenous hormone levels. Identification of these factors is important to understand the mechanisms by which they could influence breast cancer risk and ultimately to identify high-risk women for prevention strategies.