Genetic and Epidemiological Approaches to Breast Density and Breast Cancer Risk

描述(由申请人提供)：申请者Elad Ziv博士是加州大学旧金山分校的医学副教授，领导着一个以患者为导向的研究项目，调查常见癌症的遗传易感性和血液学特征。齐夫博士项目的一个主要重点是研究乳腺癌易感性的遗传因素。作为这项提议的一部分，Dr。 ZIV将寻找乳房X光检查乳房密度和乳腺癌风险之间关联的遗传因素。乳房X光检查的乳房密度被认为是乳腺癌的强烈风险因素，也是一种高度可遗传的特征。齐夫博士将分析他的团队正在进行的一项大型全基因组关联研究，将年龄和BMI调整后乳房密度最高五分之一的500名女性与乳房密度最低五分之一的500名女性进行比较。他将对复制数据集中的前1500个变异进行复制分析，复制数据集中还有500名女性和500名女性，其中500名女性来自年龄和体重指数调整后密度最低的五分之一。此外，他的团队将寻找与乳房凹陷和乳腺癌风险都相关的基因变异。他们将使用他的团队生成的乳腺癌易感性GWAS数据集和公开可用的乳腺癌GWAS数据集，对乳房密度和乳腺癌GWAS数据集进行联合分析。齐夫博士和他的同事还将使用下一代测序来寻找可能解释这些特征之间重叠的罕见变异。特别是，有很强乳腺癌家族史的女性，也是年龄和BMI调整后乳房密度最高的五分之一的女性，将被选为整个外显子组测序。作为这项提议的一部分，齐夫博士将扩大他的能力，指导初级调查人员，并培养更多技能，以最大限度地发挥他作为导师的潜力。齐夫博士已经指导了超过15名初级教员、研究员、住院医生和学生。他参与了3个T32项目，以指导研究员。作为这项提议的一部分，齐夫博士将接受更多博士后级别的指导，并继续指导初级教员，即目前与他一起工作的研究员。他还将接受额外的培训，以提高他的指导和科学技能。 与公共健康相关：这项提案将寻找乳房密度和乳腺癌风险之间联系的基因变异。众所周知，乳房密度是乳腺癌的一个重要风险因素。申请者还将利用这项建议继续并加强他作为初级调查人员导师的角色，这些调查人员从事以患者为中心的研究，研究癌症易感性的遗传和环境因素。

DESCRIPTION (provided by applicant): The applicant, Dr. Elad Ziv, is an associate professor of medicine at UCSF and leads a patient oriented research program that investigates genetic susceptibility to common cancers and hematological traits. A major focus of Dr. Ziv's program is the study of genetic factors underlying breast cancer susceptibility. As part of this proposal, Dr. Ziv will search for genetic factors underlying the association between mammographic breast density and breast cancer risk. Mammographic breast density is known to be a strong risk factor for breast cancer and is also a highly heritable trait. Dr. Ziv will analyze a large genome wide association study (GWAS) that his group is generating, comparing 500 women from the top quintile of age and BMI-adjusted breast density to 500 women from the bottom quintile. He will perform a replication analysis of the top 1500 variants in a replication dataset of another 500 women from the top and 500 women from the bottom quintile of age and BMI adjusted density. In addition, his group will search for genetic variants that are associated with both breast densit and breast cancer risk. They will perform a combined analysis of breast density and breast cancer GWAS datasets, using GWAS datasets of breast cancer susceptibility that his group has generated and a publicly available breast cancer GWAS datasets. Dr. Ziv and colleagues will also use next generation sequencing to search for rare variants that may explain the overlap between these traits. In particular, women with a strong family history of breast cancer who are also in the top quintile of age and BMI-adjusted breast density will be selected for whole exome sequencing. As part of this proposal, Dr. Ziv will expand his capacity to mentor junior investigators and develop additional skills to maximize his potential as a mentor. Dr. Ziv has mentored over 15 junior faculty members, fellows, residents and students. He is affiliated with 3 T32 programs for mentoring fellows. As part of this proposal, Dr. Ziv will take on additional mentees at the post-doctoral level and continue to mentor the junior faculty, fellows currently working with him. He will also pursue additional training that will enhance his mentoring and scientific skills. PUBLIC HEALTH RELEVANCE: This proposal will search for genetic variants that underlie the association between breast density and breast cancer risk. Breast density is known to be a strong risk factor for breast cancer. The applicant will also use this proposal to continue and enhance his role as a mentor to junior investigators pursuing patient oriented research, studying genetic and environmental factors that underlie cancer susceptibility.