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Prediction of interval breast cancer risk using genetic variants

使用遗传变异预测间期乳腺癌风险

基本信息

批准号：
10534065
负责人：
Yiwey Shieh
金额：
$ 26.03万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10534065
关键词：
Address Adopted Atlases Award Biological Biological Markers Biostatistical Methods Breast Breast Cancer Detection Breast Cancer Risk Factor Breast Cancer Treatment California Cancer Biology Cancer Center Cancer Control Cessation of life Clinical Clinical Data Clinical Trials Comprehensive Cancer Center Country Data Development Disease Effectiveness Environment Epidemiologist Estrogen Receptor Status Failure Family Funding Gene Expression Gene Expression Profile Gene Expression Profiling Genetic Models Goals Guidelines Health High Risk Woman Institutes International Internist Lead Link Magnetic Resonance Imaging Malignant Neoplasms Mammographic screening Mammography Measures Medical center Mentors Methods Modeling Molecular Morbidity - disease rate Outcome Pathway interactions Performance Periodicity Phenotype Positioning Attribute Prevention Prevention approach Research Research Design Research Personnel Resources Risk Risk Factors Role San Francisco Screening for cancer Single Nucleotide Polymorphism Statistical Models Surgeon Taxonomy Testing The Cancer Genome Atlas Time Training Tumor Biology United States Universities Woman Work aggressive breast cancer base breast density cancer genetics cancer heterogeneity cancer risk career case control clinical risk cohort genetic signature genetic variant improved individualized prevention innovation malignant breast neoplasm mortality novel marker novel strategies personalized approach personalized screening polygenic risk score precision medicine predictive modeling prospective risk prediction model risk stratification screening skills tool transcriptomics translational study treatment trial tumor

项目摘要

Project Summary/Abstract This is a resubmission of a K08 award application for Dr. Yiwey Shieh, a general internist at the University of California, San Francisco (UCSF). Dr. Shieh’s long-term career goal is to become a leading clinician- investigator working at the intersection of precision medicine and cancer screening/prevention. This K08 award will provide Dr. Shieh with the support necessary to: 1) develop an understanding of breast cancer biology and tumor gene expression profiling, 2) expand his analytical skills in genetics and prediction modeling, 3) obtain the skills needed to conduct late-translational studies on personalized cancer screening, and 4) build an inde- pendent research career. To help him achieve these goals, Dr. Shieh has assembled an exemplary team of mentors with complementary expertise. Dr. Elad Ziv, a leading cancer genetic epidemiologist, will serve as the primary mentor and oversee completion of research aims and training goals. Co-mentors include: Dr. Laura van’t Veer, an expert in gene expression analysis of breast cancer; Dr. Mi-Ok Kim, an expert in biostatistical methods and study design; and Dr. Laura Esserman, a breast surgeon and leading innovator in precision on- cology. The proposed work will benefit from the available expertise and rich institutional environment of UCSF, specifically the Helen Diller Family Comprehensive Cancer Center, one of the top cancer centers in the coun- try. Dr. Shieh will leverage the above resources to address an important problem in cancer control, namely the limited ability of current breast cancer screening strategies to detect biologically aggressive cancers. These cancers tend to present symptomatically following a normal mammogram as “interval cancers”, and often at advanced stages. Dr. Shieh’s past work has focused on predicting overall breast cancer risk using clinical risk models and polygenic risk scores (PRS) representing the combined effects of multiple single nucleotide poly- morphisms (SNPs). Dr. Shieh proposes to adopt this approach to construct a risk model for interval cancers based on preliminary data suggesting that previously discovered SNPs may hold additional prediction for breast cancer phenotype. Given the ability of gene expression profiling to provide detailed tumor phenotypic information, Dr. Shieh proposes to identify gene expression signatures correlated with rapidly-developing (ag- gressive) interval cancers (Aim 1). Dr. Shieh will then use these gene expression signatures to select SNPs associated with aggressiveness (Aim 2). These selected SNPs will be used to construct a PRS for aggressive cancer. Finally, Dr. Shieh will test the ability of this PRS to predict interval cancers, both alone and in combina- tion with breast density and clinical risk factors (Aim 3). The proposed aims will leverage Dr. Shieh’s unique access to data from clinical trials, tumor atlases, and breast cancer screening cohorts. The results will directly lead to subsequent studies on using an interval cancer risk model to prospectively inform screening and pre- vention, as well as studies on the role of novel biomarkers in refining risk stratification among high-risk women.

项目总结/文摘