Functional Effects of Ovarian Cancer Risk Variants

卵巢癌风险变异的功能影响

基本信息

批准号：
9216819
负责人：
MATTHEW L FREEDMAN
金额：
$ 68.65万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9216819
关键词：
Address Affect Alleles Automobile Driving BRCA1 Mutation BRCA1 gene BRCA2 Mutation BRCA2 gene Biological Biological Assay Biology Cancer Etiology Cancer-Predisposing Gene Candidate Disease Gene Catalogs Cessation of life Clinical Complex Computing Methodologies Data Data Set Developed Countries Developing Countries Development Disease Disease model Etiology Experimental Models Family Gene Targeting Genes Genetic Genetic Risk Genetic Variation Genetic study Genome Genotype Goals Heritability Histologic Human Genetics Individual International Lead Malignant Neoplasms Malignant neoplasm of ovary Maps Mendelian disorder Meta-Analysis Methodology Methods Modeling Oncogenic Open Reading Frames Ovarian Pathogenesis Pathway interactions Penetrance Persons Phenotype Population Positioning Attribute Prevention approach Prevention strategy Publishing Quantitative Trait Loci Recording of previous events Regulatory Element Risk Risk Factors Role Stage at Diagnosis Susceptibility Gene Techniques Technology Tissues United States National Institutes of Health Variant Woman Work base cancer risk cancer type case control chromatin immunoprecipitation chromosome conformation capture clinical biomarkers design disorder prevention epigenome epigenomics genetic association genetic information genetic risk factor genetic variant genome editing genome wide association study genome-wide histone modification improved in vitro Model innovation molecular phenotype mortality mutation carrier new therapeutic target novel oncology outcome forecast population based risk variant screening trait tumorigenesis

项目摘要

Abstract Genome wide association studies (GWAS) have so far identified more than 20 common low penetrance variants for ovarian cancer; but it is estimated that thousands more risk variants await discovery. In the post-GWAS era a complex set of challenges for the identification, functional characterization and utility of susceptibility alleles have emerged including: (i) Identifying the causal genetic variants and regulatory targets driving cancer development at risk loci; (ii) Identifying the susceptibility genes associated with risk variants; (iii) Establishing if there are common biological networks that explain the functional mechanisms underlying multiple risk loci. Clinically, identifying the genetic risk component of ovarian cancer will likely lead to improved disease prevention through population screening and disease prevention strategies; and understanding the function of risk loci may lead to the discovery of clinical biomarkers and novel targeted therapies, analogous to the paradigm of PARP therapy for BRCA1 or BRCA2 mutation carriers. The current proposal is designed to address many of these challenges for ovarian cancer in the post- GWAS era including: (1) Identifying additional novel, common variant susceptibility alleles for the different histological subtypes of ovarian cancer; (2) Establishing the functional mechanisms driving disease at ovarian cancer risk loci based on the identification and characterization of the likely casual SNPs and targets susceptibility genes are risk loci; (3) Using genome wide profiling of functional models based on perturbation of ovarian cancer susceptibility genes, to identify common mechanisms and biological pathways driving tumorigenesis; (4) To integrate functional datasets with genetic association datasets to improve the power of these studies to identify additional ovarian cancer susceptibility loci.

抽象的迄今为止，基因组广泛的关联研究（GWAS）已经确定了20多个常见的低渗透率卵巢癌的变体；但是据估计，有成千上万的风险变体正在等待发现。在 GWAS后时代是一系列复杂的挑战，用于识别，功能表征和实用性出现了易感性等位基因，包括：（i）确定因果遗传变异和调节促使癌症发展的目标处于风险位置；（ii）识别与风险相关的易感基因变体；（iii）确定是否有共同的生物网络来解释功能机制基础多个风险基因座。临床上，确定卵巢癌的遗传风险成分可能会通过人口筛查和预防疾病策略改善疾病预防的改善；和了解风险基因座的功能可能会导致发现临床生物标志物和针对性的新型疗法，类似于BRCA1或BRCA2突变载体的PARP治疗范例。当前的提案旨在应对卵巢癌的许多挑战。 GWAS时代包括：（1）确定不同的新颖，常见的变体易感性等位基因卵巢癌的组织学亚型；（2）建立驱动疾病的功能机制卵巢癌风险基因基因基因基于可能休闲SNP的识别和表征靶标敏感性基因是风险基因座；（3）基于功能模型的基因组广泛分析卵巢癌易感基因的扰动，以识别共同的机制和生物学驱动肿瘤发生的途径；（4）将功能数据集与遗传关联数据集集成到提高这些研究的力量，以鉴定额外的卵巢癌敏感性基因座。