权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Characterizing non-coding somatic and germline variant interactions in ovarian cancer

卵巢癌中非编码体细胞和种系变异相互作用的特征

基本信息

批准号：
10405651
负责人：
ALEXANDER GUSEV
金额：
$ 66.37万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10405651
关键词：
Address Automobile Driving BRCA1 gene Binding Sites Biological Assay CRISPR screen CRISPR/Cas technology Cancer Biology Candidate Disease Gene Cell physiology Cells Cessation of life ChIP-seq Chemoresistance Chromosomes Clinical Code DNA Sequence Alteration Data Development Disease Enhancers Epithelial Cells Epithelial ovarian cancer Evolution Gene Expression Genes Genetic Genetic Code Genetic Risk Genetic Variation Genome Genomic Segment Genotype Goals Heritability Human Genetics In Vitro Interdisciplinary Study Intervention Invaded Knowledge Malignant Neoplasms Malignant neoplasm of ovary Mammalian Oviducts Modeling Molecular Conformation Mutate Mutation Nucleotides Outcome Ovarian Pathogenesis Penetrance Phenotype Prevention approach Proteins Regulator Genes Regulatory Element Research Role Somatic Mutation Susceptibility Gene Syndrome TP53 gene Tissues Untranslated RNA Validation Variant cancer initiation cancer predisposition cancer risk chromosome conformation capture clinical translation epigenomics gene regulatory network genetic variant genome editing genome sequencing genome wide association study genome-wide mortality novel ovarian neoplasm population based precursor cell programs risk variant three-dimensional modeling tool trait transcription factor treatment response tumor whole genome

项目摘要

ABSTRACT A fundamental goal of human genetics is to decipher the relationship between genotype and phenotype. Cancer is defined as a disease comprising a heritable genetic component that confers cancer predisposition and an acquired (somatic) component where disease is driven by an accumulation of genetic mutations leading to ever increasing deregulation of normal cellular functions. Population based genome wide association studies (GWAS) and whole genome sequencing (WGS) analyses have identified thousands of germline risk variants for ovarian cancer and somatic non-coding mutations involved in ovarian cancer development. Identifying genomic regions where there are interactions between germline and somatic variants may enable us to identify the critical drivers of disease. We have established an end-to-end pipeline that can efficiently evaluate the functional significance of thousands of genetic variants in disease at once. We have also established ex-vivo models of fallopian tube secretary epithelial cells (precursors of ovarian cancer) and in vitro 3D models of chemoresistant ovarian cancer. In this proposal, we plan to address provocative question #3 “Do genetic interactions between germline variations and somatic mutations contribute to differences in tumor evolution or response to therapy?” with the following specific aims: (1) Use computational approaches, to identify genomic regions where germline and somatic genetic variants converge to indicate shared target genes and regulatory networks driving ovarian cancer development; (2) Use chromosome conformation capture assays to validate interactions between regulatory targets and their target genes; (3) Use CRISPR/Cas9 screens to establish the functional significance of germline-somatic interacting regions in ovarian cancer development.

摘要