Common biology underlying pleiotropic breast, prostate and ovarian cancer risk loci

多效性乳腺癌、前列腺癌和卵巢癌风险位点的共同生物学基础

基本信息

批准号：
10684639
负责人：
MATTHEW L FREEDMAN
金额：
$ 62.27万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10684639
关键词：
8q24 Affect African American Asian Automobile Driving BRCA1 gene BRCA2 gene Biological Biological Assay Biology Breast Breast Cancer Model CISH gene CRISPR interference CRISPR/Cas technology Candidate Disease Gene Cellular biology Clinical Code Complex Computing Methodologies DNA Data Set Development Disease Dryness Elements Epidemiology Etiology European Experimental Models Gene Expression Gene Expression Profiling Gene Expression Regulation Gene Targeting Genes Genetic Genetic Code Genetic Predisposition to Disease Genetic Variation Genetic study Genotype Goals Hispanic ancestry Hormonal Human Human Genetics Incidence Individual Leadership Luciferases Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of prostate Maps Mediating Mendelian disorder Meta-Analysis Methodology Methods Modeling Molecular Molecular Target Mutation Open Reading Frames Ovarian Pathogenesis Pathway Analysis Pathway interactions Persons Phenotype Population Positioning Attribute Predisposition Prevention strategy Prostate Regional Cancer Regulator Genes Regulatory Element Research Personnel Resolution Risk Risk Factors Role Susceptibility Gene Tissues Transcriptional Regulation Untranslated RNA Variant Work c-myc Genes cancer risk cancer type candidate identification candidate validation case control chromosome conformation capture disorder risk epigenomics gene interaction genetic association genetic information genetic variant genome editing genome wide association study genome-wide genomic locus in vitro Model knock-down malignant breast neoplasm molecular marker neoplastic novel overexpression pleiotropism risk prediction risk variant screening trait transcriptomics

项目摘要

ABSTRACT A fundamental goal of human genetics is to decipher the relationship between genotype and phenotype. Genome-wide association studies (GWAS) have identified thousands of common variants associated with numerous traits and diseases; but for the vast majority of genetic associations the underlying functional mechanisms are unknown. The key challenges in elucidating the biology underlying GWAS risk loci are: (i) to identify the susceptibility gene(s) at risk loci and their functional role in disease pathogenesis; (ii) to identify the causal risk variant(s) initiating disease development; and (iii) to establish the regulatory mechanisms by which risk variant(s) affect target gene expression An emerging feature of common variant risk loci is pleiotropy, where a risk locus shows evidence of susceptibility to two or more phenotypes. Breast, prostate and ovarian cancers share common etiologies. GWAS have so far identified more than 400 confirmed risk loci for these cancers. We have performed a meta- analysis of breast, prostate and ovarian cancers identifying more than 100 novel pleiotropic risk regions that suggest these cancers have a shared genetic component and similar underlying biology. Substantially larger genotyping studies continue to be performed in the human population and for these cancers which will provide the opportunity to identify additional breast, prostate and ovarian cancer pleiotropic risk loci. Our groups have also developed functional assays, including chromosome conformation capture, CRISPR/Cas9 genome editing, and experimental models of breast, prostate and ovarian cancer that enables us to establish the underlying biology driving neoplastic development at these risk loci in these cancer types. The overarching goals of this study are to identify shared genetic susceptibility alleles for breast, prostate and ovarian (BPO) cancers driven by non-coding DNA variation, and to establish the shared functional mechanisms that underlie disease risk for these cancers. The specific aims are: (1) To identify the credible causal risk variants, regulatory targets and candidate genes at pleiotropic BPO risk loci; (2) To utilize functional screening assays to prioritize causal risk variants, regulatory targets, and candidate genes at BPO risk loci; (3) To determine causality for risk variants, candidate genes and regulatory elements at BPO risk loci.

抽象的人类遗传学的一个基本目标是破译基因型与表型之间的关系。全基因组关联研究（GWAS）已经确定了数千种与许多特征和疾病；但是对于绝大多数遗传关联，基本功能机制是未知的。阐明GWAS风险基因座基础生物学的主要挑战是：（i）确定处于危险基因座的易感基因及其在疾病发病机理中的功能作用；（ii）识别引发疾病发展的因果风险变异；（iii）通过哪种风险变异影响靶基因表达普通变体风险基因座的新兴特征是多效性，其中风险基因座显示了对两个或多个表型的敏感性。乳房，前列腺和卵巢癌具有共同的病因。到目前为止，GWAS已确定了这些癌症的400多个确认的风险基因座。我们进行了元 - 分析乳房，前列腺和卵巢癌，鉴定了100多个新型的多效风险区域建议这些癌症具有共同的遗传成分和相似的基本生物学。大大更大基因分型研究继续在人口中进行，对于这些癌症，这些研究将提供有机会识别额外的乳房，前列腺和卵巢癌多效风险基因座。我们的团体有还开发了功能分析，包括染色体构象捕获，CRISPR/CAS9基因组编辑以及乳腺癌，前列腺和卵巢癌的实验模型，使我们能够建立在这些癌症类型中，驱动这些风险基因座的肿瘤发育的基本生物学。这项研究的总体目标是确定共同的遗传易感性等位基因乳房，前列腺和由非编码DNA变异驱动的卵巢（BPO）癌症，并建立共享功能疾病构成这些癌症风险的机制。具体目的是：（1）确定可靠的 Pleiotiropic BPO风险基因座的因果风险变异，监管靶标和候选基因；（2）利用功能筛选测定法，以确定BPO风险基因座的因果风险变异，调节目标和候选基因；（3）确定BPO风险基因座的风险变异的因果关系，候选基因和调节元素。