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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：
10366397
负责人：
MATTHEW L FREEDMAN
金额：
$ 66.84万
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/10366397
关键词：
8q24 Affect African American Asian ancestry 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 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 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 case control chromosome conformation capture disorder risk epigenomics genetic association genetic information genetic variant genome editing genome wide association study genome-wide genomic locus in vitro Model knock-down malignant breast neoplasm neoplastic novel overexpression pleiotropism risk prediction risk variant screening targeted biomarker 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.

摘要人类遗传学的一个基本目标是破译基因型和表型之间的关系。全基因组关联研究（GWAS）已经确定了数千种与基因突变相关的常见变异。许多性状和疾病;但对于绝大多数遗传关联，机制不明。阐明GWAS风险位点的生物学基础的关键挑战是：（i）确定风险位点的易感基因及其在疾病发病机制中的功能作用;（ii）确定引发疾病发展的因果风险变体;以及（iii）通过以下方式建立监管机制哪些风险变体影响靶基因表达常见变异风险基因座的一个新出现的特征是多效性，其中风险基因座显示以下证据：对两种或多种表型的易感性。乳腺癌、前列腺癌和卵巢癌有共同的病因。迄今为止，GWAS已经确定了400多个已证实的这些癌症的风险位点。我们做了一个Meta- 乳腺癌、前列腺癌和卵巢癌的分析，确定了100多个新的多效性风险区域，这表明这些癌症具有共同的遗传成分和相似的基础生物学。大得多基因分型研究继续在人群中进行，对于这些癌症，有机会确定额外的乳腺癌，前列腺癌和卵巢癌多效性风险位点。我们的团队还开发了功能分析，包括染色体构象捕获，CRISPR/Cas9基因组，编辑和乳腺癌，前列腺癌和卵巢癌的实验模型，使我们能够建立在这些癌症类型的这些风险位点驱动肿瘤发展的潜在生物学。这项研究的首要目标是确定乳腺癌、前列腺癌和乳腺癌共有的遗传易感性等位基因。卵巢癌（BPO）由非编码DNA变异驱动，并建立共享的功能这些癌症疾病风险的基础机制。具体目标是：（1）识别可信的多效性BPO风险基因座的致病风险变体、调控靶点和候选基因;（2）利用功能性筛选测定，以优先考虑BPO风险位点的因果风险变体、调控靶标和候选基因;（3）确定BPO风险位点的风险变异、候选基因和调控元件的因果关系。