Functional Effects of Ovarian Cancer Risk Variants

卵巢癌风险变异的功能影响

• 批准号: 10083194
• 负责人: MATTHEW L FREEDMAN
• 金额: $ 61.3万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10083194
• 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; Development; Disease; Disease model; Etiology; Experimental Models; Family; 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; Oncology; Open Reading Frames; Ovarian; Pathogenesis; Pathway interactions; Penetrance; Persons; Phenotype; Population; Positioning Attribute; Prevention approach; Prevention strategy; Prognosis; 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; causal variant; chromatin immunoprecipitation; chromosome conformation capture; clinical biomarkers; design; disorder prevention; epigenome editing; 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; population based; risk prediction; risk variant; screening; trait; tumorigenesis

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 全基因组关联研究 (GWAS) 迄今为止已确定了 20 多种常见的低外显率 卵巢癌的变异；但据估计，还有数千种风险变异等待发现。在 后 GWAS 时代的识别、功能表征和效用面临一系列复杂的挑战 易感性等位基因已经出现，包括：（i）识别因果遗传变异和调控 在风险位点驱动癌症发展的目标； (ii) 识别与风险相关的易感基因 变体； (iii) 确定是否存在解释功能机制的共同生物网络 潜在的多个风险位点。临床上，识别卵巢癌的遗传风险成分可能会 通过人群筛查和疾病预防策略改善疾病预防；和 了解风险位点的功能可能有助于发现临床生物标志物和新的靶向药物 疗法，类似于 BRCA1 或 BRCA2 突变携带者的 PARP 疗法范例。 当前的提案旨在解决卵巢癌术后的许多挑战。 GWAS 时代包括：(1) 识别不同的其他新颖、常见变异易感性等位基因 卵巢癌的组织学亚型； (2) 建立驱动疾病的功能机制 基于可能的偶然 SNP 的识别和表征的卵巢癌风险位点和 目标易感基因为风险位点； (3) 使用基于全基因组功能模型的分析 干扰卵巢癌易感基因，以确定常见机制和生物学 驱动肿瘤发生的途径； (4) 将功能数据集与遗传关联数据集整合起来 提高这些研究确定其他卵巢癌易感位点的能力。

项目成果

Augmenting and directing long-range CRISPR-mediated activation in human cells.

增强和指导人类细胞中 CRISPR 介导的长程激活。

• 发表时间: 2021-09
• 影响因子: 48
• 作者: Tak, Y Esther;Horng, Joy E;Perry, Nicholas T;Schultz, Hayley T;Iyer, Sowmya;Yao, Qiuming;Zou, Luli S;Aryee, Martin J;Pinello, Luca;Joung, J Keith
• 通讯作者: Joung, J Keith

A Study of High-Grade Serous Ovarian Cancer Origins Implicates the SOX18 Transcription Factor in Tumor Development.

一项关于高级别浆液性卵巢癌起源的研究表明 SOX18 转录因子与肿瘤发展有关。

• DOI: 10.1016/j.celrep.2019.10.122
• 发表时间: 2019-12-10
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: K. Lawrenson;M. A. Fonseca;Annie Y. Liu;Felipe Segato Dezem;Janet M. Lee;Xianzhi Lin;R. Corona;F. Abbasi;K. Vavra;Huy Q. Dinh;N. Gill;Ji;Simon G. Coetzee;Yvonne G Lin;T. Pejovic;P. Mhawech;A. Rowat;R. Drapkin;B. Karlan;Dennis J. Hazelett;M. Freedman;S. Gayther;H. Noushmehr
• 通讯作者: H. Noushmehr

Single-cell transcriptomics identifies gene expression networks driving differentiation and tumorigenesis in the human fallopian tube.

单细胞转录组学鉴定了驱动人类输卵管分化和肿瘤发生的基因表达网络。

• 发表时间: 2021-04-13
• 影响因子: 8.8
• 作者: Dinh, Huy Q;Lin, Xianzhi;Abbasi, Forough;Nameki, Robbin;Haro, Marcela;Olingy, Claire E;Chang, Heidi;Hernandez, Lourdes;Gayther, Simon A;Wright, Kelly N;Aspuria, Paul;Karlan, Beth Y;Corona, Rosario I;Li, Andrew;Rimel, B J;Siedhoff, Ma
• 通讯作者: Siedhoff, Ma

A multi-level investigation of the genetic relationship between endometriosis and ovarian cancer histotypes.

子宫内膜异位症与卵巢癌组织型之间遗传关系的多层次研究。

• 发表时间: 2022-03-15
• 作者: Mortlock, Sally;Corona, Rosario I;Kho, Pik Fang;Pharoah, Paul;Seo, Ji;Freedman, Matthew L;Gayther, Simon A;Siedhoff, Matthew T;Rogers, Peter A W;Leuchter, Ronald;Walsh, Christine S;Cass, Ilana;Karlan, Beth Y;Rimel, B J;Ovarian Cancer As
• 通讯作者: Ovarian Cancer As

Ovarian Cancer Risk Variants Are Enriched in Histotype-Specific Enhancers and Disrupt Transcription Factor Binding Sites.

卵巢癌风险变异体富含组织型特异性增强子并破坏转录因子结合位点。

• 发表时间: 2020
• 影响因子: 9.8
• 作者: Jones, Michelle R;Peng, Pei;Coetzee, Simon G;Tyrer, Jonathan;Reyes, Alberto Luiz P;Corona, Rosario I;Davis, Brian;Chen, Stephanie;Dezem, Felipe;Seo, Ji;Kar, Siddartha;Dareng, Eileen;Ovarian Cancer Association Consortium;Berman, Benj
• 通讯作者: Berman, Benj