Integrating genomic and transcriptomic data to identify breast cancer susceptibility genes

整合基因组和转录组数据来识别乳腺癌易感基因

• 批准号: 10650297
• 负责人: Jirong Long
• 金额: $ 66.32万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650297
• 关键词: ABCC1 gene; Acceleration; African; African ancestry; Asia; Asian; Asian ancestry; Asian population; Bioinformatics; Biological; Biological Assay; Biological Process; Breast Cancer Genetics; Breast Cancer Patient; Breast Cancer Risk Factor; Breast Cancer gene; Cancer Biology; Cancer Control; Cancer-Predisposing Gene; Candidate Disease Gene; Cell physiology; Complex; Data; Disease; Disease susceptibility; ERBB2 gene; Estrogen Receptors; Etiology; European; European ancestry; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Models; Genetic Risk; Genetic study; Genome; Genomics; Genotype; Genotype-Tissue Expression Project; Hereditary Breast Carcinoma; Heritability; In Vitro; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Maps; Methodology; Modeling; Patient Care; Phenotype; Pilot Projects; Play; Race; Risk; Role; Sample Size; Sampling; Testing; The Cancer Genome Atlas; Tissue Sample; Tissues; Translating; Tumor Tissue; Woman; cancer genetics; cancer risk; causal variant; cost; cost efficient; density; disorder prevention; disorder risk; genetic predictors; genetic variant; genome sequencing; genome wide association study; genomic data; improved; in vitro Assay; malignant breast neoplasm; molecular subtypes; novel; novel strategies; predictive modeling; racial difference; racial population; risk variant; trait; transcriptome; transcriptome sequencing; transcriptomics; translational genetics; whole genome

Project Summary Genetic factors play an important role in the etiology of both sporadic and familial breast cancer. Since 2007, common genetic variants in ~200 loci have been identified in genome-wide association studies (GWAS) in relation to breast cancer risk. However, it is often difficult to translate GWAS findings to disease prevention and treatment since causal genes in the large majority of GWAS-identified loci are unknown. Furthermore, a large fraction of breast cancer heritability remains unexplained. Recent studies suggest that nearly 80% of disease heritability can be explained by genetic variants regulating gene expression. Herein, we propose three well-powered transcriptome-wide association studies (TWAS) to systematically investigate the association of breast cancer risk with gene expression across the transcriptome of African, Asian and European descendants. In Aim 1, we will perform RNA sequencing and high-density genotyping assays using normal breast tissue samples and build race-specific gene expression prediction models using data from 1000 women of African, Asian and European descent. These models will be applied to the GWAS data generated from approximately 320,000 breast cancer patients and controls to impute gene expression for association analyses of predicted gene expression with risk of breast cancer overall and by estrogen receptor and HER2 status. In Aim 2, we will select the top 50 genes identified in Aim 1 for in vitro functional assays to assess their influence on major cell functions related to cancer biology. In Aim 3, we will evaluate whether TWAS-identified genes may express differently in normal breast tissues and breast cancer tissues collected from African, Asian, and European descendants to assess whether these genes may contribute to racial differences in breast cancer risk by molecular subtypes. With strong methodology and a large sample size, we believe that this proposed study should be able to identify and characterize a large number of novel genes related to breast cancer risk. Uncovering breast cancer susceptibility genes will greatly improve the understanding of the genetic and biological basis for breast cancer and accelerate the translation of genetic findings to disease prevention and patient care.

项目摘要 遗传因素在散发性和家族性乳腺癌的病因中起着重要作用。 自2007年以来，已在全基因组范围内确定了约200个基因座上的常见遗传变异 与乳腺癌风险相关的协会研究(GWAS)。然而，通常很难做到 将GWAS的发现转化为疾病预防和治疗，因为原因基因很大 大多数GWAS鉴定的基因座都是未知的。此外，很大一部分乳腺癌 遗传性仍未得到解释。最近的研究表明，近80%的疾病遗传性 可以通过调节基因表达的遗传变异来解释。在这里，我们提出了三个 强大的转录组广泛的关联研究(TWAS)系统地研究 非洲人乳腺癌风险与转录组基因表达的关系 亚洲和欧洲的后裔。在目标1中，我们将进行RNA测序和高密度 利用正常乳腺组织样本进行基因分型分析并建立种族特异性基因表达 预测模型使用了1000名非洲、亚洲和欧洲后裔女性的数据。这些 模型将应用于从大约320,000例乳腺癌中产生的GWAS数据 用于预测基因关联分析的患者和对照的基因表达 雌激素受体和HER2状态与乳腺癌风险的总体表达。在AIM 2，我们将选择在Aim 1中确定的前50个基因进行体外功能分析，以评估它们的 对与癌症生物学相关的主要细胞功能的影响。在目标3中，我们将评估 Twas鉴定的基因可能在正常乳腺组织和乳腺癌中表达不同 从非洲、亚洲和欧洲的后代身上收集的组织来评估这些 基因可能通过分子亚型导致乳腺癌风险的种族差异。使用 方法学强，样本量大，我们认为这项拟议的研究应该是 能够识别和表征大量与乳腺癌风险相关的新基因。 揭示乳腺癌易感基因将极大地提高人们对乳腺癌易感基因的认识 乳腺癌的遗传学和生物学基础，加速基因研究成果的转化 到疾病预防和病人护理。

项目成果

Associations of genetic susceptibility to 16 cancers with risk of breast cancer overall and by intrinsic subtypes.

• DOI: 10.1016/j.xhgg.2021.100077
• 发表时间: 2022-01-13
• 期刊: HGG advances
• 作者: Choi J;Jia G;Wen W;Tao R;Long J;Shu XO;Zheng W
• 通讯作者: Zheng W

Incorporating Polygenic Risk Scores and Nongenetic Risk Factors for Breast Cancer Risk Prediction Among Asian Women.

• DOI: 10.1001/jamanetworkopen.2021.49030
• 发表时间: 2022-03-01
• 期刊: JAMA network open
• 影响因子: 13.8
• 作者: Yang Y;Tao R;Shu X;Cai Q;Wen W;Gu K;Gao YT;Zheng Y;Kweon SS;Shin MH;Choi JY;Lee ES;Kong SY;Park B;Park MH;Jia G;Li B;Kang D;Shu XO;Long J;Zheng W
• 通讯作者: Zheng W