Polygenic Risk Prediction of Breast Cancer for Women of African Descent

非洲裔女性乳腺癌的多基因风险预测

基本信息

批准号：
10748724
负责人：
Dezheng Huo
金额：
$ 51.53万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-19 至 2028-07-01
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10748724
关键词：
Address African African American African American population African ancestry Age Asian Asian ancestry Asian population Assessment tool Breast Cancer Detection Breast Cancer Genetics Breast Cancer Model Breast Cancer Risk Factor Case/Control Studies Clinical Cohort Studies Complex Data Data Pooling Data Set Development Elasticity Epidemiology Estrogen Receptors Estrogen receptor negative Estrogen receptor positive Ethnic Population European ancestry Family history of Funding Gene Frequency Genes Genetic Genetic Counseling Genetic Diseases Incidence Individual Investigation Knowledge Lasso Left Life Style Linkage Disequilibrium Mammographic screening Maps Methods Modeling Mutation Noise Outcome Penetrance Performance Population Predisposition Prevention Public Domains Quantitative Trait Loci RNA Splicing Race Racial Equity Reproductive History Risk Risk Assessment Risk Factors Sample Size Scoring Method Signal Transduction Statistical Methods Susceptibility Gene Target Populations Testing Training Translating Variant Veterans Woman access disparities ancestry analysis black women cancer subtypes causal variant clinical practice cohort early onset genetic predictors genetic variant genome wide association study genome-wide genome-wide analysis genomic locus high risk improved innovation malignant breast neoplasm mortality multi-ethnic non-genetic novel polygenic risk score precision medicine racial disparity racial population risk prediction risk prediction model risk stratification risk variant screening statistics tool transcriptome transcriptome sequencing transcriptomics translational impact triple-negative invasive breast carcinoma

项目摘要

PROJECT ABSTRACT African Americans have the highest breast cancer mortality rate, highest incidence rate of early-onset breast cancer, and highest incidence rate of triple-negative breast cancer in the U.S. More than 220 susceptibility loci for breast cancer have been identified by genome-wide association studies (GWAS), mainly in population of European ancestry. Polygenic risk scores (PRS), which aggregate common genetic variants identified by GWAS, have been developed to predict genetic risk of breast cancer for European ancestry women and used in clinical practice, but the PRS for African American women has suboptimal accuracy. Therefore, we propose a comprehensive analytical study that leverages several types of existing genetic datasets for breast cancer available to us and in public domains to address three specific aims. First, we aim to conduct cross-ancestry fine-mapping analysis to identify a credible set of causal variants in 237 breast cancer susceptibility loci. Then we will develop parsimonious and robust PRS from the credible set of variants. We have compiled and harmonized genetic data from breast cancer GWASs in women of African ancestry, including 18,034 cases and 22,104 controls, and leverage the association results from European ancestry (>133,000 cases and >291,000 controls) and Asian (>22,000 cases and >22,000 controls) populations. Second, we aim to develop precise PRS using genome-wide data with several novel cross-ancestry statistical methods. We will develop PRS models for overall breast cancer and its subtypes (estrogen receptor positive and negative, and triple-negative breast cancer). Then we will validate the models generated in aims 1-2 in independent datasets (>14,000 cases and >82,000 controls) from case-control studies, ongoing cohort studies, and an ongoing risk-adaptive breast cancer screening trial. Third, we will integrate the best performed PRS with existing risk prediction models that are based on non-genetic risk factors. The resulting absolute risk models have a good potential to translate knowledge from GWAS to inform the practice of genetic counseling, breast cancer screening and prevention for African Americans. It has good potential to advance racial equity in breast cancer.

项目摘要非裔美国人乳腺癌死亡率最高，早发型发病率最高乳腺癌，美国三阴性乳腺癌发病率最高超过 220 乳腺癌易感位点已通过全基因组关联研究（GWAS）确定，主要是在欧洲血统的人口中。多基因风险评分 (PRS)，汇总常见的遗传变异经 GWAS 鉴定，已开发用于预测欧洲血统患乳腺癌的遗传风险女性并用于临床实践，但非裔美国女性的 PRS 准确性欠佳。因此，我们提出一项综合分析研究，利用现有的几种类型的遗传我们可以在公共领域使用乳腺癌数据集来实现三个特定目标。首先，我们的目标是进行跨祖先精细绘图分析，以确定 237 个乳房中一组可信的因果变异癌症易感性位点。然后，我们将从可靠的变体集中开发简约且强大的 PRS。我们汇编并协调了非洲血统女性乳腺癌 GWAS 的遗传数据，包括 18,034 个病例和 22,104 个对照，并利用欧洲血统的关联结果（>133,000 例病例和 >291,000 例对照）和亚洲（>22,000 例病例和 >22,000 例对照）人群。其次，我们的目标是使用全基因组数据和几种新颖的跨血统统计数据来开发精确的 PRS 方法。我们将为整体乳腺癌及其亚型（雌激素受体阳性）开发PRS模型以及阴性和三阴性乳腺癌）。然后我们将验证目标 1-2 中生成的模型来自病例对照研究、正在进行的队列研究的独立数据集（>14,000 例病例和 >82,000 例对照），以及正在进行的风险适应性乳腺癌筛查试验。第三，我们将整合表现最好的 PRS 与基于非遗传风险因素的现有风险预测模型。由此产生的绝对风险模型具有很好的潜力将 GWAS 的知识转化为遗传咨询实践，非裔美国人的乳腺癌筛查和预防。它具有促进种族平等的巨大潜力乳腺癌。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Germline variants and somatic mutation signatures of breast cancer across populations of African and European ancestry in the US and Nigeria.

美国和尼日利亚非洲和欧洲血统人群乳腺癌的种系变异和体细胞突变特征。

DOI：
10.1002/ijc.32498
发表时间：
2019
期刊：
International journal of cancer
影响因子：
6.4
作者：
Wang,Shengfeng;Pitt,JasonJ;Zheng,Yonglan;Yoshimatsu,ToshioF;Gao,Guimin;Sanni,Ayodele;Oluwasola,Olayiwola;Ajani,Mustapha;Fitzgerald,Dominic;Odetunde,Abayomi;Khramtsova,Galina;Hurley,Ian;Popoola,Abiodun;Falusi,Adeyinka;Ogundira
通讯作者：
Ogundira

Validation of the Nigerian Breast Cancer Study Model for Predicting Individual Breast Cancer Risk in Cameroon and Uganda.

DOI：
10.1158/1055-9965.epi-22-0869
发表时间：
2023-01-09
期刊：
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
影响因子：
0
作者：
通讯作者：

Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes.

DOI：
10.1038/s41467-021-27079-w
发表时间：
2021-11-26
期刊：
Nature communications
影响因子：
16.6
作者：
Ansari-Pour N;Zheng Y;Yoshimatsu TF;Sanni A;Ajani M;Reynier JB;Tapinos A;Pitt JJ;Dentro S;Woodard A;Rajagopal PS;Fitzgerald D;Gruber AJ;Odetunde A;Popoola A;Falusi AG;Babalola CP;Ogundiran T;Ibrahim N;Barretina J;Van Loo P;Chen M;White KP;Ojengbede O;Obafunwa J;Huo D;Wedge DC;Olopade OI
通讯作者：
Olopade OI

An enhancer variant associated with breast cancer susceptibility in Black women regulates TNFSF10 expression and antitumor immunity in triple-negative breast cancer.

DOI：
10.1093/hmg/ddac168
发表时间：
2023-01-01
期刊：
Human molecular genetics
影响因子：
3.5
作者：
通讯作者：

Benign breast disease and breast cancer risk in African women: A case-control study.

非洲女性的良性乳腺疾病和乳腺癌风险：病例对照研究。

DOI：
10.21203/rs.3.rs-3301977/v1
发表时间：
2023
期刊：
Research square
影响因子：
0
作者：
Omoleye,OlasubomiJ;Freeman,JincongQ;Oluwasanu,Mojisola;Adeniji-Sofoluwe,Adenike;Woodard,AnnaE;Aribisala,BenjaminS;Adejumo,PriscaO;Ntekim,Atara;Makumbi,Timothy;Ndom,Paul;Ajayi,IkeOluwapoO;Olopade,OlufunmilayoI;Huo,Dezheng
通讯作者：
Huo,Dezheng