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Using Genomics to Reduce Breast Cancer Disparities in the African Diaspora

利用基因组学减少非洲侨民的乳腺癌差异

基本信息

批准号：
8298031
负责人：
Dezheng Huo
金额：
$ 207.08万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-19 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8298031
关键词：
Accounting African African American Age Alcohol consumption Alleles Antioxidants Bilirubin Bioinformatics Biological Markers Biotechnology Blood Blood specimen Cancer Etiology Chronic Communities Complex Computational Biology Computer Simulation Cultural Backgrounds DNA Sequence Data Data Storage and Retrieval Environmental Risk Factor Epidemiology Ethnic Origin Ethnic group Etiology Founder Generation Genes Genetic Genetic Variation Genome Genomics Genotype Health Health Benefit Heterogeneity Hormones Indigenous Inflammation Inherited Knowledge Mammary Neoplasms Measures Medical History Modeling Molecular Target Mutation Neighborhoods Outcome Penetrance Persons Phase Phenotype Physical activity Plasma Play Population Premenopause Puberty Public Health Radiation Recording of previous events Recruitment Activity Research Infrastructure Resources Risk Risk Factors Role Sampling Smoking Somatic Mutation Statistical Models Testing The Cancer Genome Atlas Therapeutic Translating Variant Vitamin D Woman Women&apos s Health Work base cancer genome cancer health disparity cancer risk case control cohort data mining data sharing experience genetic profiling genome sequencing genome wide association study global health health disparity health equity improved insight lifestyle factors malignant breast neoplasm mortality novel novel strategies oncology racial and ethnic racial/ethnic difference reproductive triple-negative invasive breast carcinoma tumor tumor progression young woman

项目摘要

DESCRIPTION (provided by applicant): It is now well recognized that African Americans experience a disproportionate burden of pre-menopausal breast cancer and higher mortality rates in comparison to other racial/ethnic groups. Recent studies demonstrate that African Americans are more likely to develop triple-negative breast cancer (TNBC) or basal- like breast cancer in particular. We recently showed that indigenous West Africans, the founder population of African Americans had even higher proportions of TNBC than do African Americans. We have recruited 1233 breast cancer cases and 1101 controls in Phase 1 of the Nigerian Breast Cancer Study (NBCS) and recruitment of additional 1500 cases and ethnicity & age-matched 1500 controls is ongoing. In addition, we are conducting a genome-wide association study (GWAS) of breast cancer in women of African Ancestry to study common variants for breast cancer and results will be available in autumn 2011. Here, we propose a high- throughput whole genome DNA sequencing and computational biology approach to examine rare, moderate- penetrance variants for breast cancers and expand the analysis of ethnic diversity in breast cancer genomes. Our specific aims are to: 1) fully sequence genomes (WGS) of normal blood and matched primary breast tumors from 200 well-phenotyped cases and 200 controls to identify germline and somatic variants for triple negative breast cancer. We will distinguish inherited from somatic variants by comparing variants identified in tumors with the paired normal blood samples and the healthy controls to evaluate the etiologic effect of the inherited variants; 2) Validate selected genes/variants in >5000 breast cancer cases and >5000 controls of African and non-African ancestry. We will first impute rare genotypes identified by whole genome sequencing into all the GWAS samples to conduct an in silico replication. Then, we will perform replication in the African American Breast Cancer Consortium, which includes Black Women's Health Study and the Triple Negative Breast Cancer Consortium. Our access to other Consortia including BCAC, CIMBA and Post GWAS U19 will provide other cohorts for replicating our studies. This integrative approach will increase our power to identify associations between rare inherited variants and the most aggressive form of breast cancer in an understudied but unique population. The replication of our study findings in other populations and our data sharing plans will bring enormous public health benefit by harnessing genomics and biotechnology to improve global health equity and reduce health disparities. PUBLIC HEALTH RELEVANCE: The primary objective of this study is to harness genomics to solve the complex problem of aggressive triple negative breast cancer (TNBC) which poses a great threat to the lives of understudied and underserved women throughout the African Diaspora. We wish to understand the etiology for TNBC in women of African ancestry and translate the knowledge into more effective management of TNBC for all women. Through this work, we hope to continue to gain insights into the mechanisms underlying racial/ethnic differences in breast cancer outcomes and develop novel approaches to reduce health inequities.

描述（由申请人提供）：现在人们普遍认识到，与其他种族/族裔群体相比，非裔美国人承受着不成比例的绝经前乳腺癌负担和更高的死亡率。最近的研究表明，非裔美国人更有可能患三阴性乳腺癌（TNBC）或基底样乳腺癌。我们最近发现，西非土著人（非裔美国人的创始人）的 TNBC 比例甚至比非裔美国人还要高。我们在尼日利亚乳腺癌研究 (NBCS) 第一阶段招募了 1233 名乳腺癌病例和 1101 名对照者，另外 1500 名病例以及种族和年龄匹配的 1500 名对照者的招募工作正在进行中。此外，我们正在非洲血统女性中开展一项乳腺癌全基因组关联研究 (GWAS)，以研究乳腺癌的常见变异，结果将于 2011 年秋季公布。在此，我们提出一种高通量全基因组 DNA 测序和计算生物学方法来检查罕见、中等外显率的乳腺癌变异，并扩大对乳腺癌基因组中种族多样性的分析。我们的具体目标是：1) 对来自 200 个表型良好的病例和 200 个对照的正常血液和匹配的原发性乳腺肿瘤进行全基因组 (WGS) 测序，以识别三阴性乳腺癌的种系和体细胞变异。我们将通过将肿瘤中发现的变异与配对的正常血液样本和健康对照进行比较来区分遗传变异和体细胞变异，以评估遗传变异的病因学作用； 2) 在 > 5000 例乳腺癌病例和 > 5000 例非洲和非非洲血统对照中验证选定的基因/变异。我们首先将通过全基因组测序鉴定出的稀有基因型归入所有 GWAS 样本中，以进行计算机复制。然后，我们将在非裔美国人乳腺癌联盟（包括黑人妇女健康研究和三阴性乳腺癌联盟）中进行复制。我们与其他联盟（包括 BCAC、CIMBA 和 Post GWAS U19）的联系将为复制我们的研究提供其他队列。这种综合方法将增强我们在未经充分研究但独特的人群中识别罕见遗传变异与最具侵袭性的乳腺癌之间关联的能力。我们的研究结果在其他人群中的复制以及我们的数据共享计划将通过利用基因组学和生物技术来改善全球健康公平并减少健康差距，从而带来巨大的公共卫生效益。公共健康相关性：本研究的主要目的是利用基因组学来解决侵袭性三阴性乳腺癌 (TNBC) 的复杂问题，该问题对整个非洲侨民中未被充分研究和服务的妇女的生命构成了巨大威胁。我们希望了解非洲血统女性 TNBC 的病因，并将这些知识转化为对所有女性进行更有效的 TNBC 管理。通过这项工作，我们希望继续深入了解乳腺癌结果中种族/民族差异的机制，并开发减少健康不平等的新方法。