Genome-wide association study of breast cancer in the African Diaspora

描述（由申请人提供）：欧洲血统以外的种族/族裔群体乳腺癌遗传流行病学数据的缺乏阻碍了减少健康差异的创新干预措施的发展。与所有其他种族相比，非洲散居妇女经历了不成比例的绝经前乳腺癌负担，原因仍然未知和研究不足。早发性乳腺癌的比例较高可能表明这些人群中有更强的遗传成分。全基因组关联研究（GWAS）揭示了几个遗传位点，赋予乳腺癌的风险。由于所有GWAS都是在欧洲血统的女性中开始发现的，并且主要在欧洲血统的女性中复制，因此我们提出了一种新的方法，用于在土著非洲女性中进行GWAS，以确定与乳腺癌风险相关的等位基因，然后将其复制到其他人群中。这种创新设计建立在我们目前对乳腺癌病因异质性的理解以及非洲血统女性和欧洲血统女性之间乳腺癌分子亚型的分布的基础上。拟议研究的主要目标是通过在非洲血统妇女的合并样本中识别乳腺癌风险等位基因来找到乳腺癌的“根本”原因，并在其他人群中复制我们的发现。为了实现这一目标，我们提出了以下具体目标：1）使用Illumina Human 1 M BeadChip平台对1，796例乳腺癌病例和1，988例非洲血统对照进行基因型分析。其中包括来自尼日利亚伊巴丹的944例病例和665例对照，来自巴巴多斯的171例病例和378例对照，来自芝加哥、底特律、费城和巴尔的摩的681例病例和945例对照; 2）对数据进行标准和新的遗传分析，以绘制与乳腺癌易感性相关的基因，3）验证基因分型，并在显示与乳腺癌风险和相关临床表型相关的基因或区域中进行精细定位研究，以及4）在其他非洲裔美国人和非非洲裔美国人人群中复制。通过汇集来自整个非洲散居地研究的独特资源，这项研究有可能确定几个基因中的风险等位基因，这些基因有助于增加乳腺癌风险，并可能对ALL女性乳腺癌的早期检测，预后和治疗产生影响。这最终将改善那些遭受早发性乳腺癌不成比例负担的人的结果。 公共卫生相关性：在美国的所有种族/族裔群体中，非裔美国人在35岁以下妇女中诊断出的乳腺癌死亡率最高，在非洲，乳腺癌是年轻妇女的一种致命疾病，部分原因是难以获得护理和对这种疾病的无知。该项目的重点是非洲移民社群中尚未得到充分研究的全球乳腺癌问题，并试图将基因组学研究的最新进展转化为有益于有患激素受体阴性乳腺癌风险的妇女的成果，这种乳腺癌是一种侵袭性乳腺癌，经常影响年轻妇女。更好地了解非洲散居妇女乳腺癌的遗传风险，应有助于更好地进行临床风险评估，并制定更有效的战略，预防、早期发现和治疗所有妇女的乳腺癌。

DESCRIPTION (provided by applicant): The paucity of data on the genetic epidemiology of breast cancer for racial/ethnic groups other than those of European ancestry hinders the development of innovative interventions to reduce health disparities. Women in the African Diaspora experience a disproportionate burden of pre-menopausal breast cancer in comparison to all other races for reasons that remain unknown and understudied. This higher proportion of early-onset breast cancer might suggest a stronger genetic component in these populations. Genome-wide association studies (GWAS) have revealed several genetic loci that confer risk of breast cancer. Because all GWAS started the discovery stage in women of European ancestry and replicated mainly in women of European ancestry, we propose a novel approach for a GWAS in indigenous African women to identify alleles associated with breast cancer risk which will then be replicated in other populations. This innovative design builds on our current understanding of the etiologic heterogeneity in breast cancer and the distribution of breast cancer molecular subtypes which differ between women of African ancestry and women of European ancestry. The major objective of the proposed studies is to get to the "root" causes of breast cancer by identifying breast cancer risk alleles in a pooled sample of women of African ancestry and to replicate our findings in other populations. To achieve this objective, we propose the following specific aims: 1) Genotype 1,796 breast cancer cases and 1,988 controls of African ancestry using the Illumina Human1M BeadChip platform. These include 944 cases and 665 controls form Ibadan, Nigeria, 171 cases and 378 controls from Barbados, and 681 cases and 945 controls from Chicago, Detroit, Philadelphia and Baltimore; 2) Conduct both standard and novel genetic analyses of the data to map genes associated with breast cancer susceptibility, 3) Verify genotyping and carry out fine-mapping studies in genes or regions showing association with breast cancer risk and related clinical phenotypes and 4) Replicate in other African American and non-African American populations. By pooling unique resources from studies throughout the African Diaspora, this study has the potential to identify risk alleles in several genes that contribute to increased breast cancer risk and may have implications for early detection, prognosis and treatment of breast cancer in ALL women. This should ultimately lead to improved outcomes for those who suffer a disproportionate burden of early-onset breast cancer. PUBLIC HEALTH RELEVANCE: Of all the racial/ethnic groups in the United States, African Americans have the highest mortality rate of breast cancer diagnosed in women under 35 years of age, and in Africa, breast cancer is a uniformly fatal affliction of young women, in part, due to poor access to care and ignorance of the disease. This project focuses on the understudied global problem of breast cancer in the African Diaspora and attempts to translate recent advances in genomics research to benefit women who are at risk of developing hormone receptor negative breast cancer, an aggressive form of breast cancer that often affects younger women. Better understanding of the genetic risks of breast cancer for women in the African Diaspora should lead to better clinical risk assessment and the development of more effective strategies for prevention, early detection and treatment of breast cancer for ALL women.