Etiology and Genomics of Breast Cancer Progression in Women of African Ancestry

非洲裔女性乳腺癌进展的病因学和基因组学

• 批准号: 10610884
• 负责人: Dezheng Huo
• 金额: $ 56.58万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-20 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10610884
• 关键词: Admixture; Affect; African; African American population; African ancestry; Alleles; Architecture; Biological Process; Blood; Breast Cancer Patient; Breast Carcinogenesis; Cancer Control; Cell Fraction; Characteristics; Clinical; Clonal Evolution; Collaborations; Communities; Data; Data Set; Development; Disease; Disparity; ERBB2 gene; Environmental Risk Factor; Epidemiology; Ethnic Origin; Ethnic Population; Etiology; European ancestry; Event; Evolution; Genes; Genetic; Genome; Genomics; Geographic Distribution; Geography; Germ-Line Mutation; Goals; Health; High Prevalence; Incidence; Indigenous; Intervention; Investigation; Left; Life Style; Link; Malignant Neoplasms; Methods; Modeling; Molecular; Mutation; Nigeria; Nigerian; Outcome; Patients; Pattern; Phenotype; Policies; Population; Process; Protein Isoforms; RNA; RNA Splicing; Reporting; Research; Research Personnel; Resolution; Risk Factors; Sampling; Somatic Mutation; TP53 gene; Techniques; Testing; The Cancer Genome Atlas; Variant; Woman; aggressive breast cancer; breast cancer genomics; breast cancer progression; breast cancer survival; cancer care; cancer cell; cancer genome; cancer subtypes; cohort; differential expression; exome sequencing; fusion gene; genetic variant; homologous recombination; hormone receptor-positive; imprint; improved; innovation; life history; malignant breast neoplasm; molecular subtypes; mortality; precision oncology; racial difference; racial population; repaired; transcriptome; transcriptome sequencing; tumor; tumor heterogeneity; tumor progression; tumorigenesis; virtual; whole genome; young woman

ABSTRACT Aggressive breast cancer disproportionately affects young women of African Ancestry across the Diaspora, who continue to die at an excessively higher rate from the disease than any other racial/ethnic group in the US. Building on our recent findings that women in Nigeria have high prevalence of tumors with homologous recombination deficiency signature, our goal is to perform in depth genomic analyses using well phenotyped tumors from Nigeria. We hypothesize that the genomic determinants of breast cancer subtypes are also molecular drivers of tumor progression and represent targets for interventions to improve clinical outcomes and close the mortality gap. Specific aims are: (1) Examine whole genomes of well-phenotyped tumor/normal pairs to identify somatic mutation signatures and subclonal architecture. Mutation signatures connect cancer mutational processes to both exogenous and endogenous risk factors. Combined with the whole- genome and whole-exome sequencing (WGS, WES) data from Nigerian breast cancer patients (100 WGS and 127 WES) and TCGA (84 WGS and 1008 WES), we will infer mutation signatures and conduct life history analysis to understand sub-clonal architecture of lethal breast cancers (Year 1); (2) Validate the distribution of somatic mutation signatures and identify risk factors associated with mutation signatures. We will perform WES of additional 500 tumor/normal pairs to validate diversity of mutation landscape and signatures in unselected breast cancer cases in Nigeria (Years 1-5). We will validate somatic mutation spectrum and signatures identified in Aim 1 and compare to data from publicly available datasets including the TCGA, ICGC, and in collaboration with the Carolina Breast Cancer Study (CBCS). We will examine association between mutation signatures, germline variants, molecular subtypes and breast cancer survival. By identifying causal links between genetic and lifestyle/environmental factors that promote aggressive tumor progression, the proposed studies will have direct pubic health impact on millions of women in the African Diaspora. (3) Examine tumor heterogeneity and clonal evolution of breast cancers by sequencing multiple regions of the tumors. Clonal architecture can be described through the clustering of variants with similar cancer cell fractions, and also by their geographical distribution, resulting in much greater resolution of subclonal architecture. We will perform multi-region (4 cores per tumor) WGS, RNA-seq and in-depth analysis of 36 tumors (18 HR- and 18 HR+) to describe genomic inter- and intra-patient tumor heterogeneity that may affect clinical outcomes (Years 1-5). We will examine differential expression levels, somatic fusion genes, and aberrant splicing patterns and correlate findings with tumor evolution to infer somatic events that drive tumor progression. This highly innovative research integrating Nigerian breast cancer researchers with the global research community has the potential to have a large and sustained impact on cancer control policies and the delivery of precision cancer care for the most lethal subtypes of breast cancer in all populations.

摘要 侵袭性乳腺癌不成比例地影响散居各地的非洲裔年轻女性， 他们继续以比美国任何其他种族/族裔群体都高得多的比率死于这种疾病。 基于我们最近的发现，即尼日利亚的女性具有高的肿瘤发病率， 重组缺陷签名，我们的目标是使用良好的表型进行深入的基因组分析， 来自尼日利亚的肿瘤。我们假设乳腺癌亚型的基因组决定因素也是 肿瘤进展的分子驱动因素，代表了改善临床结局的干预措施的靶点， 缩小死亡率差距。具体目标是：（1）检查表型良好的肿瘤/正常的全基因组 配对以鉴定体细胞突变特征和亚克隆结构。突变签名连接 癌症突变过程与外源性和内源性风险因素有关。结合整体- 来自尼日利亚乳腺癌患者的基因组和全外显子组测序（WGS，WES）数据（100个WGS 和127 WES）和TCGA（84 WGS和1008 WES），我们将推断突变特征并进行生活史研究。 分析以了解致命性乳腺癌的亚克隆结构（第1年）;（2）确定分布 体细胞突变签名，并确定与突变签名相关的风险因素。我们将 对另外500个肿瘤/正常对进行WES，以验证 尼日利亚的乳腺癌病例数（1-5年）。我们将验证体细胞突变谱， 目标1中确定的签名，并与来自公开数据集（包括TCGA，ICGC， 并与卡罗莱纳乳腺癌研究（CBCS）合作。我们将研究 突变特征、生殖系变异、分子亚型和乳腺癌存活率。通过确定因果关系 遗传和生活方式/环境因素之间的联系，促进侵袭性肿瘤进展， 拟议的研究将对非洲散居地数百万妇女的公共卫生产生直接影响。（三） 通过对乳腺癌的多个区域进行测序来检查肿瘤异质性和克隆进化。 肿瘤克隆结构可以通过具有相似癌细胞的变体的聚类来描述 组分，也由它们的地理分布，导致更大的分辨率亚克隆 架构我们将进行多区域（每个肿瘤4个核心）WGS，RNA-seq和深入分析36个肿瘤。 肿瘤（18 HR-和18 HR+），以描述可能影响 临床结果（1-5年）。我们将研究差异表达水平，体细胞融合基因， 异常剪接模式和与肿瘤演变相关的发现，以推断驱动肿瘤的体细胞事件 进展这项高度创新的研究将尼日利亚乳腺癌研究人员与全球 研究界有可能对癌症控制政策产生巨大而持续的影响， 为所有人群中最致命的乳腺癌亚型提供精确的癌症护理。