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

摘要 侵袭性乳腺癌对海外非洲裔年轻女性的影响不成比例， 他们死于这种疾病的比率仍然比美国其他任何种族/民族都要高。 根据我们最近的发现，尼日利亚妇女患同源肿瘤的比例很高。 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，是改善临床结果和干预的靶点 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，以确定体细胞突变特征和亚克隆结构。突变签名连接 癌症的突变过程对外源性和内源性危险因素都有影响。再加上整个- 尼日利亚乳腺癌患者的基因组和全外显子组测序(100个WGS)数据 和TCGA(84个WGS和1008个WES)，我们将推断突变特征并进行生活史 了解致死性乳腺癌亚克隆构筑的分析(1)；(2)验证分布 对体细胞突变特征进行分析，并确定与突变特征相关的风险因素。我们会 对另外500个肿瘤/正常对进行WES，以验证突变图谱和签名的多样性 尼日利亚未经选择的乳腺癌病例(1-5岁)。我们将验证体细胞突变谱并 并将AIM 1中识别的签名与来自包括TCGA、ICGC、 并与卡罗莱纳乳腺癌研究(CBCS)合作。我们将研究它们之间的关联 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 促进肿瘤侵袭性进展的遗传和生活方式/环境因素之间的联系， 拟议的研究将对散居海外的数百万非洲妇女的公共健康产生直接影响。(3) 通过测序检测乳腺癌的多个区域的肿瘤异质性和克隆性进化 肿瘤。克隆结构可以通过具有相似癌细胞的变异体的聚集来描述 组分，以及它们的地理分布，导致亚克隆的分辨率更高 建筑。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(18HR-和18HR+)用于描述可能影响患者间和患者内肿瘤基因组异质性 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，以及 异常剪接模式和与肿瘤进化相关的发现以推断驱动肿瘤的躯体事件 进步。这项高度创新的研究将尼日利亚的乳腺癌研究人员与全球 研究界有可能对癌症控制政策和 精确癌症的交付为所有人群中最致命的乳腺癌亚型提供护理。

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.