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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

基本信息

批准号：
10399437
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-20 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10399437
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 ERBB2 gene Environmental Risk Factor Ethnic Origin Ethnic group Etiology European Event Evolution Genes Genetic Genome Genomics Geographic Distribution Geography 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 Spliced Genes 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 genomic epidemiology homologous recombination hormone receptor-positive imprint improved innovation life history malignant breast neoplasm molecular subtypes mortality precision oncology racial and ethnic racial difference repaired transcriptome transcriptome sequencing tumor tumor heterogeneity tumor progression tumorigenesis virtual whole genome young woman

项目摘要

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.

抽象的侵袭性乳腺癌不成比例地影响散居海外的非洲裔年轻女性，他们死于这种疾病的比率仍然高于美国任何其他种族/族裔群体。根据我们最近的发现，尼日利亚女性的同源肿瘤患病率很高重组缺陷特征，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，代表了改善临床结果和干预措施的目标缩小死亡率差距。具体目标是：（1）检查表型良好的肿瘤/正常人的全基因组配对来识别体细胞突变特征和亚克隆结构。突变签名连接外源性和内源性危险因素的癌症突变过程。结合整体—— 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分析以了解致命性乳腺癌的亚克隆结构（第一年）； (2) 验证分布体细胞突变特征并识别与突变特征相关的风险因素。我们将对另外 500 个肿瘤/正常对进行 WES，以验证突变景观和特征的多样性尼日利亚未选择的乳腺癌病例（1-5 年）。我们将验证体细胞突变谱并目标 1 中确定的签名，并与公开数据集（包括 TCGA、ICGC、并与卡罗莱纳州乳腺癌研究 (CBCS) 合作。我们将检查之间的关联突变特征、种系变异、分子亚型和乳腺癌存活率。通过识别因果关系促进侵袭性肿瘤进展的遗传和生活方式/环境因素之间的联系，拟议的研究将对数百万散居非洲的妇女产生直接的公共健康影响。 (3) 通过对多个区域进行测序来检查乳腺癌的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分数，以及它们的地理分布，导致亚克隆的分辨率更高建筑学。我们将对 36 个肿瘤进行多区域（每个肿瘤 4 个核心）WGS、RNA-seq 和深入分析肿瘤（18 HR- 和 18 HR+）来描述可能影响的基因组间和患者内肿瘤异质性临床结果（1-5 年）。我们将检查差异表达水平、体细胞融合基因，以及异常剪接模式并将发现与肿瘤进化相关联，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乳腺癌研究人员结合起来研究界有可能对癌症控制政策和癌症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准的癌症护理。