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.

抽象的侵略性乳腺癌不成比例地影响整个侨民的非洲血统的年轻妇女与美国其他任何种族/族裔群体相比，他们继续以疾病的速度更高的人死亡。基于我们最近的发现，尼日利亚的妇女患有同源的肿瘤患病率很高重组缺乏签名，我们的目标是使用表现良好的深度基因组分析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目标缩小死亡率差距。具体目的是：（1）检查良好型肿瘤/正常的全基因组对识别体细胞突变特征和亚克隆体系结构的成对。突变特征连接癌症突变过程均针对外源性和内源性危险因素。与整个来自尼日利亚乳腺癌患者的基因组和全外观测序（WGS，WES）数据（100 WGS 和127 WES）和TCGA（84 WG和1008 WES），我们将推断突变签名并进行生活历史分析以了解致命乳腺癌的亚连通结构（第1年）；（2）验证分布体细胞突变特征并确定与突变特征相关的危险因素。我们将执行另外500个肿瘤/正常对的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和在AIM 1中标识的签名，并将其与来自TCGA，ICGC，ICGC，ICGC，包括的数据进行比较并与卡罗来纳州乳腺癌研究（CBC）合作。我们将研究突变特征，种系变异，分子亚型和乳腺癌存活。通过识别因果关系遗传与生活方式/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侨民的数百万妇女产生直接的耻骨健康影响。（3）通过测序多个区域，检查乳腺癌的肿瘤异质性和克隆进化肿瘤。可以通过具有相似癌细胞的变体的聚类来描述克隆结构分数以及它们的地理分布，从而导致了下克隆的分辨率更大建筑学。我们将对36 肿瘤（18 hr-和18 hr+），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，体融合基因和异常的剪接模式并将发现与肿瘤的进化相关，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融合研究界有可能对癌症控制政策产生巨大而持续的影响在所有人群中，以最致命的乳腺癌亚型提供精确的癌症护理。