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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：
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
项目类别：
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

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.

摘要