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African Ancestry Associated Gene Expression Profiles in Triple Negative Breast Cancer Underlie Altered Tumor Biology and Clinical Outcome in Women of African Descent

ABSTRACT: Women of sub-Saharan African descent have disproportionately higher incidence of Triple Negative Breast Cancer (TNBC), and TNBC-specific mortality. Population comparative studies show racial differences in TNBC biology, including higher prevalence of basal-like and Quadruple-Negative subtypes in African Americans (AA). However, previous investigations relied on self-reported race (SRR) of primarily United States (US) populations. Due to heterogenous genetic admixture, and biological consequences of social determinants, the true association of African ancestry with TNBC biology is unclear. To address this, we conducted RNAseq on an international cohort of AAs, west and east Africans with TNBC. Using comprehensive genetic ancestry estimation in this African-enriched cohort, we found expression of 613 genes associated with African ancestry and 2000+ associated with regional African ancestry. A subset of African-associated genes also showed differences in normal breast tissue. Pathway enrichment and deconvolution of tumor cellular composition revealed tumor-associated immunological profiles are distinct in patients of African descent.

ORGANISM(S): Homo sapiens

PROVIDER: GSE211167 | GEO | 2022/11/09

REPOSITORIES: GEO

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Peptide Ancestry Informative Markers in Uterine Neoplasms from Women of European, African and Asian Ancestry

Project description:Characterization of ancestry-linked peptide variants in disease-relevant patient tissues represents a foundational step to connect patient ancestry with molecular disease pathogenesis. Nonsynonymous single nucleotide polymorphisms (SNPs) encoding missense substitutions within tryptic peptides exhibiting high allele frequencies in European, African, and East Asian populations, termed peptide ancestry informative markers (pAIMs), were prioritized from 1000 genomes. In silico analysis shows that as few as 20 pAIMs can determine ancestry proportions similarly to >260K SNPs (R2=0.9905). Multiplexed proteomic analysis of >100 human endometrial cancer cell lines and uterine leiomyoma (ULM) tissues combined resulted in the quantitation of 62 pAIMs that correlate with self-described race and genotype-confirmed patient ancestry. Candidates include a D451E substitution in GC vitamin D-binding protein previously associated with altered vitamin D levels in African and European populations. These efforts describe a generalized set of markers for proteoancestry assessment that will further support studies investigating the impact of ancestry on the human proteome and how this relates to the pathogenesis of uterine neoplasms.

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Uncovering the role admixture in health disparities: Association of hepatocyte gene expression and DNA methylation to African Ancestry in African-Americans [Methylation]

Project description:In African Americans (AA), the proportion of West African ancestry (WAA) may explain the genetic drivers of health disparities in disease. Analysis of RNA sequencing data from sixty AA-derived primary hepatocytes identified 32 gene expression profiles associated with WAA (FDR <0.05) with enrichment in angiogenesis and inflammatory pathways (FDR <0.1). Association of DNA methylation to WAA identified 1037 differentially methylated regions (FDR <0.05), with hypomethylated genes enriched for drug response pathways. Within the PharmGKB pharmacogene, VDR, PTGIS, ALDH1A1, CYP2C19 and P2RY1 were associated with WAA (p <0.05) with replication of CYP2C19 and VDR in the GTEx liver cohort. For every 1% increment in WAA, P2RY1 gene expression increased by 1.6% and CYP2C19 gene expression decreased by 1.4%, suggesting effects on clopidogrel response and platelet aggregation. We conclude that WAA contributes to variablity in hepatic gene expression and DNA methylation with identified genes indicative of health disparities prevalent in AAs.

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Uncovering the role admixture in health disparities: Association of hepatocyte gene expression and DNA methylation to African Ancestry in African-Americans [RNA-seq]

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Project description:Study of genes that are differentially spliced and differentially expressed between African Americans and whites with lung squamous cell cancer. Despite racial disparities in lung cancer, the molecular landscape of lung cancer in patients of African ancestry remains underexplored. Population-related differences in alternative RNA splicing have not been explored. We identified differentially spliced genes and differentially expressed genes between lung squamous cell carcinoma from patients of West African and European ancestry.

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