Integrative comparison of the genomic and transcriptomic landscape between prostate cancer patients of predominantly African or European genetic ancestry

PLoS Genet. 2020 Feb 14;16(2):e1008641. doi: 10.1371/journal.pgen.1008641. eCollection 2020 Feb.

Abstract

Men of predominantly African Ancestry (AA) have higher prostate cancer (CaP) incidence and worse survival than men of predominantly European Ancestry (EA). While socioeconomic factors drive this disparity, genomic factors may also contribute to differences in the incidence and mortality rates. To compare the prevalence of prostate tumor genomic alterations and transcriptomic profiles by patient genetic ancestry, we evaluated genomic profiles from The Cancer Genome Atlas (TCGA) CaP cohort (n = 498). Patient global and local genetic ancestry were estimated by computational algorithms using genotyping data; 414 (83.1%) were EA, 61 (12.2%) were AA, 11 (2.2%) were East Asian Ancestry (EAA), 10 (2.0%) were Native American (NA), and 2 (0.4%) were other ancestry. Genetic ancestry was highly concordant with self-identified race/ethnicity. Subsequent analyses were limited to 61 AA and 414 EA cases. Significant differences were observed by ancestry in the frequency of SPOP mutations (20.3% AA vs. 10.0% EA; p = 5.6×10-03), TMPRSS2-ERG fusions (29.3% AA vs. 39.6% EA; p = 4.4×10-02), and PTEN deletions/losses (11.5% AA vs. 30.2% EA; p = 3.5×10-03). Differentially expressed genes (DEGs) between AAs and EAs showed significant enrichment for prostate eQTL target genes (p = 8.09×10-48). Enrichment of highly expressed DEGs for immune-related pathways was observed in AAs, and for PTEN/PI3K signaling in EAs. Nearly one-third of DEGs (31.3%) were long non-coding RNAs (DE-lncRNAs). The proportion of DE-lncRNAs with higher expression in AAs greatly exceeded that with lower expression in AAs (p = 1.2×10-125). Both ChIP-seq and RNA-seq data suggested a stronger regulatory role for AR signaling pathways in DE-lncRNAs vs. non-DE-lncRNAs. CaP-related oncogenic lncRNAs, such as PVT1, PCAT1 and PCAT10/CTBP1-AS, were found to be more highly expressed in AAs. We report substantial heterogeneity in the prostate tumor genome and transcriptome between EA and AA. These differences may be biological contributors to racial disparities in CaP incidence and outcomes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • African Americans / genetics*
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism
  • Chromatin Immunoprecipitation Sequencing
  • Cohort Studies
  • European Continental Ancestry Group / genetics*
  • Gene Expression Regulation, Neoplastic
  • Genome, Human / genetics
  • Health Status Disparities*
  • Humans
  • Incidence
  • Male
  • Middle Aged
  • Mutation
  • Nuclear Proteins / genetics
  • Oncogene Proteins, Fusion / genetics
  • PTEN Phosphohydrolase / genetics
  • Prostatic Neoplasms / epidemiology
  • Prostatic Neoplasms / genetics*
  • RNA, Long Noncoding / metabolism
  • RNA-Seq
  • Receptors, Androgen / genetics
  • Repressor Proteins / genetics
  • Transcriptome / genetics

Substances

  • AR protein, human
  • Biomarkers, Tumor
  • Nuclear Proteins
  • Oncogene Proteins, Fusion
  • RNA, Long Noncoding
  • Receptors, Androgen
  • Repressor Proteins
  • SPOP protein, human
  • TMPRSS2-ERG fusion protein, human
  • PTEN Phosphohydrolase
  • PTEN protein, human