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

• Published in: PLoS genetics Vol. 16; no. 2; p. e1008641
• Main Authors: Yuan, Jiao, Kensler, Kevin H., Hu, Zhongyi, Zhang, Youyou, Zhang, Tianli, Jiang, Junjie, Xu, Mu, Pan, Yutian, Long, Meixiao, Montone, Kathleen T., Tanyi, Janos L., Fan, Yi, Zhang, Rugang, Hu, Xiaowen, Rebbeck, Timothy R., Zhang, Lin
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14.02.2020; Public Library of Science (PLoS)
• Subjects: 1-Phosphatidylinositol 3-kinase; Algorithms; Biology and Life Sciences; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Black or African American - genetics; Cancer genetics; Care and treatment; Chromatin Immunoprecipitation Sequencing; Cohort Studies; Comparative analysis; Computer applications; Epidemiology; Ethnicity; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Genetic aspects; Genome, Human - genetics; Genomes; Genomics; Genotyping; Gynecology; Health aspects; Health Status Disparities; Hispanic Americans; Humans; Incidence; Male; Medicine and Health Sciences; Middle Aged; Minority & ethnic groups; Mortality; Mutation; Native Americans; Non-coding RNA; Nuclear Proteins - genetics; Obstetrics; Oncogene Proteins, Fusion - genetics; Oncology; Patients; Prevalence studies (Epidemiology); Prostate cancer; Prostatic Neoplasms - epidemiology; Prostatic Neoplasms - genetics; PTEN Phosphohydrolase - genetics; PTEN protein; Public health; Race; Racial differences; Receptors, Androgen - genetics; Repressor Proteins - genetics; Ribonucleic acid; RNA; RNA, Long Noncoding - metabolism; RNA-Seq; Signal transduction; Socioeconomic factors; Transcriptome - genetics; Transcriptomics; Tumors; White People - genetics; Ohio; United States > US; Massachusetts; Pennsylvania
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1008641

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.