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

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

GSTP1 positive prostatic adenocarcinomas are more common in Black than White men in the United States

“…To determine whether there is a different etiology for prostate cancers developing in Black versus Whte patients, it may be instructive to look at gene expression studies. Interestingly, when probing for differences in gene expression in prostate cancers from Black men and White men, a number of studies (21,(51)(52)(53) , albeit not all (54) , have reported increases in inflammatory cytokine signaling in tumors from men of African descent. While inflammatory signaling and altered inflammatory cell infiltrates in the tumor microenvironment may occur during any and all temporal phases of cancer development and progression, we have previously postulated that chronic long standing inflammation may lead to prostate cancer most likely via lesions we termed proliferative inflammatory atrophy (42,55,56) .…”

“…In addition, there appear to be at least some biological differences in disease pathogenesis and malignant progression, potentially based on associations of perceived race with genetic variation, or, as a result of different carcinogenic exposures. For example, when compared to prostate cancers from predominantly White men, prostate cancers from Black men contain fewer TMPRSS2-ERG fusions (19)(20)(21)(22) , fewer PTEN deletions (20)(21)(22)(23) , and more SPOP mutations (21,22) .…”

The Genetic Complexity of Prostate Cancer

“…PTEN loss is associated with adverse findings in early PCa and occurs in approximatively 15% as homozygous deletions. PTEN loss or mRNA-based genomic signatures can be useful to help determine whether definitive therapy is required, and its loss seems to be more frequent in patients with African ancestry [45]. Early investigations already showed that loss of PTEN, even when detected by immunohistochemistry, was a predictor of aggressive metastatic disease.…”

Identification of Candidate Genes Associated with Susceptibility to Ovarian Clear Cell Adenocarcinoma Using cis-eQTL Analysis

“…While socioeconomic factors have significant relevance in these disparities, ethnic difference in Ov-CCA prevalence suggests the presence of Ov-CCA-specific genetic alterations associated with ancestry. In this regard, recent advances in breast and prostate cancer research have demonstrated that genetic factors related to ancestry may be associate with tumorigenesis [17,18].…”

“…In this study, we conducted cis-eQTL analyses to identify candidate susceptibility loci using 94 previously reported genetic mutations in Ov-CCA as the phenotypic trait [19]. Given that disease-specific ancestral disparities can be used as the phenotypic trait in eQTL analysis [17,18], we hypothesized that specific susceptibility loci and its associated genes can be identified in Ov-CCA by Japanese ancestry. Lastly, to validate potential functional role of the identified novel susceptibility loci and associated genes in Ov-CCA, we performed expression and survival analysis of the identified genes in both our gene expression datasets and TCGA (The Cancer Genome Atlas) datasets.…”