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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). 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.

SUBMITTER: Yuan J

PROVIDER: S-EPMC7046294 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Yuan Jiao J Kensler Kevin H KH Hu Zhongyi Z Zhang Youyou Y Zhang Tianli T Jiang Junjie J Xu Mu M Pan Yutian Y Long Meixiao M Montone Kathleen T KT Tanyi Janos L JL Fan Yi Y Zhang Rugang R Hu Xiaowen X Rebbeck Timothy R TR Zhang Lin L

PLoS genetics 20200214 2

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 = 49 ...[more]

PMID: 32059012

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Project description:While recent integrative analyses of copy number and gene expression data in breast cancer have revealed a complex molecular landscape with multiple subtypes and many oncogenic/tumour suppressor driver events, much less is known about the role of DNA methylation in shaping breast cancer taxonomy and defining driver events.Here, we applied a powerful integrative network algorithm to matched DNA methylation and RNA-Seq data for 724 estrogen receptor (ER)-positive (ER+) breast cancers and 111 normal adjacent tissue specimens from The Cancer Genome Atlas (TCGA) project, in order to identify putative epigenetic driver events and to explore the resulting molecular taxonomy. This revealed the existence of nine functionally deregulated epigenetic hotspots encompassing a total of 146 genes, which we were able to validate in independent data sets encompassing over 1000 ER+ breast cancers. Integrative clustering of the matched messenger RNA (mRNA) and DNA methylation data over these genes resulted in only two clusters, which correlated very strongly with the luminal-A and luminal B subtypes. Overall, luminal-A and luminal-B breast cancers shared the same epigenetically deregulated hotspots but with luminal-B cancers exhibiting increased aberrant DNA methylation patterns relative to normal tissue. We show that increased levels of DNA methylation and mRNA expression deviation from the normal state define a marker of poor prognosis. Our data further implicates epigenetic silencing of WNT signalling antagonists and bone morphogenetic proteins (BMP) as key events underlying both luminal subtypes but specially of luminal-B breast cancer. Finally, we show that DNA methylation changes within the identified epigenetic interactome hotspots do not exhibit mutually exclusive patterns within the same cancer sample, instead exhibiting coordinated changes within the sample.Our results indicate that the integrative DNA methylation and transcriptomic landscape of ER+ breast cancer is surprisingly homogeneous, defining two main subtypes which strongly correlate with luminal-A/B subtype status. In particular, we identify WNT and BMP signalling as key epigenetically deregulated tumour suppressor pathways in luminal ER+ breast cancer, with increased deregulation seen in luminal-B breast cancer.

Dataset Information

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

Publications

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

Similar Datasets

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