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Integrative proteomics in prostate cancer uncovers robustness against genomic and transcriptomic aberrations during disease progression.

ABSTRACT: To understand functional consequences of genetic and transcriptional aberrations in prostate cancer, the proteomic changes during disease formation and progression need to be revealed. Here we report high-throughput mass spectrometry on clinical tissue samples of benign prostatic hyperplasia (BPH), untreated primary prostate cancer (PC) and castration resistant prostate cancer (CRPC). Each sample group shows a distinct protein profile. By integrative analysis we show that, especially in CRPC, gene copy number, DNA methylation, and RNA expression levels do not reliably predict proteomic changes. Instead, we uncover previously unrecognized molecular and pathway events, for example, several miRNA target correlations present at protein but not at mRNA level. Notably, we identify two metabolic shifts in the citric acid cycle (TCA cycle) during prostate cancer development and progression. Our proteogenomic analysis uncovers robustness against genomic and transcriptomic aberrations during prostate cancer progression, and significantly extends understanding of prostate cancer disease mechanisms.

SUBMITTER: Latonen L

PROVIDER: S-EPMC5862881 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Integrative proteomics in prostate cancer uncovers robustness against genomic and transcriptomic aberrations during disease progression.

Latonen Leena L Afyounian Ebrahim E Jylhä Antti A Nättinen Janika J Aapola Ulla U Annala Matti M Kivinummi Kati K KK Tammela Teuvo T L TTL Beuerman Roger W RW Uusitalo Hannu H Nykter Matti M Visakorpi Tapio T

Nature communications 20180321 1

To understand functional consequences of genetic and transcriptional aberrations in prostate cancer, the proteomic changes during disease formation and progression need to be revealed. Here we report high-throughput mass spectrometry on clinical tissue samples of benign prostatic hyperplasia (BPH), untreated primary prostate cancer (PC) and castration resistant prostate cancer (CRPC). Each sample group shows a distinct protein profile. By integrative analysis we show that, especially in CRPC, ge ...[more]

PMID: 29563510

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Project description: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.

Project description:Prostate cancer prevalence in African Americans (AA) is over 1.5 times the prevalence in European Americans (EA). Among over a hundred index risk SNPs for prostate cancer, only a few can be verified using the available AAs' data. Their relevance to the prevalence inequality and other racial disparities has not been fully determined. We investigated this issue by an integrative analysis of five public datasets. We categorized the datasets into two classes. The training class consisted of the datasets generated by three genome-wide association studies. The test class contained the prostate adenocarcinoma data of The Cancer Genome Atlas and the data of African and European super-populations in the 1000-Genome project. The polygenic risk scores (PRS) of test samples for cancer occurrence were calculated according to the effects of genetic variants estimated from the training samples. We obtained the following findings. Africans' PRSs are higher than Europeans' scores (P < 1 × 10-6). AA patients' PRSs are higher than EA patients' scores (P < 3×10-9). The patients with tumors presenting fusion or abnormal expression in ERG and other E26 transformation-specific (ETS) family genes have lower PRSs than the patients without such aberrations (P < 7×10-5). Five tumor progression-related genes have the expression levels being significantly correlated with PRS (FDR < 0.01). Additional simulation analysis shows that the high prostate cancer prevalence in African populations makes it challenging to identify individual risk variants using African men's data. These results implicate that the index risk SNP-based PRS is compatible with the observed racial disparity in prostate cancer prevalence and ETS abnormal cancers may be less heritable compared with other subtypes.Prevention relevanceThis study reveals the relevance of index risk SNP markers with racial disparities in prostate cancer. The findings also indicate that PRS can be used in prostate cancer subtype prediction.

Dataset Information

Integrative proteomics in prostate cancer uncovers robustness against genomic and transcriptomic aberrations during disease progression.

Publications

Integrative proteomics in prostate cancer uncovers robustness against genomic and transcriptomic aberrations during disease progression.

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