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

Leena Latonen,Roger W Beuerman,Teuvo T L Tammela,Ulla Aapola,Kati K Kivinummi,Tapio Visakorpi,Matti Annala,Matti Nykter,Janika Nättinen,Hannu Uusitalo,Ebrahim Afyounian,Antti Jylhä

doi:10.1038/s41467-018-03573-6

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.

Highlights

To understand functional consequences of genetic and transcriptional aberrations in prostate cancer, the proteomic changes during disease formation and progression need to be revealed
With sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS), we identified a total of 213,979 peptides, corresponding to 1,753,161 identified spectra in an assembly of 4601 protein groups using false discovery rate of 1%
With over 3000 individual proteins quantified in each of the benign prostatic hyperplasia (BPH), PC and castration resistant prostate cancer (CRPC) samples analyzed, we described the protein level alterations occurring in clinical prostate cancer, and found several previously undescribed biological events with important implications and potential for future studies

Summary

Introduction

To understand functional consequences of genetic and transcriptional aberrations in prostate cancer, the proteomic changes during disease formation and progression need to be revealed. 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). Our proteogenomic analysis uncovers robustness against genomic and transcriptomic aberrations during prostate cancer progression, and significantly extends understanding of prostate cancer disease mechanisms. Recent developments in mass spectrometric methods[11,12,13] have enabled high throughput analysis of clinical patient samples, and the first integrative studies involving large scale, mass spectrometry-based proteomics of human cancer have recently been published[14,15,16]. We provide the first integrative view on human prostate cancer with the proteome of clinical patient samples of benign prostatic hyperplasia (BPH), untreated primary prostate cancer (PC) and locally recurrent CRPC. Global effect of gene dosage on expression mRNA Protein mRNA / PC mRNA / CRPC Protein / PC Protein / CRPC

Methods

Results

Conclusion