Whole-genome plasma sequencing reveals focal amplifications as a driving force in metastatic prostate cancer.

Genomic alterations in metastatic prostate cancer remain incompletely characterized. Here we analyse 493 prostate cancer cases from the TCGA database and perform whole-genome plasma sequencing on 95 plasma samples derived from 43 patients with metastatic prostate cancer. From these samples, we identify established driver aberrations in a cancer-related gene in nearly all cases (97.7%), including driver gene fusions (TMPRSS2:ERG), driver focal deletions (PTEN, RYBP and SHQ1) and driver amplifications (AR and MYC). In serial plasma analyses, we observe changes in focal amplifications in 40% of cases. The mean time interval between new amplifications was 26.4 weeks (range: 5-52 weeks), suggesting that they represent rapid adaptations to selection pressure. An increase in neuron-specific enolase is accompanied by clonal pattern changes in the tumour genome, most consistent with subclonal diversification of the tumour. Our findings suggest a high plasticity of prostate cancer genomes with newly occurring focal amplifications as a driving force in progression.

Nature communications. 2016 Jun 22*** epublish ***

Peter Ulz, Jelena Belic, Ricarda Graf, Martina Auer, Ingrid Lafer, Katja Fischereder, Gerald Webersinke, Karl Pummer, Herbert Augustin, Martin Pichler, Gerald Hoefler, Thomas Bauernhofer, Jochen B Geigl, Ellen Heitzer, Michael R Speicher

Institute of Human Genetics, Medical University of Graz, A-8010 Graz, Austria., Institute of Human Genetics, Medical University of Graz, A-8010 Graz, Austria., Institute of Human Genetics, Medical University of Graz, A-8010 Graz, Austria., Institute of Human Genetics, Medical University of Graz, A-8010 Graz, Austria., Institute of Human Genetics, Medical University of Graz, A-8010 Graz, Austria., Department of Urology, Medical University of Graz, A-8036 Graz, Austria., Department of Internal Medicine I, Hospital Barmherzige Schwestern Linz, A-4020 Linz, Austria., Department of Urology, Medical University of Graz, A-8036 Graz, Austria., Department of Urology, Medical University of Graz, A-8036 Graz, Austria., Department of Internal Medicine, Division of Oncology, Medical University of Graz, A-8036 Graz, Austria., Institute of Pathology, Medical University of Graz, A-8036 Graz, Austria., Department of Internal Medicine, Division of Oncology, Medical University of Graz, A-8036 Graz, Austria., Institute of Human Genetics, Medical University of Graz, A-8010 Graz, Austria., Institute of Human Genetics, Medical University of Graz, A-8010 Graz, Austria., Institute of Human Genetics, Medical University of Graz, A-8010 Graz, Austria.