title: Whole-genome plasma sequencing reveals focal amplifications as a driving force in metastatic prostate cancer.
abstract: 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.
authors.affiliation: Institute of Human Genetics, Medical University of Graz, A-8010 Graz, Austria.
authors.forename: Peter
authors.identifier: 0000-0001-5941-1160
authors.initials: P
authors.lastname: Ulz
authors.affiliation: Institute of Human Genetics, Medical University of Graz, A-8010 Graz, Austria.
authors.forename: Jelena
authors.initials: J
authors.lastname: Belic
authors.affiliation: Institute of Human Genetics, Medical University of Graz, A-8010 Graz, Austria.
authors.forename: Ricarda
authors.initials: R
authors.lastname: Graf
authors.affiliation: Institute of Human Genetics, Medical University of Graz, A-8010 Graz, Austria.
authors.forename: Martina
authors.initials: M
authors.lastname: Auer
authors.affiliation: Institute of Human Genetics, Medical University of Graz, A-8010 Graz, Austria.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Lafer
authors.affiliation: Department of Urology, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Katja
authors.initials: K
authors.lastname: Fischereder
authors.affiliation: Department of Internal Medicine I, Hospital Barmherzige Schwestern Linz, A-4020 Linz, Austria.
authors.forename: Gerald
authors.initials: G
authors.lastname: Webersinke
authors.affiliation: Department of Urology, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Karl
authors.initials: K
authors.lastname: Pummer
authors.affiliation: Department of Urology, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Herbert
authors.initials: H
authors.lastname: Augustin
authors.affiliation: Department of Internal Medicine, Division of Oncology, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Pichler
authors.affiliation: Institute of Pathology, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Gerald
authors.initials: G
authors.lastname: Hoefler
authors.affiliation: Department of Internal Medicine, Division of Oncology, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bauernhofer
authors.affiliation: Institute of Human Genetics, Medical University of Graz, A-8010 Graz, Austria.
authors.forename: Jochen B
authors.initials: JB
authors.lastname: Geigl
authors.affiliation: Institute of Human Genetics, Medical University of Graz, A-8010 Graz, Austria.
authors.forename: Ellen
authors.initials: E
authors.lastname: Heitzer
authors.affiliation: Institute of Human Genetics, Medical University of Graz, A-8010 Graz, Austria.
authors.forename: Michael R
authors.identifier: 0000-0003-0105-955X
authors.initials: MR
authors.lastname: Speicher
mesh_terms: D001706:Biopsy; D002454:Cell Differentiation; D002869:Chromosome Aberrations; D016000:Cluster Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D017353:Gene Deletion; D018628:Gene Dosage; D015894:Genome, Human; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood* / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D004273:DNA, Neoplasm; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D017430:Prostate-Specific Antigen