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Cancer Cell. 2018 Dec 10;34(6):996-1011.e8. doi: 10.1016/j.ccell.2018.10.016.

Molecular Evolution of Early-Onset Prostate Cancer Identifies Molecular Risk Markers and Clinical Trajectories.

Author information

1
Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
2
Finsen Laboratory, Rigshospitalet, DK-2200, Copenhagen, Denmark; Biotech Research & Innovation Centre (BRIC), University of Copenhagen, DK-2200, Copenhagen, Denmark.
3
Max Planck Institute for Molecular Genetics, Otto Warburg Laboratory Gene Regulation and Systems Biology of Cancer, Ihnestrasse 63-73, 14195 Berlin, Germany.
4
Department of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
5
Division Applied Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
6
Division of Cancer Genome Research, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
7
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69120 Heidelberg, Germany.
8
Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Department for Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology and Bioquant, University of Heidelberg, Heidelberg 69120, Germany; Department of Pediatric Immunology, Hematology and Oncology, University Hospital, Heidelberg 69120, Germany.
9
Centre for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, Forskningsparken, University of Oslo, 0316 Oslo, Norway; Institute for Cancer Genetics and Informatics, Oslo University Hospital, 0316 Oslo, Norway; Department of Core Facilities, Institute for Cancer Research, Oslo University Hospital, 0316 Oslo, Norway.
10
Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, Durham, 27709 NC, USA.
11
Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, Durham, 27709 NC, USA.
12
Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany.
13
PROGETHER Prostate Cancer Network, 0316 Oslo, Norway.
14
Martini-Clinic Prostate Cancer Center at the University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany.
15
Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
16
Department of Urology, UT Southwestern Medical Center, Dallas, TX 75390-9110, USA.
17
Informatics & Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
18
Division of Cancer Genome Research, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; NCT Trial Center, National Center for Tumor Diseases and German Cancer Research Center, 69120 Heidelberg, Germany.
19
Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Department for Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology and Bioquant, University of Heidelberg, Heidelberg 69120, Germany.
20
Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Bioinformatics and Omics Data Analytics (B240), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
21
Manchester Cancer Research Centre, University of Manchester, 555 Wilmslow Road, Manchester, UK.
22
Ontario Institute for Cancer Research, Toronto, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Canada.
23
German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; Division of Translational Oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
24
Division Applied Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
25
Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
26
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69120 Heidelberg, Germany. Electronic address: korbel@embl.de.
27
Martini-Clinic Prostate Cancer Center at the University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany; Charité Universitätsmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Germany. Electronic address: thorsten.schlomm@charite.de.
28
Finsen Laboratory, Rigshospitalet, DK-2200, Copenhagen, Denmark; Biotech Research & Innovation Centre (BRIC), University of Copenhagen, DK-2200, Copenhagen, Denmark; European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69120 Heidelberg, Germany; Charité Universitätsmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Germany. Electronic address: joachim.weischenfeldt@bric.ku.dk.

Abstract

Identifying the earliest somatic changes in prostate cancer can give important insights into tumor evolution and aids in stratifying high- from low-risk disease. We integrated whole genome, transcriptome and methylome analysis of early-onset prostate cancers (diagnosis ≤55 years). Characterization across 292 prostate cancer genomes revealed age-related genomic alterations and a clock-like enzymatic-driven mutational process contributing to the earliest mutations in prostate cancer patients. Our integrative analysis identified four molecular subgroups, including a particularly aggressive subgroup with recurrent duplications associated with increased expression of ESRP1, which we validate in 12,000 tissue microarray tumors. Finally, we combined the patterns of molecular co-occurrence and risk-based subgroup information to deconvolve the molecular and clinical trajectories of prostate cancer from single patient samples.

KEYWORDS:

APOBEC; cancer genomics; early-onset cancer; epigenetic risk-score; mutational processes; prostate cancer; structural variants; tumor evolution; tumor evolution prediction

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