Abstract

Metastatic castration-resistant prostate cancer (mCRPC) has a highly complex genomic landscape. With the recent development of novel treatments, accurate stratification strategies are needed. Here we present the whole-genome sequencing (WGS) analysis of fresh-frozen metastatic biopsies from 197 mCRPC patients. Using unsupervised clustering based on genomic features, we define eight distinct genomic clusters. We observe potentially clinically relevant genotypes, including microsatellite instability (MSI), homologous recombination deficiency (HRD) enriched with genomic deletions and BRCA2 aberrations, a tandem duplication genotype associated with CDK12−/− and a chromothripsis-enriched subgroup. Our data suggests that stratification on WGS characteristics may improve identification of MSI, CDK12−/− and HRD patients. From WGS and ChIP-seq data, we show the potential relevance of recurrent alterations in non-coding regions identified with WGS and highlight the central role of AR signaling in tumor progression. These data underline the potential value of using WGS to accurately stratify mCRPC patients into clinically actionable subgroups.

Details

Title
The genomic landscape of metastatic castration-resistant prostate cancers reveals multiple distinct genotypes with potential clinical impact
Author
van Dessel, Lisanne F 1 ; Job van Riet 2 ; Smits, Minke 3 ; Zhu, Yanyun 4 ; Hamberg, Paul 5 ; Michiel S van der Heijden 6 ; Bergman, Andries M 7 ; van Oort, Inge M 8 ; de Wit, Ronald 1 ; Voest, Emile E 9 ; Steeghs, Neeltje 10 ; Yamaguchi, Takafumi N 11 ; Livingstone, Julie 11   VIAFID ORCID Logo  ; Boutros, Paul C 12   VIAFID ORCID Logo  ; Martens, John W M 13   VIAFID ORCID Logo  ; Sleijfer, Stefan 13 ; Cuppen, Edwin 14 ; Zwart, Wilbert 15 ; Harmen J G van de Werken 16   VIAFID ORCID Logo  ; Mehra, Niven 3   VIAFID ORCID Logo  ; Lolkema, Martijn P 13   VIAFID ORCID Logo 

1  Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands 
2  Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands; Cancer Computational Biology Center, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Urology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands 
3  Department of Medical Oncology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands 
4  Division on Oncogenomics, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Oncode Institute, Utrecht, The Netherlands 
5  Department of Internal Medicine, Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands 
6  Center for Personalized Cancer Treatment, Rotterdam, The Netherlands; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands 
7  Division on Oncogenomics, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands 
8  Department of Urology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands 
9  Oncode Institute, Utrecht, The Netherlands; Center for Personalized Cancer Treatment, Rotterdam, The Netherlands; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands 
10  Center for Personalized Cancer Treatment, Rotterdam, The Netherlands; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands 
11  Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada 
12  Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada; Department of Human Genetics, University of California Los Angeles, Los Angeles, USA; Department of Urology, University of California Los Angeles, Los Angeles, USA; Jonsson Comprehensive Cancer Centre, University of California Los Angeles, Los Angeles, USA 
13  Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands; Center for Personalized Cancer Treatment, Rotterdam, The Netherlands 
14  Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands; Hartwig Medical Foundation, Amsterdam, The Netherlands 
15  Division on Oncogenomics, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Oncode Institute, Utrecht, The Netherlands; Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands 
16  Cancer Computational Biology Center, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Urology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands 
Pages
1-13
Publication year
2019
Publication date
Nov 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-019-13084-7
ProQuest document ID
2316418102
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.