The genomic landscape of metastatic castration-resistant prostate cancers reveals multiple distinct genotypes with potential clinical impact

Lisanne F. Dessel, Job Riet, Minke Smits, Yanyun Zhu, Paul Hamberg, Michiel S. Heijden, Andries M. Bergman, Inge M. Oort, Ronald Wit, Emile E. Voest, Neeltje Steeghs, Takafumi N. Yamaguchi, Julie Livingstone, Paul C. Boutros, John W. M. Martens, Stefan Sleijfer, Edwin Cuppen, Wilbert Zwart, Harmen J. G. Werken, Niven Mehra and Martijn P. Lolkema ()
Additional contact information
Lisanne F. Dessel: Erasmus University Medical Center Rotterdam
Job Riet: Erasmus University Medical Center Rotterdam
Minke Smits: Radboud University Nijmegen Medical Center
Yanyun Zhu: The Netherlands Cancer Institute
Paul Hamberg: Franciscus Gasthuis & Vlietland
Michiel S. Heijden: Center for Personalized Cancer Treatment
Andries M. Bergman: The Netherlands Cancer Institute
Inge M. Oort: Radboud University Nijmegen Medical Center
Ronald Wit: Erasmus University Medical Center Rotterdam
Emile E. Voest: Oncode Institute
Neeltje Steeghs: Center for Personalized Cancer Treatment
Takafumi N. Yamaguchi: Ontario Institute for Cancer Research
Julie Livingstone: Ontario Institute for Cancer Research
Paul C. Boutros: Ontario Institute for Cancer Research
John W. M. Martens: Erasmus University Medical Center Rotterdam
Stefan Sleijfer: Erasmus University Medical Center Rotterdam
Edwin Cuppen: University Medical Center Utrecht
Wilbert Zwart: The Netherlands Cancer Institute
Harmen J. G. Werken: Erasmus University Medical Center Rotterdam
Niven Mehra: Radboud University Nijmegen Medical Center
Martijn P. Lolkema: Erasmus University Medical Center Rotterdam

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13084-7

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