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

Author

Listed:
  • Lisanne F. Dessel

    (Erasmus University Medical Center Rotterdam)

  • Job Riet

    (Erasmus University Medical Center Rotterdam
    Erasmus University Medical Center Rotterdam
    Erasmus University Medical Center Rotterdam)

  • Minke Smits

    (Radboud University Nijmegen Medical Center)

  • Yanyun Zhu

    (The Netherlands Cancer Institute
    Oncode Institute)

  • Paul Hamberg

    (Franciscus Gasthuis & Vlietland)

  • Michiel S. Heijden

    (Center for Personalized Cancer Treatment
    The Netherlands Cancer Institute
    The Netherlands Cancer Institute)

  • Andries M. Bergman

    (The Netherlands Cancer Institute
    The Netherlands Cancer Institute)

  • Inge M. Oort

    (Radboud University Nijmegen Medical Center)

  • Ronald Wit

    (Erasmus University Medical Center Rotterdam)

  • Emile E. Voest

    (Oncode Institute
    Center for Personalized Cancer Treatment
    The Netherlands Cancer Institute)

  • Neeltje Steeghs

    (Center for Personalized Cancer Treatment
    The Netherlands Cancer Institute)

  • Takafumi N. Yamaguchi

    (Ontario Institute for Cancer Research)

  • Julie Livingstone

    (Ontario Institute for Cancer Research)

  • Paul C. Boutros

    (Ontario Institute for Cancer Research
    University of Toronto
    University of Toronto
    University of California Los Angeles)

  • John W. M. Martens

    (Erasmus University Medical Center Rotterdam
    Center for Personalized Cancer Treatment)

  • Stefan Sleijfer

    (Erasmus University Medical Center Rotterdam
    Center for Personalized Cancer Treatment)

  • Edwin Cuppen

    (University Medical Center Utrecht
    Hartwig Medical Foundation)

  • Wilbert Zwart

    (The Netherlands Cancer Institute
    Oncode Institute
    Eindhoven University of Technology)

  • Harmen J. G. Werken

    (Erasmus University Medical Center Rotterdam
    Erasmus University Medical Center Rotterdam)

  • Niven Mehra

    (Radboud University Nijmegen Medical Center)

  • Martijn P. Lolkema

    (Erasmus University Medical Center Rotterdam
    Center for Personalized Cancer Treatment)

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.

Suggested Citation

  • 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 , 2019. "The genomic landscape of metastatic castration-resistant prostate cancers reveals multiple distinct genotypes with potential clinical impact," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13084-7
    DOI: 10.1038/s41467-019-13084-7
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    Cited by:

    1. M. G. Filippone & D. Gaglio & R. Bonfanti & F. A. Tucci & E. Ceccacci & R. Pennisi & M. Bonanomi & G. Jodice & M. Tillhon & F. Montani & G. Bertalot & S. Freddi & M. Vecchi & A. Taglialatela & M. Roma, 2022. "CDK12 promotes tumorigenesis but induces vulnerability to therapies inhibiting folate one-carbon metabolism in breast cancer," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    2. Zhe Jiang & YoungJun Ju & Amjad Ali & Philip E. D. Chung & Patryk Skowron & Dong-Yu Wang & Mariusz Shrestha & Huiqin Li & Jeff C. Liu & Ioulia Vorobieva & Ronak Ghanbari-Azarnier & Ethel Mwewa & Maria, 2023. "Distinct shared and compartment-enriched oncogenic networks drive primary versus metastatic breast cancer," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    3. Michael Fraser & Julie Livingstone & Jeffrey L. Wrana & Antonio Finelli & Housheng Hansen He & Theodorus van der Kwast & Alexandre R. Zlotta & Robert G. Bristow & Paul C. Boutros, 2021. "Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    4. Maud Rijnders & J. Alberto Nakauma-González & Debbie G. J. Robbrecht & Alberto Gil-Jimenez & Hayri E. Balcioglu & Astrid A. M. Oostvogels & Maureen J. B. Aarts & Joost L. Boormans & Paul Hamberg & Mic, 2024. "Gene-expression-based T-Cell-to-Stroma Enrichment (TSE) score predicts response to immune checkpoint inhibitors in urothelial cancer," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    5. Anouk C. Jong & Alexandra Danyi & Job Riet & Ronald Wit & Martin Sjöström & Felix Feng & Jeroen Ridder & Martijn P. Lolkema, 2023. "Predicting response to enzalutamide and abiraterone in metastatic prostate cancer using whole-omics machine learning," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    6. Antonio Rodriguez-Calero & John Gallon & Dilara Akhoundova & Sina Maletti & Alison Ferguson & Joanna Cyrta & Ursula Amstutz & Andrea Garofoli & Viola Paradiso & Scott A. Tomlins & Ekkehard Hewer & Ver, 2022. "Alterations in homologous recombination repair genes in prostate cancer brain metastases," Nature Communications, Nature, vol. 13(1), pages 1-10, December.

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