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

Lisanne F. van Dessel, Job van Riet, Minke Smits, Yanyun Zhu, Paul Hamberg, Michiel S. van der Heijden, Andries M. Bergman, Inge M. van Oort, Ronald de 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. van de Werken, Niven MehraMartijn P. Lolkema

Research output: Contribution to journalArticleAcademicpeer-review

27 Citations (Scopus)

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.

Original languageEnglish
Article number5251
Number of pages13
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 1 Dec 2019

Keywords

  • BRCA2 Protein/genetics
  • Bone Neoplasms/genetics
  • Chromatin Immunoprecipitation Sequencing
  • Cyclin-Dependent Kinases/genetics
  • DNA Copy Number Variations
  • Enhancer Elements, Genetic/genetics
  • Genotype
  • Humans
  • Liver Neoplasms/genetics
  • Lymph Nodes
  • Male
  • Microsatellite Instability
  • Neoplasm Metastasis
  • Oncogene Proteins, Fusion/genetics
  • Prostatic Neoplasms/genetics
  • Prostatic Neoplasms, Castration-Resistant/classification
  • Receptors, Androgen/genetics
  • Recombinational DNA Repair/genetics
  • Soft Tissue Neoplasms/genetics
  • Whole Genome Sequencing

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