1. The genomic landscape of metastatic castration-resistant prostate cancers reveals multiple distinct genotypes with potential clinical impact.
- Author
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van Dessel, Lisanne F, van Riet, Job, Smits, Minke, Zhu, Yanyun, Hamberg, Paul, van der Heijden, Michiel S, Bergman, Andries M, van Oort, Inge M, de Wit, Ronald, Voest, Emile E, Steeghs, Neeltje, Yamaguchi, Takafumi N, Livingstone, Julie, Boutros, Paul C, Martens, John WM, Sleijfer, Stefan, Cuppen, Edwin, Zwart, Wilbert, van de Werken, Harmen JG, Mehra, Niven, and Lolkema, Martijn P
- Subjects
Lymph Nodes ,Humans ,Bone Neoplasms ,Liver Neoplasms ,Soft Tissue Neoplasms ,Prostatic Neoplasms ,Neoplasm Metastasis ,Cyclin-Dependent Kinases ,Oncogene Proteins ,Fusion ,BRCA2 Protein ,Receptors ,Androgen ,Genotype ,Male ,Microsatellite Instability ,Enhancer Elements ,Genetic ,DNA Copy Number Variations ,Recombinational DNA Repair ,Prostatic Neoplasms ,Castration-Resistant ,Whole Genome Sequencing ,Chromatin Immunoprecipitation Sequencing ,Oncogene Proteins ,Fusion ,Receptors ,Androgen ,Enhancer Elements ,Genetic ,Castration-Resistant ,Biotechnology ,Genetics ,Cancer ,Prostate Cancer ,Urologic Diseases ,Human Genome - 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.
- Published
- 2019