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- Title
The genomic landscape of metastatic castration-resistant prostate cancers reveals multiple distinct genotypes with potential clinical impact.
- Authors
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 W. M.; Sleijfer, Stefan; Cuppen, Edwin; Zwart, Wilbert; van de Werken, Harmen J. G.; Mehra, Niven
- 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. Detecting genomic abnormalities in metastatic castration-resistant prostate cancer (mCRPC) may impact clinical treatment. Here, the authors present whole-genome sequencing of metastatic biopsies from 197 mCRPC patients, highlighting the landscape of microsatellite stability, homologous repair deficiency, and other genomic subgroups.
- Subjects
CASTRATION-resistant prostate cancer; GENOTYPES; NUCLEOTIDE sequencing; CHROMOTHRIPSIS; CANCER invasiveness
- Publication
Nature Communications, 2019, Vol 10, Issue 1, pN.PAG
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-019-13084-7