Structural Alterations Driving Castration-Resistant Prostate Cancer Revealed by Linked-Read Genome Sequencing

PCF/SU2C International Prostate Cancer Dream Team

Research output: Contribution to journalArticlepeer-review

233 Scopus citations

Abstract

Nearly all prostate cancer deaths are from metastatic castration-resistant prostate cancer (mCRPC), but there have been few whole-genome sequencing (WGS) studies of this disease state. We performed linked-read WGS on 23 mCRPC biopsy specimens and analyzed cell-free DNA sequencing data from 86 patients with mCRPC. In addition to frequent rearrangements affecting known prostate cancer genes, we observed complex rearrangements of the AR locus in most cases. Unexpectedly, these rearrangements include highly recurrent tandem duplications involving an upstream enhancer of AR in 70%–87% of cases compared with <2% of primary prostate cancers. A subset of cases displayed AR or MYC enhancer duplication in the context of a genome-wide tandem duplicator phenotype associated with CDK12 inactivation. Our findings highlight the complex genomic structure of mCRPC, nominate alterations that may inform prostate cancer treatment, and suggest that additional recurrent events in the non-coding mCRPC genome remain to be discovered. Linked-read genome sequencing data from patients highlight that amplification of an enhancer upstream of the androgen receptor locus is a key feature of metastatic castration-resistant prostate cancer.

Original languageEnglish (US)
Pages (from-to)433-447.e19
JournalCell
Volume174
Issue number2
DOIs
StatePublished - Jul 12 2018

Bibliographical note

Publisher Copyright:
© 2018 Elsevier Inc.

Keywords

  • CDK12
  • MYC
  • androgen receptor
  • castration-resistant prostate cancer
  • cell-free DNA
  • enhancer
  • linked read whole-genome sequencing
  • non-coding cancer genome
  • structural variants
  • tandem duplicator phenotype

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