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

86 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

Funding Information:
We thank the many patients and their families for their generosity in contributing to this study. This work was supported by the Department of Defense (W81XWH-17-1-0358) (to S.R.V.), Prostate Cancer Foundation Young Investigator Award (to S.R.V.), Canadian Institutes of Health Research (MFE-140389) (to G.H.), Norwegian Cancer Society (PR-2007-0166) (to A.M.H.), NIH (K08 CA188615 to E.M.V.; R01CA174777 to S.M.D.; P01CA163227 to P.S.N.; NIH R01 CA215489 to R.B.); NCI (R35 CA197568) (to M.M.); PCF-V Foundation (to E.M.V.), Movember/PCF (to S.M.D.), Gerstner Family Foundation (to V.A.A.), Prostate SPORE (P50CA097186), Fund for Innovation in Cancer Informatics (R.B.), and American Cancer Society Research Professorship (to M.M.). Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research (SU2C-AACR-DT0712). We dedicate this manuscript to the late Martin Meyerson.

Funding Information:
We thank the many patients and their families for their generosity in contributing to this study. This work was supported by the Department of Defense ( W81XWH-17-1-0358 ) (to S.R.V.), Prostate Cancer Foundation Young Investigator Award (to S.R.V.), Canadian Institutes of Health Research ( MFE-140389 ) (to G.H.), Norwegian Cancer Society ( PR-2007-0166 ) (to A.M.H.), NIH ( K08 CA188615 to E.M.V.; R01CA174777 to S.M.D.; P01CA163227 to P.S.N.; NIH R01 CA215489 to R.B.); NCI ( R35 CA197568 ) (to M.M.); PCF-V Foundation (to E.M.V.), Movember/PCF (to S.M.D.), Gerstner Family Foundation (to V.A.A.), Prostate SPORE ( P50CA097186 ), Fund for Innovation in Cancer Informatics (R.B.), and American Cancer Society Research Professorship (to M.M.). Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research ( SU2C-AACR-DT0712 ). We dedicate this manuscript to the late Martin Meyerson.

Funding Information:
G.H., S.S.F., and V.A.A.: patent application WO2017161175A1. C.-Z.Z.: co-founder, advisor, and share-holder, Pillar Biosciences. E.M.V.: consultant, Tango Therapeutics, Genome Medical, Invitae; research funding, Bristol-Meyers Squibb and Novartis. A.D.C.: research funding from Bayer. G.G.: research funding from Bayer and IBM. M.M.: scientific advisory board chair and equity holder, OrigiMed; research funding, Bayer; inventor of a patent for EGFR mutation diagnosis in lung cancer, licensed to LabCorp.

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

Fingerprint

Dive into the research topics of 'Structural Alterations Driving Castration-Resistant Prostate Cancer Revealed by Linked-Read Genome Sequencing'. Together they form a unique fingerprint.

Cite this