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

Srinivas R Viswanathan; Gavin Ha; Andreas M Hoff; Jeremiah A Wala; Jian Carrot-Zhang; Christopher W Whelan; Nicholas J Haradhvala; Samuel S Freeman; Sarah C Reed; Justin Rhoades; Paz Polak; Michelle Cipicchio; Stephanie A Wankowicz; Alicia Wong; Tushar Kamath; Zhenwei Zhang; Gregory J Gydush; Denisse Rotem; PCF/SU2C International Prostate Cancer Dream Team; J Christopher Love; Gad Getz; Stacey Gabriel; Cheng-Zhong Zhang; Scott M Dehm; Peter S Nelson; Eliezer M Van Allen; Atish D Choudhury; Viktor A Adalsteinsson; Rameen Beroukhim; Mary-Ellen Taplin; Matthew Meyerson

doi:10.1016/j.cell.2018.05.036

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

Cell. 2018 Jul 12;174(2):433-447.e19. doi: 10.1016/j.cell.2018.05.036. Epub 2018 Jun 18.

Authors

Srinivas R Viswanathan¹, Gavin Ha¹, Andreas M Hoff², Jeremiah A Wala¹, Jian Carrot-Zhang¹, Christopher W Whelan³, Nicholas J Haradhvala⁴, Samuel S Freeman⁵, Sarah C Reed⁶, Justin Rhoades⁶, Paz Polak⁷, Michelle Cipicchio⁶, Stephanie A Wankowicz⁸, Alicia Wong⁶, Tushar Kamath⁵, Zhenwei Zhang⁹, Gregory J Gydush⁶, Denisse Rotem⁶; PCF/SU2C International Prostate Cancer Dream Team; J Christopher Love¹⁰, Gad Getz¹¹, Stacey Gabriel⁶, Cheng-Zhong Zhang¹², Scott M Dehm¹³, Peter S Nelson¹⁴, Eliezer M Van Allen⁸, Atish D Choudhury¹⁵, Viktor A Adalsteinsson¹⁰, Rameen Beroukhim¹⁶, Mary-Ellen Taplin¹⁵, Matthew Meyerson¹⁷

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA.
² Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
³ Harvard Medical School, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
⁵ Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA.
⁶ Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁷ Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁸ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁰ Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Koch Institute, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹¹ Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
¹² Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biomedical Informatics, Harvard Medical School, Cambridge, MA, USA.
¹³ Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
¹⁴ Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
¹⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
¹⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Brigham and Women's Hospital, Boston, MA, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Boston, MA, USA. Electronic address: matthew_meyerson@dfci.harvard.edu.

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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Aged
Anilides / therapeutic use
Cyclin-Dependent Kinases / genetics
Cyclin-Dependent Kinases / metabolism
Enhancer Elements, Genetic / genetics
Gene Duplication
Gene Rearrangement
Genes, myc
Genetic Loci
Haplotypes
Humans
Male
Middle Aged
Neoplasm Metastasis
PTEN Phosphohydrolase / genetics
Phenotype
Prostate-Specific Antigen / blood
Prostatic Neoplasms, Castration-Resistant / drug therapy
Prostatic Neoplasms, Castration-Resistant / genetics
Prostatic Neoplasms, Castration-Resistant / pathology*
Protein Kinase Inhibitors / therapeutic use
Pyridines / therapeutic use
Receptors, Androgen / genetics*
Whole Genome Sequencing*

Substances

Anilides
Protein Kinase Inhibitors
Pyridines
Receptors, Androgen
cabozantinib
CDK12 protein, human
Cyclin-Dependent Kinases
PTEN Phosphohydrolase
PTEN protein, human
Prostate-Specific Antigen

Abstract

Publication types

MeSH terms

Substances

Grants and funding