Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer

David A Quigley; Ha X Dang; Shuang G Zhao; Paul Lloyd; Rahul Aggarwal; Joshi J Alumkal; Adam Foye; Vishal Kothari; Marc D Perry; Adina M Bailey; Denise Playdle; Travis J Barnard; Li Zhang; Jin Zhang; Jack F Youngren; Marcin P Cieslik; Abhijit Parolia; Tomasz M Beer; George Thomas; Kim N Chi; Martin Gleave; Nathan A Lack; Amina Zoubeidi; Robert E Reiter; Matthew B Rettig; Owen Witte; Charles J Ryan; Lawrence Fong; Won Kim; Terence Friedlander; Jonathan Chou; Haolong Li; Rajdeep Das; Hui Li; Ruhollah Moussavi-Baygi; Hani Goodarzi; Luke A Gilbert; Primo N Lara Jr; Christopher P Evans; Theodore C Goldstein; Joshua M Stuart; Scott A Tomlins; Daniel E Spratt; R Keira Cheetham; Donavan T Cheng; Kyle Farh; Julian S Gehring; Jörg Hakenberg; Arnold Liao; Philip G Febbo; John Shon; Brad Sickler; Serafim Batzoglou; Karen E Knudsen; Housheng H He; Jiaoti Huang; Alexander W Wyatt; Scott M Dehm; Alan Ashworth; Arul M Chinnaiyan; Christopher A Maher; Eric J Small; Felix Y Feng

doi:10.1016/j.cell.2018.06.039

Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer

Cell. 2018 Jul 26;174(3):758-769.e9. doi: 10.1016/j.cell.2018.06.039. Epub 2018 Jul 19.

Authors

David A Quigley¹, Ha X Dang², Shuang G Zhao³, Paul Lloyd⁴, Rahul Aggarwal⁴, Joshi J Alumkal⁵, Adam Foye⁴, Vishal Kothari⁶, Marc D Perry⁶, Adina M Bailey⁴, Denise Playdle⁴, Travis J Barnard⁶, Li Zhang⁴, Jin Zhang⁷, Jack F Youngren⁴, Marcin P Cieslik⁸, Abhijit Parolia⁸, Tomasz M Beer⁹, George Thomas¹⁰, Kim N Chi¹¹, Martin Gleave¹², Nathan A Lack¹², Amina Zoubeidi¹², Robert E Reiter¹³, Matthew B Rettig¹⁴, Owen Witte¹⁵, Charles J Ryan¹⁶, Lawrence Fong⁴, Won Kim⁴, Terence Friedlander⁴, Jonathan Chou⁴, Haolong Li⁶, Rajdeep Das⁶, Hui Li⁶, Ruhollah Moussavi-Baygi⁶, Hani Goodarzi¹⁷, Luke A Gilbert¹⁸, Primo N Lara Jr¹⁹, Christopher P Evans²⁰, Theodore C Goldstein²¹, Joshua M Stuart²², Scott A Tomlins²³, Daniel E Spratt³, R Keira Cheetham²⁴, Donavan T Cheng²⁴, Kyle Farh²⁴, Julian S Gehring²⁴, Jörg Hakenberg²⁴, Arnold Liao²⁴, Philip G Febbo²⁴, John Shon²⁴, Brad Sickler²⁴, Serafim Batzoglou²⁴, Karen E Knudsen²⁵, Housheng H He²⁶, Jiaoti Huang²⁷, Alexander W Wyatt¹², Scott M Dehm²⁸, Alan Ashworth²⁹, Arul M Chinnaiyan³⁰, Christopher A Maher³¹, Eric J Small³², Felix Y Feng³³

Affiliations

¹ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Epidemiology and Biostatistics, UCSF, San Francisco, CA, USA.
² McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, USA; Department of Internal Medicine, Washington University in St. Louis, St. Louis, MO, USA.
³ Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
⁴ Division of Hematology and Oncology, Department of Medicine, UCSF, San Francisco, CA, USA.
⁵ Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA; Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA.
⁶ Department of Radiation Oncology, UCSF, San Francisco, CA, USA.
⁷ Cancer Biology Division, Department of Radiation Oncology, Washington University in St. Louis, MO USA; Institute for Informatics (I(2)), Washington University in St. Louis, MO.
⁸ Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, Ann Arbor, MI, USA.
⁹ Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
¹⁰ Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA; Department of Pathology, Oregon Health and Science University, Portland, OR, USA.
¹¹ Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; British Columbia Cancer Agency, Vancouver Centre, Vancouver, BC, Canada.
¹² Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
¹³ Jonsson Comprehensive Cancer Center, Department of Urology, UCLA, Los Angeles, CA, USA; VA Greater Los Angeles Healthcare System, Department of Medicine, Los Angeles, CA, USA.
¹⁴ Jonsson Comprehensive Cancer Center, Department of Urology, UCLA, Los Angeles, CA, USA.
¹⁵ Department of Microbiology, Immunology, and Molecular Genetics at the David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
¹⁶ Division of Hematology, Oncology, and Transplant, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
¹⁷ Department of Biophysics and Biochemistry, UCSF, San Francisco, CA, USA; Department of Urology, UCSF, San Francisco, CA, USA.
¹⁸ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, UCSF, San Francisco, CA, USA.
¹⁹ Division of Hematology Oncology, Department of Internal Medicine, University of California Davis, Sacramento, CA, USA; Comprehensive Cancer Center, University of California Davis, Sacramento, CA, USA.
²⁰ Comprehensive Cancer Center, University of California Davis, Sacramento, CA, USA; Department of Urologic Surgery, University of California Davis, Sacramento, CA, USA.
²¹ Division of Hematology and Oncology, Department of Medicine, UCSF, San Francisco, CA, USA; UC Sant Cruz Genome Institute and Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA, USA.
²² UC Sant Cruz Genome Institute and Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA, USA.
²³ Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Urology, University of Michigan, Ann Arbor, MI, USA.
²⁴ Illumina, Inc., San Diego, CA, USA.
²⁵ Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
²⁶ Princess Margaret Cancer Centre/University Health Network, Toronto, ON, Canada.
²⁷ Department of Pathology, Duke University, Durham, NC, USA.
²⁸ Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
²⁹ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA; Division of Hematology and Oncology, Department of Medicine, UCSF, San Francisco, CA, USA.
³⁰ Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA; Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA. Electronic address: arul@med.umich.edu.
³¹ McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, USA; Department of Internal Medicine, Washington University in St. Louis, St. Louis, MO, USA. Electronic address: christophermaher@wustl.edu.
³² Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA; Division of Hematology and Oncology, Department of Medicine, UCSF, San Francisco, CA, USA. Electronic address: eric.small@ucsf.edu.
³³ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA; Division of Hematology and Oncology, Department of Medicine, UCSF, San Francisco, CA, USA; Department of Radiation Oncology, UCSF, San Francisco, CA, USA; Department of Urology, UCSF, San Francisco, CA, USA. Electronic address: felix.feng@ucsf.edu.

Abstract

While mutations affecting protein-coding regions have been examined across many cancers, structural variants at the genome-wide level are still poorly defined. Through integrative deep whole-genome and -transcriptome analysis of 101 castration-resistant prostate cancer metastases (109X tumor/38X normal coverage), we identified structural variants altering critical regulators of tumorigenesis and progression not detectable by exome approaches. Notably, we observed amplification of an intergenic enhancer region 624 kb upstream of the androgen receptor (AR) in 81% of patients, correlating with increased AR expression. Tandem duplication hotspots also occur near MYC, in lncRNAs associated with post-translational MYC regulation. Classes of structural variations were linked to distinct DNA repair deficiencies, suggesting their etiology, including associations of CDK12 mutation with tandem duplications, TP53 inactivation with inverted rearrangements and chromothripsis, and BRCA2 inactivation with deletions. Together, these observations provide a comprehensive view of how structural variations affect critical regulators in metastatic prostate cancer.

Keywords: BRCA2; androgen receptor; castration resistant prostate cancer; chromothripsis; gene fusion; genomics; metastases; structural variation; tandem duplication; whole-genome sequencing.

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
Aged, 80 and over
BRCA2 Protein / metabolism
Cyclin-Dependent Kinases / metabolism
DNA Copy Number Variations
Exome
Gene Expression Profiling / methods
Genomic Structural Variation / genetics*
Genomics / methods
Humans
Male
Middle Aged
Mutation
Neoplasm Metastasis / genetics
Prostatic Neoplasms / genetics*
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism
Receptors, Androgen / genetics
Receptors, Androgen / metabolism
Tandem Repeat Sequences / genetics
Tumor Suppressor Protein p53 / metabolism
Whole Genome Sequencing / methods

Substances

AR protein, human
BRCA2 Protein
BRCA2 protein, human
MYC protein, human
Proto-Oncogene Proteins c-myc
Receptors, Androgen
TP53 protein, human
Tumor Suppressor Protein p53
CDK12 protein, human
Cyclin-Dependent Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding