Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer

David A. Quigley, Ha X. Dang, Shuang G. Zhao, Paul Lloyd, Rahul Aggarwal, Joshi 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 (Tom) Beer, George Thomas, Kim N. ChiMartin 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, 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

Research output: Contribution to journalArticle

52 Citations (Scopus)

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. Integrative whole-genome and -transcriptome sequencing provides a comprehensive view of structural variations that affect major regulators in prostate cancer and would escape detection by exome-based approaches.

Original languageEnglish (US)
Pages (from-to)758-769.e9
JournalCell
Volume174
Issue number3
DOIs
StatePublished - Jul 26 2018

Fingerprint

Genomic Structural Variation
Exome
Prostatic Neoplasms
Genes
Androgen Receptors
DNA Repair-Deficiency Disorders
Long Noncoding RNA
Genome
Mutation
Intergenic DNA
Castration
Gene Expression Profiling
Transcriptome
Open Reading Frames
Amplification
Tumors
Neoplasms
Carcinogenesis
Repair
Neoplasm Metastasis

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Quigley, D. A., Dang, H. X., Zhao, S. G., Lloyd, P., Aggarwal, R., Alumkal, J., ... Feng, F. Y. (2018). Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer. Cell, 174(3), 758-769.e9. https://doi.org/10.1016/j.cell.2018.06.039

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

In: Cell, Vol. 174, No. 3, 26.07.2018, p. 758-769.e9.

Research output: Contribution to journalArticle

Quigley, DA, Dang, HX, Zhao, SG, Lloyd, P, Aggarwal, R, Alumkal, J, Foye, A, Kothari, V, Perry, MD, Bailey, AM, Playdle, D, Barnard, TJ, Zhang, L, Zhang, J, Youngren, JF, Cieslik, MP, Parolia, A, Beer, TT, Thomas, G, Chi, KN, Gleave, M, Lack, NA, Zoubeidi, A, Reiter, RE, Rettig, MB, Witte, O, Ryan, CJ, Fong, L, Kim, W, Friedlander, T, Chou, J, Li, H, Das, R, Li, H, Moussavi-Baygi, R, Goodarzi, H, Gilbert, LA, Lara, PN, Evans, CP, Goldstein, TC, Stuart, JM, Tomlins, SA, Spratt, DE, Cheetham, RK, Cheng, DT, Farh, K, Gehring, JS, Hakenberg, J, Liao, A, Febbo, PG, Shon, J, Sickler, B, Batzoglou, S, Knudsen, KE, He, HH, Huang, J, Wyatt, AW, Dehm, SM, Ashworth, A, Chinnaiyan, AM, Maher, CA, Small, EJ & Feng, FY 2018, 'Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer', Cell, vol. 174, no. 3, pp. 758-769.e9. https://doi.org/10.1016/j.cell.2018.06.039
Quigley DA, Dang HX, Zhao SG, Lloyd P, Aggarwal R, Alumkal J et al. Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer. Cell. 2018 Jul 26;174(3):758-769.e9. https://doi.org/10.1016/j.cell.2018.06.039
Quigley, David A. ; Dang, Ha X. ; Zhao, Shuang G. ; Lloyd, Paul ; Aggarwal, Rahul ; Alumkal, Joshi ; Foye, Adam ; Kothari, Vishal ; Perry, Marc D. ; Bailey, Adina M. ; Playdle, Denise ; Barnard, Travis J. ; Zhang, Li ; Zhang, Jin ; Youngren, Jack F. ; Cieslik, Marcin P. ; Parolia, Abhijit ; Beer, Tomasz (Tom) ; Thomas, George ; Chi, Kim N. ; Gleave, Martin ; Lack, Nathan A. ; Zoubeidi, Amina ; Reiter, Robert E. ; Rettig, Matthew B. ; Witte, Owen ; Ryan, Charles J. ; Fong, Lawrence ; Kim, Won ; Friedlander, Terence ; Chou, Jonathan ; Li, Haolong ; Das, Rajdeep ; Li, Hui ; Moussavi-Baygi, Ruhollah ; Goodarzi, Hani ; Gilbert, Luke A. ; Lara, Primo N. ; Evans, Christopher P. ; Goldstein, Theodore C. ; Stuart, Joshua M. ; Tomlins, Scott A. ; Spratt, Daniel E. ; Cheetham, R. Keira ; Cheng, Donavan T. ; Farh, Kyle ; Gehring, Julian S. ; Hakenberg, Jörg ; Liao, Arnold ; Febbo, Philip G. ; Shon, John ; Sickler, Brad ; Batzoglou, Serafim ; Knudsen, Karen E. ; He, Housheng H. ; Huang, Jiaoti ; Wyatt, Alexander W. ; Dehm, Scott M. ; Ashworth, Alan ; Chinnaiyan, Arul M. ; Maher, Christopher A. ; Small, Eric J. ; Feng, Felix Y. / Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer. In: Cell. 2018 ; Vol. 174, No. 3. pp. 758-769.e9.
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AU - Foye, Adam

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AU - Thomas, George

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AU - Gleave, Martin

AU - Lack, Nathan A.

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AU - Moussavi-Baygi, Ruhollah

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AU - Gilbert, Luke A.

AU - Lara, Primo N.

AU - Evans, Christopher P.

AU - Goldstein, Theodore C.

AU - Stuart, Joshua M.

AU - Tomlins, Scott A.

AU - Spratt, Daniel E.

AU - Cheetham, R. Keira

AU - Cheng, Donavan T.

AU - Farh, Kyle

AU - Gehring, Julian S.

AU - Hakenberg, Jörg

AU - Liao, Arnold

AU - Febbo, Philip G.

AU - Shon, John

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AU - He, Housheng H.

AU - Huang, Jiaoti

AU - Wyatt, Alexander W.

AU - Dehm, Scott M.

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AU - Chinnaiyan, Arul M.

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AU - Small, Eric J.

AU - Feng, Felix Y.

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KW - BRCA2

KW - castration resistant prostate cancer

KW - chromothripsis

KW - gene fusion

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KW - structural variation

KW - tandem duplication

KW - whole-genome sequencing

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