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Patterns of Structural Variation Define Prostate Cancer Across Disease States

View ORCID ProfileMeng Zhou, View ORCID ProfileMinjeong Ko, View ORCID ProfileAnna C. Hoge, View ORCID ProfileKelsey Luu, View ORCID ProfileYuzhen Liu, View ORCID ProfileMagdalena L. Russell, View ORCID ProfileWilliam W. Hannon, Zhenwei Zhang, View ORCID ProfileJian Carrot-Zhang, Rameen Beroukhim, View ORCID ProfileEliezer M. Van Allen, View ORCID ProfileAtish D. Choudhury, View ORCID ProfilePeter S. Nelson, View ORCID ProfileMatthew L. Freedman, Mary-Ellen Taplin, View ORCID ProfileMatthew Meyerson, View ORCID ProfileSrinivas R. Viswanathan, View ORCID ProfileGavin Ha
doi: https://doi.org/10.1101/2022.01.09.475586
Meng Zhou
1Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215
2Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142
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Minjeong Ko
4Public Health Sciences and Human Biology Divisions, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Seattle, WA 98109
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  • ORCID record for Minjeong Ko
Anna C. Hoge
4Public Health Sciences and Human Biology Divisions, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Seattle, WA 98109
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Kelsey Luu
4Public Health Sciences and Human Biology Divisions, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Seattle, WA 98109
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  • ORCID record for Kelsey Luu
Yuzhen Liu
4Public Health Sciences and Human Biology Divisions, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Seattle, WA 98109
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Magdalena L. Russell
4Public Health Sciences and Human Biology Divisions, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Seattle, WA 98109
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  • ORCID record for Magdalena L. Russell
William W. Hannon
4Public Health Sciences and Human Biology Divisions, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Seattle, WA 98109
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Zhenwei Zhang
1Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215
5Department of Pathology, UMass Memorial Medical Center, 1 Innovation Dr. #2, Worcester, MA 01605
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Jian Carrot-Zhang
1Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215
2Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142
3Harvard Medical School, 25 Shattuck St, Boston, MA 02115
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Rameen Beroukhim
1Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215
2Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142
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Eliezer M. Van Allen
1Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215
2Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142
6Center for Cancer Genomics, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215
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Atish D. Choudhury
1Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215
3Harvard Medical School, 25 Shattuck St, Boston, MA 02115
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Peter S. Nelson
4Public Health Sciences and Human Biology Divisions, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Seattle, WA 98109
7Department of Genome Sciences, University of Washington, 1959 Pacific St, Seattle, WA, 98195
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Matthew L. Freedman
1Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215
3Harvard Medical School, 25 Shattuck St, Boston, MA 02115
8Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215
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Mary-Ellen Taplin
1Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215
3Harvard Medical School, 25 Shattuck St, Boston, MA 02115
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  • For correspondence: mtaplin@partners.org matthew_meyerson@dfci.harvard.edu srinivas_viswanathan@dfci.harvard.edu gha@fredhutch.org
Matthew Meyerson
1Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215
2Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142
3Harvard Medical School, 25 Shattuck St, Boston, MA 02115
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  • For correspondence: mtaplin@partners.org matthew_meyerson@dfci.harvard.edu srinivas_viswanathan@dfci.harvard.edu gha@fredhutch.org
Srinivas R. Viswanathan
1Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215
2Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142
3Harvard Medical School, 25 Shattuck St, Boston, MA 02115
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  • For correspondence: mtaplin@partners.org matthew_meyerson@dfci.harvard.edu srinivas_viswanathan@dfci.harvard.edu gha@fredhutch.org
Gavin Ha
4Public Health Sciences and Human Biology Divisions, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Seattle, WA 98109
7Department of Genome Sciences, University of Washington, 1959 Pacific St, Seattle, WA, 98195
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  • For correspondence: mtaplin@partners.org matthew_meyerson@dfci.harvard.edu srinivas_viswanathan@dfci.harvard.edu gha@fredhutch.org
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SUMMARY

The complex genomic landscape of prostate cancer evolves across disease states under therapeutic pressure directed toward inhibiting androgen receptor (AR) signaling. While significantly altered genes in prostate cancer have been extensively defined, there have been fewer systematic analyses of how structural variation reflects the genomic landscape of this disease. We comprehensively characterized structural alterations across 278 localized and 143 metastatic prostate cancers profiled by whole genome and transcriptome sequencing. We observed distinct significantly recurrent breakpoints in localized and metastatic castration-resistant prostate cancers (mCRPC), with pervasive alterations in noncoding regions flanking the AR, MYC, FOXA1, and LSAMP genes in mCRPC. We defined nine subclasses of mCRPC based on signatures of structural variation, each associated with distinct genetic features and clinical outcomes. Our results comprehensively define patterns of structural variation in prostate cancer and identify clinically actionable subgroups based on whole genome profiling.

Competing Interest Statement

A.D.C.: Honoraria: OncLive, Bayer, Targeted Oncology, Aptitude Health, Journal of Clinical Pathways, Cancer Network; Consulting: Blackstone; Advisory Board: Clovis, Dendreon, Bayer, Eli Lilly, AstraZeneca, Astellas, Blue Earth; Research Funding: Bayer E.M.V.: Advisory/Consulting: Tango Therapeutics, Genome Medical, Invitae, Enara Bio, Janssen, Manifold Bio, Monte Rosa; Research support: Novartis, BMS; Equity: Tango Therapeutics, Genome Medical, Syapse, Enara Bio, Manifold Bio, Microsoft, Monte Rosa; Travel reimbursement: Roche/Genentech; Patents: Institutional patents filed on chromatin mutations and immunotherapy response, and methods for clinical interpretation; intermittent legal consulting on patents for Foaley & Hoag M-E.T.: Advisory boards: Janssen, Pfizer, Astra Zeneca, Bayer M.L.F.: Served as a consultant to and has equity in Nuscan Diagnostics. This activity is outside of the scope of this manuscript. M.M.: Consultant for Bayer, Interline and Isobl; an inventor of patents licensed to LabCorp and Bayer; and receives research funding from Bayer, Janssen, and Ono Pharmaceuticals. P.S.N.: Served as a consultant to Bristol Myers Squibb, Janssen, and Pfizer in work unrelated to the present study. S.R.V.: Consulting (current or previous 3 years), MPM Capital and Vida Ventures; spouse is an employee of and holds equity in Kojin Therapeutics. All other authors declare no competing interests.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 11, 2022.
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Patterns of Structural Variation Define Prostate Cancer Across Disease States
Meng Zhou, Minjeong Ko, Anna C. Hoge, Kelsey Luu, Yuzhen Liu, Magdalena L. Russell, William W. Hannon, Zhenwei Zhang, Jian Carrot-Zhang, Rameen Beroukhim, Eliezer M. Van Allen, Atish D. Choudhury, Peter S. Nelson, Matthew L. Freedman, Mary-Ellen Taplin, Matthew Meyerson, Srinivas R. Viswanathan, Gavin Ha
bioRxiv 2022.01.09.475586; doi: https://doi.org/10.1101/2022.01.09.475586
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Patterns of Structural Variation Define Prostate Cancer Across Disease States
Meng Zhou, Minjeong Ko, Anna C. Hoge, Kelsey Luu, Yuzhen Liu, Magdalena L. Russell, William W. Hannon, Zhenwei Zhang, Jian Carrot-Zhang, Rameen Beroukhim, Eliezer M. Van Allen, Atish D. Choudhury, Peter S. Nelson, Matthew L. Freedman, Mary-Ellen Taplin, Matthew Meyerson, Srinivas R. Viswanathan, Gavin Ha
bioRxiv 2022.01.09.475586; doi: https://doi.org/10.1101/2022.01.09.475586

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