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Co-evolution of AR gene copy number and structural complexity in endocrine therapy resistant prostate cancer

Zivanovic, Andrej (författare)
Masonic Cancer Center, University of Minnesota, MN, Minneapolis, United States
Miller, Jeffrey T. (författare)
Minnesota Supercomputing Institute, University of Minnesota, MN, Minneapolis, United States
Munro, Sarah A. (författare)
Minnesota Supercomputing Institute, University of Minnesota, MN, Minneapolis, United States
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Knutson, Todd P. (författare)
Minnesota Supercomputing Institute, University of Minnesota, MN, Minneapolis, United States
Li, Yingming (författare)
Masonic Cancer Center, University of Minnesota, MN, Minneapolis, United States
Passow, Courtney N. (författare)
University of Minnesota Genomics Center, University of Minnesota, MN, Minneapolis, United States
Simonaitis, Pijus (författare)
Department of Computer Science, Princeton University, NJ, Princeton, United States
Lynch, Molly (författare)
Masonic Cancer Center, University of Minnesota, MN, Minneapolis, United States
Oseth, LeAnn (författare)
Masonic Cancer Center, University of Minnesota, MN, Minneapolis, United States
Zhao, Shuang G. (författare)
Department of Human Oncology, University of Wisconsin-Madison, WI, Madison, United States; Carbone Cancer Center, University of Wisconsin-Madison, WI, Madison, United States; William S. Middleton Memorial Veterans Hospital Madison, WI, Madison, United States
Feng, Felix Y. (författare)
Departments of Radiation Oncology Urology, and Medicine, University of California San Francisco, CA, San Francisco, United States; Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, CA, San Francisco, United States
Wikström, Pernilla (författare)
Umeå universitet,Patologi
Corey, Eva (författare)
Department of Urology, University of Washington, WA, Seattle, United States
Morrissey, Colm (författare)
Department of Urology, University of Washington, WA, Seattle, United States
Henzler, Christine (författare)
Minnesota Supercomputing Institute, University of Minnesota, MN, Minneapolis, United States
Raphael, Benjamin J. (författare)
Department of Computer Science, Princeton University, NJ, Princeton, United States
Dehm, Scott M. (författare)
Masonic Cancer Center, University of Minnesota, MN, Minneapolis, United States; Department of Laboratory Medicine and Pathology, University of Minnesota, MN, Minneapolis, United States; Department of Urology, University of Minnesota, MN, Minneapolis, United States
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 (creator_code:org_t)
Oxford University Press, 2023
2023
Engelska.
Ingår i: NAR Cancer. - : Oxford University Press. - 2632-8674. ; 5:3
Relaterad länk:
https://doi.org/10.1...
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https://umu.diva-por... (primary) (Raw object)
https://urn.kb.se/re...
https://doi.org/10.1...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
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  • Androgen receptor (AR) inhibition is standard of care for advanced prostate cancer (PC). However, efficacy is limited by progression to castration-resistant PC (CRPC), usually due to AR re-activation via mechanisms that include AR amplification and structural rearrangement. These two classes of AR alterations often co-occur in CRPC tumors, but it is unclear whether this reflects intercellular or intracellular heterogeneity of AR. Resolving this is important for developing new therapies and predictive biomarkers. Here, we analyzed 41 CRPC tumors and 6 patient-derived xenografts (PDXs) using linked-read DNA-sequencing, and identified 7 tumors that developed complex, multiply-rearranged AR gene structures in conjunction with very high AR copy number. Analysis of PDX models by optical genome mapping and fluorescence in situ hybridization showed that AR residing on extrachromosomal DNA (ecDNA) was an underlying mechanism, and was associated with elevated levels and diversity of AR expression. This study identifies co-evolution of AR gene copy number and structural complexity via ecDNA as a mechanism associated with endocrine therapy resistance.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

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