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Co-evolution of AR gene copy number and structural complexity in endocrine therapy resistant prostate cancer.
Zivanovic, Andrej; Miller, Jeffrey T; Munro, Sarah A; Knutson, Todd P; Li, Yingming; Passow, Courtney N; Simonaitis, Pijus; Lynch, Molly; Oseth, LeAnn; Zhao, Shuang G; Feng, Felix Y; Wikström, Pernilla; Corey, Eva; Morrissey, Colm; Henzler, Christine; Raphael, Benjamin J; Dehm, Scott M.
Afiliación
  • Zivanovic A; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
  • Miller JT; Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN, USA.
  • Munro SA; Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN, USA.
  • Knutson TP; Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN, USA.
  • Li Y; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
  • Passow CN; University of Minnesota Genomics Center, University of Minnesota, Minneapolis, MN, USA.
  • Simonaitis P; Department of Computer Science, Princeton University, Princeton, NJ, USA.
  • Lynch M; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
  • Oseth L; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
  • Zhao SG; Department of Human Oncology, University of Wisconsin-Madison, Madison, WI, USA.
  • Feng FY; Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA.
  • Wikström P; William S. Middleton Memorial Veterans Hospital, Madison, Madison, WI, USA.
  • Corey E; Departments of Radiation Oncology, Urology, and Medicine, University of California San Francisco, San Francisco, CA, USA.
  • Morrissey C; Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA, USA.
  • Henzler C; Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
  • Raphael BJ; Department of Urology, University of Washington, Seattle, WA, USA.
  • Dehm SM; Department of Urology, University of Washington, Seattle, WA, USA.
NAR Cancer ; 5(3): zcad045, 2023 Sep.
Article en En | MEDLINE | ID: mdl-37636316
ABSTRACT
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.
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Texto completo: 1 Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: NAR Cancer Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: NAR Cancer Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos