Co-evolution of <i>AR</i> gene copy number and structural complexity in endocrine therapy resistant prostate cancer-Reference-Cited by-同舟云学术

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

Published:2023-06-09 Issue:3 Volume:5 Page:
ISSN:2632-8674
Container-title:NAR Cancer
language:en
Short-container-title:

Author:

Zivanovic Andrej¹,Miller Jeffrey T²,Munro Sarah A²,Knutson Todd P²,Li Yingming¹,Passow Courtney N³,Simonaitis Pijus⁴,Lynch Molly¹,Oseth LeAnn¹,Zhao Shuang G⁵⁶⁷,Feng Felix Y⁸⁹,Wikström Pernilla¹⁰,Corey Eva¹¹,Morrissey Colm¹¹,Henzler Christine²,Raphael Benjamin J⁴,Dehm Scott M¹¹²¹³^ORCID

Affiliation:

1. Masonic Cancer Center, University of Minnesota , Minneapolis , MN , USA

2. Minnesota Supercomputing Institute, University of Minnesota , Minneapolis , MN , USA

3. University of Minnesota Genomics Center, University of Minnesota , Minneapolis , MN , USA

4. Department of Computer Science, Princeton University , Princeton , NJ , USA

5. Department of Human Oncology, University of Wisconsin-Madison , Madison , WI , USA

6. Carbone Cancer Center, University of Wisconsin-Madison , Madison , WI , USA

7. William S. Middleton Memorial Veterans Hospital , Madison , Madison , WI , USA

8. Departments of Radiation Oncology, Urology, and Medicine, University of California San Francisco , San Francisco , CA , USA

9. Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco , San Francisco , CA , USA

10. Department of Medical Biosciences, Pathology, Umeå University , Umeå , Sweden

11. Department of Urology, University of Washington , Seattle , WA , USA

12. Department of Laboratory Medicine and Pathology, University of Minnesota , Minneapolis , MN , USA

13. Department of Urology, University of Minnesota , Minneapolis , MN , USA

Abstract

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.

Funder

National Cancer Institute

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,Oncology

Link

https://academic.oup.com/narcancer/article-pdf/5/3/zcad045/51243957/zcad045.pdf

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