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

Andrej Zivanovic; Jeffrey T. Miller; Sarah A. Munro; Todd P. Knutson; Yingming Li; Courtney N. Passow; Pijus Simonaitis; Molly Lynch; Le Ann Oseth; Shuang G. Zhao; Felix Y. Feng; Pernilla Wikström; Eva Corey; Colm Morrissey; Christine Henzler; Benjamin J. Raphael; Scott M. Dehm

doi:10.1093/narcan/zcad045

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

Andrej Zivanovic, Jeffrey T. Miller, Sarah A. Munro, Todd P. Knutson, Yingming Li, Courtney N. Passow, Pijus Simonaitis, Molly Lynch, Le Ann Oseth, Shuang G. Zhao, Felix Y. Feng, Pernilla Wikström, Eva Corey, Colm Morrissey, Christine Henzler, Benjamin J. Raphael, Scott M. Dehm

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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.

Original language	English (US)
Article number	zcad045
Journal	NAR Cancer
Volume	5
Issue number	3
DOIs	https://doi.org/10.1093/narcan/zcad045
State	Published - Sep 1 2023

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© 2023 The Author(s). Published by Oxford University Press on behalf of NAR Cancer.

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Zivanovic, A., Miller, J. T., Munro, S. A., Knutson, T. P., Li, Y., Passow, C. N., Simonaitis, P., Lynch, M., Oseth, L. A., Zhao, S. G., Feng, F. Y., Wikström, P., Corey, E., Morrissey, C., Henzler, C., Raphael, B. J., & Dehm, S. M. (2023). Co-evolution of AR gene copy number and structural complexity in endocrine therapy resistant prostate cancer. NAR Cancer, 5(3), Article zcad045. https://doi.org/10.1093/narcan/zcad045

Zivanovic, A, Miller, JT, Munro, SA , Knutson, TP , Li, Y, Passow, CN, Simonaitis, P, Lynch, M, Oseth, LA, Zhao, SG, Feng, FY, Wikström, P, Corey, E, Morrissey, C, Henzler, C, Raphael, BJ & Dehm, SM 2023, 'Co-evolution of AR gene copy number and structural complexity in endocrine therapy resistant prostate cancer', NAR Cancer, vol. 5, no. 3, zcad045. https://doi.org/10.1093/narcan/zcad045

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

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.",

author = "Andrej Zivanovic and Miller, {Jeffrey T.} and Munro, {Sarah A.} and Knutson, {Todd P.} and Yingming Li and Passow, {Courtney N.} and Pijus Simonaitis and Molly Lynch and Oseth, {Le Ann} and Zhao, {Shuang G.} and Feng, {Felix Y.} and Pernilla Wikstr{\"o}m and Eva Corey and Colm Morrissey and Christine Henzler and Raphael, {Benjamin J.} and Dehm, {Scott M.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s). Published by Oxford University Press on behalf of NAR Cancer.",

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month = sep,

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doi = "10.1093/narcan/zcad045",

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AU - Zivanovic, Andrej

AU - Miller, Jeffrey T.

AU - Munro, Sarah A.

AU - Knutson, Todd P.

AU - Li, Yingming

AU - Passow, Courtney N.

AU - Simonaitis, Pijus

AU - Lynch, Molly

AU - Oseth, Le Ann

AU - Zhao, Shuang G.

AU - Feng, Felix Y.

AU - Wikström, Pernilla

AU - Corey, Eva

AU - Morrissey, Colm

AU - Henzler, Christine

AU - Raphael, Benjamin J.

AU - Dehm, Scott M.

PY - 2023/9/1

Y1 - 2023/9/1

N2 - 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.

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

Abstract

Bibliographical note

PubMed: MeSH publication types

UN SDGs

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