Distinct DNA methylation patterns associated with treatment resistance in metastatic castration resistant prostate cancer

Abstract Androgens are a major driver of prostate cancer (PCa) and continue to be a critical treatment target for advanced disease, which includes castration therapy and antiandrogens. However, resistance to these therapies leading to metastatic castration-resistant prostate cancer (mCRPC), and the...

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Autores principales:	Madonna R. Peter, Misha Bilenky, Alastair Davies, Ruth Isserlin, Gary D. Bader, Neil E. Fleshner, Martin Hirst, Amina Zoubeidi, Bharati Bapat
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8a0d4c3f1dab4fb8aab66b888d10d9ef
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spelling	oai:doaj.org-article:8a0d4c3f1dab4fb8aab66b888d10d9ef2021-12-02T11:45:01ZDistinct DNA methylation patterns associated with treatment resistance in metastatic castration resistant prostate cancer10.1038/s41598-021-85812-32045-2322https://doaj.org/article/8a0d4c3f1dab4fb8aab66b888d10d9ef2021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-85812-3https://doaj.org/toc/2045-2322Abstract Androgens are a major driver of prostate cancer (PCa) and continue to be a critical treatment target for advanced disease, which includes castration therapy and antiandrogens. However, resistance to these therapies leading to metastatic castration-resistant prostate cancer (mCRPC), and the emergence of treatment-induced neuroendocrine disease (tNEPC) remains an ongoing challenge. Instability of the DNA methylome is well established as a major hallmark of PCa development and progression. Therefore, investigating the dynamics of the methylation changes going from the castration sensitive to the tNEPC state would provide insights into novel mechanisms of resistance. Using an established xenograft model of CRPC, genome-wide methylation analysis was performed on cell lines representing various stages of PCa progression. We confirmed extensive methylation changes with the development of CRPC and tNEPC using this model. This included key genes and pathways associated with cellular differentiation and neurodevelopment. Combined analysis of methylation and gene expression changes further highlighted genes that could potentially serve as therapeutic targets. Furthermore, tNEPC-related methylation signals from this model were detectable in circulating cell free DNA (cfDNA) from mCRPC patients undergoing androgen-targeting therapies and were associated with a faster time to clinical progression. These potential biomarkers could help with identifying patients with aggressive disease.Madonna R. PeterMisha BilenkyAlastair DaviesRuth IsserlinGary D. BaderNeil E. FleshnerMartin HirstAmina ZoubeidiBharati BapatNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Madonna R. Peter Misha Bilenky Alastair Davies Ruth Isserlin Gary D. Bader Neil E. Fleshner Martin Hirst Amina Zoubeidi Bharati Bapat Distinct DNA methylation patterns associated with treatment resistance in metastatic castration resistant prostate cancer
description	Abstract Androgens are a major driver of prostate cancer (PCa) and continue to be a critical treatment target for advanced disease, which includes castration therapy and antiandrogens. However, resistance to these therapies leading to metastatic castration-resistant prostate cancer (mCRPC), and the emergence of treatment-induced neuroendocrine disease (tNEPC) remains an ongoing challenge. Instability of the DNA methylome is well established as a major hallmark of PCa development and progression. Therefore, investigating the dynamics of the methylation changes going from the castration sensitive to the tNEPC state would provide insights into novel mechanisms of resistance. Using an established xenograft model of CRPC, genome-wide methylation analysis was performed on cell lines representing various stages of PCa progression. We confirmed extensive methylation changes with the development of CRPC and tNEPC using this model. This included key genes and pathways associated with cellular differentiation and neurodevelopment. Combined analysis of methylation and gene expression changes further highlighted genes that could potentially serve as therapeutic targets. Furthermore, tNEPC-related methylation signals from this model were detectable in circulating cell free DNA (cfDNA) from mCRPC patients undergoing androgen-targeting therapies and were associated with a faster time to clinical progression. These potential biomarkers could help with identifying patients with aggressive disease.
format	article
author	Madonna R. Peter Misha Bilenky Alastair Davies Ruth Isserlin Gary D. Bader Neil E. Fleshner Martin Hirst Amina Zoubeidi Bharati Bapat
author_facet	Madonna R. Peter Misha Bilenky Alastair Davies Ruth Isserlin Gary D. Bader Neil E. Fleshner Martin Hirst Amina Zoubeidi Bharati Bapat
author_sort	Madonna R. Peter
title	Distinct DNA methylation patterns associated with treatment resistance in metastatic castration resistant prostate cancer
title_short	Distinct DNA methylation patterns associated with treatment resistance in metastatic castration resistant prostate cancer
title_full	Distinct DNA methylation patterns associated with treatment resistance in metastatic castration resistant prostate cancer
title_fullStr	Distinct DNA methylation patterns associated with treatment resistance in metastatic castration resistant prostate cancer
title_full_unstemmed	Distinct DNA methylation patterns associated with treatment resistance in metastatic castration resistant prostate cancer
title_sort	distinct dna methylation patterns associated with treatment resistance in metastatic castration resistant prostate cancer
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/8a0d4c3f1dab4fb8aab66b888d10d9ef
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Distinct DNA methylation patterns associated with treatment resistance in metastatic castration resistant prostate cancer

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