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Nucleosome Patterns in Circulating Tumor DNA Reveal Transcriptional Regulation of Advanced Prostate Cancer Phenotypes
Advanced prostate cancers comprise distinct phenotypes, but tumor classification remains clinically challenging. Here, we harnessed circulating tumor DNA (ctDNA) to study tumor phenotypes by ascertaining nucleosome positioning patterns associated with transcription regulation. We sequenced plasma ct...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9976992/ https://www.ncbi.nlm.nih.gov/pubmed/36399432 http://dx.doi.org/10.1158/2159-8290.CD-22-0692 |
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author | De Sarkar, Navonil Patton, Robert D. Doebley, Anna-Lisa Hanratty, Brian Adil, Mohamed Kreitzman, Adam J. Sarthy, Jay F. Ko, Minjeong Brahma, Sandipan Meers, Michael P. Janssens, Derek H. Ang, Lisa S. Coleman, Ilsa M. Bose, Arnab Dumpit, Ruth F. Lucas, Jared M. Nunez, Talina A. Nguyen, Holly M. McClure, Heather M. Pritchard, Colin C. Schweizer, Michael T. Morrissey, Colm Choudhury, Atish D. Baca, Sylvan C. Berchuck, Jacob E. Freedman, Matthew L. Ahmad, Kami Haffner, Michael C. Montgomery, R. Bruce Corey, Eva Henikoff, Steven Nelson, Peter S. Ha, Gavin |
author_facet | De Sarkar, Navonil Patton, Robert D. Doebley, Anna-Lisa Hanratty, Brian Adil, Mohamed Kreitzman, Adam J. Sarthy, Jay F. Ko, Minjeong Brahma, Sandipan Meers, Michael P. Janssens, Derek H. Ang, Lisa S. Coleman, Ilsa M. Bose, Arnab Dumpit, Ruth F. Lucas, Jared M. Nunez, Talina A. Nguyen, Holly M. McClure, Heather M. Pritchard, Colin C. Schweizer, Michael T. Morrissey, Colm Choudhury, Atish D. Baca, Sylvan C. Berchuck, Jacob E. Freedman, Matthew L. Ahmad, Kami Haffner, Michael C. Montgomery, R. Bruce Corey, Eva Henikoff, Steven Nelson, Peter S. Ha, Gavin |
author_sort | De Sarkar, Navonil |
collection | PubMed |
description | Advanced prostate cancers comprise distinct phenotypes, but tumor classification remains clinically challenging. Here, we harnessed circulating tumor DNA (ctDNA) to study tumor phenotypes by ascertaining nucleosome positioning patterns associated with transcription regulation. We sequenced plasma ctDNA whole genomes from patient-derived xenografts representing a spectrum of androgen receptor active (ARPC) and neuroendocrine (NEPC) prostate cancers. Nucleosome patterns associated with transcriptional activity were reflected in ctDNA at regions of genes, promoters, histone modifications, transcription factor binding, and accessible chromatin. We identified the activity of key phenotype-defining transcriptional regulators from ctDNA, including AR, ASCL1, HOXB13, HNF4G, and GATA2. To distinguish NEPC and ARPC in patient plasma samples, we developed prediction models that achieved accuracies of 97% for dominant phenotypes and 87% for mixed clinical phenotypes. Although phenotype classification is typically assessed by IHC or transcriptome profiling from tumor biopsies, we demonstrate that ctDNA provides comparable results with diagnostic advantages for precision oncology. SIGNIFICANCE: This study provides insights into the dynamics of nucleosome positioning and gene regulation associated with cancer phenotypes that can be ascertained from ctDNA. New methods for classification in phenotype mixtures extend the utility of ctDNA beyond assessments of somatic DNA alterations with important implications for molecular classification and precision oncology. This article is highlighted in the In This Issue feature, p. 517 |
format | Online Article Text |
id | pubmed-9976992 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-99769922023-03-02 Nucleosome Patterns in Circulating Tumor DNA Reveal Transcriptional Regulation of Advanced Prostate Cancer Phenotypes De Sarkar, Navonil Patton, Robert D. Doebley, Anna-Lisa Hanratty, Brian Adil, Mohamed Kreitzman, Adam J. Sarthy, Jay F. Ko, Minjeong Brahma, Sandipan Meers, Michael P. Janssens, Derek H. Ang, Lisa S. Coleman, Ilsa M. Bose, Arnab Dumpit, Ruth F. Lucas, Jared M. Nunez, Talina A. Nguyen, Holly M. McClure, Heather M. Pritchard, Colin C. Schweizer, Michael T. Morrissey, Colm Choudhury, Atish D. Baca, Sylvan C. Berchuck, Jacob E. Freedman, Matthew L. Ahmad, Kami Haffner, Michael C. Montgomery, R. Bruce Corey, Eva Henikoff, Steven Nelson, Peter S. Ha, Gavin Cancer Discov Research Articles Advanced prostate cancers comprise distinct phenotypes, but tumor classification remains clinically challenging. Here, we harnessed circulating tumor DNA (ctDNA) to study tumor phenotypes by ascertaining nucleosome positioning patterns associated with transcription regulation. We sequenced plasma ctDNA whole genomes from patient-derived xenografts representing a spectrum of androgen receptor active (ARPC) and neuroendocrine (NEPC) prostate cancers. Nucleosome patterns associated with transcriptional activity were reflected in ctDNA at regions of genes, promoters, histone modifications, transcription factor binding, and accessible chromatin. We identified the activity of key phenotype-defining transcriptional regulators from ctDNA, including AR, ASCL1, HOXB13, HNF4G, and GATA2. To distinguish NEPC and ARPC in patient plasma samples, we developed prediction models that achieved accuracies of 97% for dominant phenotypes and 87% for mixed clinical phenotypes. Although phenotype classification is typically assessed by IHC or transcriptome profiling from tumor biopsies, we demonstrate that ctDNA provides comparable results with diagnostic advantages for precision oncology. SIGNIFICANCE: This study provides insights into the dynamics of nucleosome positioning and gene regulation associated with cancer phenotypes that can be ascertained from ctDNA. New methods for classification in phenotype mixtures extend the utility of ctDNA beyond assessments of somatic DNA alterations with important implications for molecular classification and precision oncology. This article is highlighted in the In This Issue feature, p. 517 American Association for Cancer Research 2023-03-01 2022-11-18 /pmc/articles/PMC9976992/ /pubmed/36399432 http://dx.doi.org/10.1158/2159-8290.CD-22-0692 Text en ©2022 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. |
spellingShingle | Research Articles De Sarkar, Navonil Patton, Robert D. Doebley, Anna-Lisa Hanratty, Brian Adil, Mohamed Kreitzman, Adam J. Sarthy, Jay F. Ko, Minjeong Brahma, Sandipan Meers, Michael P. Janssens, Derek H. Ang, Lisa S. Coleman, Ilsa M. Bose, Arnab Dumpit, Ruth F. Lucas, Jared M. Nunez, Talina A. Nguyen, Holly M. McClure, Heather M. Pritchard, Colin C. Schweizer, Michael T. Morrissey, Colm Choudhury, Atish D. Baca, Sylvan C. Berchuck, Jacob E. Freedman, Matthew L. Ahmad, Kami Haffner, Michael C. Montgomery, R. Bruce Corey, Eva Henikoff, Steven Nelson, Peter S. Ha, Gavin Nucleosome Patterns in Circulating Tumor DNA Reveal Transcriptional Regulation of Advanced Prostate Cancer Phenotypes |
title | Nucleosome Patterns in Circulating Tumor DNA Reveal Transcriptional Regulation of Advanced Prostate Cancer Phenotypes |
title_full | Nucleosome Patterns in Circulating Tumor DNA Reveal Transcriptional Regulation of Advanced Prostate Cancer Phenotypes |
title_fullStr | Nucleosome Patterns in Circulating Tumor DNA Reveal Transcriptional Regulation of Advanced Prostate Cancer Phenotypes |
title_full_unstemmed | Nucleosome Patterns in Circulating Tumor DNA Reveal Transcriptional Regulation of Advanced Prostate Cancer Phenotypes |
title_short | Nucleosome Patterns in Circulating Tumor DNA Reveal Transcriptional Regulation of Advanced Prostate Cancer Phenotypes |
title_sort | nucleosome patterns in circulating tumor dna reveal transcriptional regulation of advanced prostate cancer phenotypes |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9976992/ https://www.ncbi.nlm.nih.gov/pubmed/36399432 http://dx.doi.org/10.1158/2159-8290.CD-22-0692 |
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