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Genome and Epigenome

Genes Predisposed to DNA Hypermethylation during Acquired Resistance to Chemotherapy Are Identified in Ovarian Tumors by Bivalent Chromatin Domains at Initial Diagnosis

Edward Curry, Constanze Zeller, Nahal Masrour, Darren K. Patten, John Gallon, Charlotte S. Wilhelm-Benartzi, Sadaf Ghaem-Maghami, David D. Bowtell and Robert Brown
Edward Curry
Department Surgery & Cancer, Imperial College London, London, United Kingdom.
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Constanze Zeller
Department Surgery & Cancer, Imperial College London, London, United Kingdom.
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Nahal Masrour
Department Surgery & Cancer, Imperial College London, London, United Kingdom.
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Darren K. Patten
Department Surgery & Cancer, Imperial College London, London, United Kingdom.
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John Gallon
Department Surgery & Cancer, Imperial College London, London, United Kingdom.
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Charlotte S. Wilhelm-Benartzi
Centre for Trials Research, Cardiff University, Cardiff, United Kingdom.
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Sadaf Ghaem-Maghami
Department Surgery & Cancer, Imperial College London, London, United Kingdom.
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David D. Bowtell
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
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Robert Brown
Department Surgery & Cancer, Imperial College London, London, United Kingdom.Institute of Cancer Research, Sutton, United Kingdom.
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  • For correspondence: b.brown@imperial.ac.uk
DOI: 10.1158/0008-5472.CAN-17-1650
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Abstract

Bivalent chromatin domains containing both active H3K4me3 and repressive H3K27me3 histone marks define gene sets poised for expression or silencing in differentiating embryonic stem (ES) cells. In cancer cells, aberrantly poised genes may facilitate changes in transcriptional states after exposure to anticancer drugs. In this study, we used ChIP-seq to characterize genome-wide positioning of H3K4me3- and H3K27me3-associated chromatin in primary high-grade serous ovarian carcinomas and in normal ovarian surface and fallopian tube tissue. Gene sets with proximal bivalent marks defined in this manner were evaluated subsequently as signatures of systematic change in DNA methylation and gene expression, comparing pairs of tissue samples taken from patients at primary presentation and relapse following chemotherapy. We found that gene sets harboring bivalent chromatin domains at their promoters in tumor tissue, but not normal epithelia, overlapped with Polycomb-repressive complex target genes as well as transcriptionally silenced genes in normal ovarian and tubal stem cells. The bivalently marked genes we identified in tumors before chemotherapy displayed increased promoter CpG methylation and reduced gene expression at relapse after chemotherapy of ovarian cancer. Overall, our results support the hypothesis that preexisting histone modifications at genes in a poised chromatin state may lead to epigenetic silencing during acquired drug resistance.

Significance: These results suggest epigenetic targets for intervention to prevent the emergence of cancer drug resistance. Cancer Res; 1–9. ©2018 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Received June 6, 2017.
  • Revision received October 12, 2017.
  • Accepted January 10, 2018.
  • ©2018 American Association for Cancer Research.

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Published OnlineFirst February 22, 2018
doi: 10.1158/0008-5472.CAN-17-1650

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Genes Predisposed to DNA Hypermethylation during Acquired Resistance to Chemotherapy Are Identified in Ovarian Tumors by Bivalent Chromatin Domains at Initial Diagnosis
Edward Curry, Constanze Zeller, Nahal Masrour, Darren K. Patten, John Gallon, Charlotte S. Wilhelm-Benartzi, Sadaf Ghaem-Maghami, David D. Bowtell and Robert Brown
Cancer Res February 22 2018 DOI: 10.1158/0008-5472.CAN-17-1650

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Genes Predisposed to DNA Hypermethylation during Acquired Resistance to Chemotherapy Are Identified in Ovarian Tumors by Bivalent Chromatin Domains at Initial Diagnosis
Edward Curry, Constanze Zeller, Nahal Masrour, Darren K. Patten, John Gallon, Charlotte S. Wilhelm-Benartzi, Sadaf Ghaem-Maghami, David D. Bowtell and Robert Brown
Cancer Res February 22 2018 DOI: 10.1158/0008-5472.CAN-17-1650
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Cancer Research Online ISSN: 1538-7445
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