Volume 5 Supplement 1

Proceedings of the Birmingham Cancer Epigenetics Conference; Translational Opportunities

Open Access

Genomic analysis reveals epigenetic ‘addiction’ underpinning follicular lymphoma and its transformation – a rationale for targeted epigenetic therapies

  • Jessica Okosun1Email author,
  • Csaba Bödör2,
  • Jun Wang3,
  • Shamzah Araf1,
  • Claude Chelala3 and
  • Jude Fitzgibbon1
Clinical EpigeneticsThe official journal of the Clinical Epigenetics Society20135(Suppl 1):S10

https://doi.org/10.1186/1868-7083-5-S1-S10

Published: 19 August 2013

Follicular lymphoma (FL) continues to pose a clinical challenge with a progressive disease course typified by multiple relapses, eventual resistance to standard therapies and transformation (tFL) in a subset of patients to the more aggressive diffuse large B cell lymphoma (DLBCL).

WGS was performed on 6 paired FL-tFL patients and corresponding germ-lines to understand the clonal dynamics of progression and recurring genetic events in FL. We identified that the dominant pattern of FL evolution to transformation was consistent with the existence of a common origin, an ancestral common progenitor cell (CPC) population. Strikingly, the CPCs were enriched for mutations in chromatin regulatory genes with every case harbouring mutations in MLL2, a histone methyltransferase, concurrent with mutations in other methyltransferases (EZH2, MLL3, PRMT2), acetyltransferases (CREBBP, MEF2B), bromodomain proteins (BRD2, CECR2), core and linker histones. Targeted deep sequencing of EZH2 showed mutations in 27% of cases in an extension cohort of 366 cases, much higher than previously reported. All mutations targeted the catalytic SET domain leading to a gain-of-function thus offering the possibility of using EZH2 inhibitors.

The plethora of genetic mutations in epigenetic regulators in FL shown in this study therefore offers a compelling model disease to strategically test epigenetically-targeted therapies.

Authors’ Affiliations

(1)
Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London
(2)
1st Department of Pathology and Experimental Cancer Research, Semmelweis University
(3)
Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London

Copyright

© Okosun et al; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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