Original Article | Published:

Lymphoma

Combined copy number and mutation analysis identifies oncogenic pathways associated with transformation of follicular lymphoma

Leukemia volume 31, pages 8391 (2017) | Download Citation

Abstract

Follicular lymphoma (FL) is typically an indolent disease, but 30–40% of FL cases transform into an aggressive lymphoma (tFL) with a poor prognosis. To identify the genetic changes that drive this transformation, we sequenced the exomes of 12 cases with paired FL and tFL biopsies and identified 45 recurrently mutated genes in the FL–tFL data set and 39 in the tFL cases. We selected 496 genes of potential importance in transformation and sequenced them in 23 additional tFL cases. Integration of the mutation data with copy-number abnormality (CNA) data provided complementary information. We found recurrent mutations of miR-142, which has not been previously been reported to be mutated in FL/tFL. The genes most frequently mutated in tFL included KMT2D (MLL2), CREBBP, EZH2, BCL2 and MEF2B. Many recurrently mutated genes are involved in epigenetic regulation, the Janus-activated kinase–signal transducer and activator of transcription (STAT) or the nuclear factor-κB pathways, immune surveillance and cell cycle regulation or are TFs involved in B-cell development. Of particular interest are mutations and CNAs affecting S1P-activated pathways through S1PR1 or S1PR2, which likely regulate lymphoma cell migration and survival outside of follicles. Our custom gene enrichment panel provides high depth of coverage for the study of clonal evolution or divergence.

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Acknowledgements

This work was supported by the Lymphoma Research Foundation Follicular Lymphoma initiative (to WCC), Lymphoma SPORE P50CA136411-01-(NCI) (to WCC) and a grant for Global Engagement from the University of Nebraska Foundation (to WCC). The University of Nebraska DNA Sequencing Core receives partial support from the NCRR (1S10RR027754-01, 5P20RR016469, RR018788-08) and the National Institute for General Medical Science (NIGMS) (8P20GM103427, GM103471-09). Research reported in this publication was supported in part by the National Cancer Institute of the National Institutes of Health under award number P30CA033572 and included work performed in the Bioinformatics Core. Thanks to Adam Cornish and Robert J Boissy for initial sequencing analysis assistance.

Author information

Author notes

    • A Bouska
    • , W Zhang
    •  & Q Gong

    These authors contributed equally to this work.

    • T W McKeithan
    •  & W C Chan

    These authors contributed equally to this work.

Affiliations

  1. Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA

    • A Bouska
    • , W Zhang
    • , J Iqbal
    • , K Fu
    •  & T C Greiner
  2. Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA

    • Q Gong
    • , A Scuto
    • , D D Weisenburger
    • , T W McKeithan
    •  & W C Chan
  3. Division of Hematology and Oncology, University of Nebraska Medical Center, Omaha, NE, USA

    • J Vose
  4. Department of Biomedicine, Aarhus University, Aarhus, Denmark

    • M Ludvigsen
  5. Center for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, British Columbia, Canada

    • R D Gascoyne
  6. Institute of Pathology, University of Würzburg, and Comprehensive Cancer Center Mainfranken, Würzburg, Germany

    • A Rosenwald
  7. Department of Clinical Pathology, Robert-Bosch-Krankenhaus, and Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany

    • G Ott
  8. Hematopathology Unit, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain

    • E Campo
  9. Department of Pathology, University of Arizona, Tucson, AZ, USA

    • L M Rimsza
  10. Department of Pathology, University of Toronto, Toronto, Ontario, Canada

    • J Delabie
  11. Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    • E S Jaffe
  12. Oregon Health Sciences Center, Portland, OR, USA

    • R M Braziel
  13. Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada

    • J M Connors
  14. Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, PR China

    • C-I Wu
  15. Department of Ecology and Evolution, University of Chicago, Chicago, IL, USA

    • C-I Wu
  16. Metabolism Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    • L M Staudt
  17. Department of Hematology, Aarhus University Hospital, Aarhus, Denmark

    • F D‘Amore

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Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to W C Chan.

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DOI

https://doi.org/10.1038/leu.2016.175

Supplementary Information accompanies this paper on the Leukemia website (http://www.nature.com/leu)

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