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.
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Bouska, A., Zhang, W., Gong, Q. et al. Combined copy number and mutation analysis identifies oncogenic pathways associated with transformation of follicular lymphoma. Leukemia 31, 83–91 (2017). https://doi.org/10.1038/leu.2016.175
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DOI: https://doi.org/10.1038/leu.2016.175
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