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

A. Bouska, W. Zhang, Q. Gong, J. Iqbal, A. Scuto, J. Vose, M. Ludvigsen, K. Fu, D. D. Weisenburger, T. C. Greiner, R. D. Gascoyne, A. Rosenwald, G. Ott, E. Campo, Lisa M Rimsza, J. Delabie, E. S. Jaffe, R. M. Braziel, J. M. Connors, C. I. WuL. M. Staudt, F. D'Amore, T. W. McKeithan, W. C. Chan

Research output: Contribution to journalArticle

31 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)83-91
Number of pages9
JournalLeukemia
Volume31
Issue number1
DOIs
StatePublished - Jan 1 2017

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Follicular Lymphoma
Mutation
Genes
Lymphoma
Clonal Evolution
Exome
Janus Kinases
Transducers
Epigenomics
Cell Movement
Cell Survival
Cell Cycle
B-Lymphocytes
Biopsy

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Combined copy number and mutation analysis identifies oncogenic pathways associated with transformation of follicular lymphoma. / Bouska, A.; Zhang, W.; Gong, Q.; Iqbal, J.; Scuto, A.; Vose, J.; Ludvigsen, M.; Fu, K.; Weisenburger, D. D.; Greiner, T. C.; Gascoyne, R. D.; Rosenwald, A.; Ott, G.; Campo, E.; Rimsza, Lisa M; Delabie, J.; Jaffe, E. S.; Braziel, R. M.; Connors, J. M.; Wu, C. I.; Staudt, L. M.; D'Amore, F.; McKeithan, T. W.; Chan, W. C.

In: Leukemia, Vol. 31, No. 1, 01.01.2017, p. 83-91.

Research output: Contribution to journalArticle

Bouska, A, Zhang, W, Gong, Q, Iqbal, J, Scuto, A, Vose, J, Ludvigsen, M, Fu, K, Weisenburger, DD, Greiner, TC, Gascoyne, RD, Rosenwald, A, Ott, G, Campo, E, Rimsza, LM, Delabie, J, Jaffe, ES, Braziel, RM, Connors, JM, Wu, CI, Staudt, LM, D'Amore, F, McKeithan, TW & Chan, WC 2017, 'Combined copy number and mutation analysis identifies oncogenic pathways associated with transformation of follicular lymphoma', Leukemia, vol. 31, no. 1, pp. 83-91. https://doi.org/10.1038/leu.2016.175
Bouska, A. ; Zhang, W. ; Gong, Q. ; Iqbal, J. ; Scuto, A. ; Vose, J. ; Ludvigsen, M. ; Fu, K. ; Weisenburger, D. D. ; Greiner, T. C. ; Gascoyne, R. D. ; Rosenwald, A. ; Ott, G. ; Campo, E. ; Rimsza, Lisa M ; Delabie, J. ; Jaffe, E. S. ; Braziel, R. M. ; Connors, J. M. ; Wu, C. I. ; Staudt, L. M. ; D'Amore, F. ; McKeithan, T. W. ; Chan, W. C. / Combined copy number and mutation analysis identifies oncogenic pathways associated with transformation of follicular lymphoma. In: Leukemia. 2017 ; Vol. 31, No. 1. pp. 83-91.
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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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T1 - Combined copy number and mutation analysis identifies oncogenic pathways associated with transformation of follicular lymphoma

AU - Bouska, A.

AU - Zhang, W.

AU - Gong, Q.

AU - Iqbal, J.

AU - Scuto, A.

AU - Vose, J.

AU - Ludvigsen, M.

AU - Fu, K.

AU - Weisenburger, D. D.

AU - Greiner, T. C.

AU - Gascoyne, R. D.

AU - Rosenwald, A.

AU - Ott, G.

AU - Campo, E.

AU - Rimsza, Lisa M

AU - Delabie, J.

AU - Jaffe, E. S.

AU - Braziel, R. M.

AU - Connors, J. M.

AU - Wu, C. I.

AU - Staudt, L. M.

AU - D'Amore, F.

AU - McKeithan, T. W.

AU - Chan, W. C.

PY - 2017/1/1

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N2 - 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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