BCL2 mutations are associated with increased risk of transformation and shortened survival in follicular lymphoma

Cristina Correia, Paula A. Schneider, Haiming Dai, Ahmet Dogan, Matthew J. Maurer, Amy K. Church, Anne J Novak, Andrew L Feldman, Xiaosheng Wu, Husheng Ding, X. Wei Meng, James R Cerhan, Susan L Slager, William R. Macon, Thomas Matthew Habermann, Judith E. Karp, Steven D. Gore, Neil Elliot Kay, Diane F Jelinek, Thomas Elmer WitzigGrzegorz S Nowakowski, Scott H Kaufmann

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Abstract

Follicular lymphoma (FL), an indolent neoplasm caused by a t(14;18) chromosomal translocation that juxtaposes the BCL2 gene and immunoglobulin locus, has a variable clinical course and frequently undergoes transformation to an aggressive lymphoma. Although BCL2 mutations have been previously described, their relationship to FL progression remains unclear. In this study, we evaluated the frequency and nature of BCL2 mutations in 2 independent cohorts of grade 1 and 2 FLs, along with the correlation between BCL2 mutations, transformation risk, and survival. The prevalence of BCL2 coding sequence mutations was 12% in FL at diagnosis and 53% at transformation (P < .0001).The presence of these BCL2 mutations at diagnosis correlated with an increased risk of transformation (hazard ratio 3.6; 95% CI, 2.0-6.2; P < .0001) and increased risk of death due to lymphoma (median survival of 9.5 years with BCL2 mutations vs 20.4 years without; P = .012). In a multivariate analysis, BCL2 mutations and high FL international prognostic index were independent risk factors for transformation and death due to lymphoma. Some mutant Bcl-2 proteins exhibited enhanced antiapoptotic capacity in vitro. Accordingly, BCL2 mutations can affect antiapoptotic Bcl-2 function, are associated with increased activation-induced cytidine deaminase expression, and correlate with increased risk of transformation and death due to lymphoma.

Original languageEnglish (US)
Pages (from-to)658-667
Number of pages10
JournalBlood
Volume125
Issue number4
DOIs
StatePublished - Jan 22 2015

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Follicular Lymphoma
Mutation
Lymphoma
Immunoglobulins
Hazards
Genetic Translocation
Immunoglobulin Genes
Genes
Multivariate Analysis
Proteins

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

BCL2 mutations are associated with increased risk of transformation and shortened survival in follicular lymphoma. / Correia, Cristina; Schneider, Paula A.; Dai, Haiming; Dogan, Ahmet; Maurer, Matthew J.; Church, Amy K.; Novak, Anne J; Feldman, Andrew L; Wu, Xiaosheng; Ding, Husheng; Meng, X. Wei; Cerhan, James R; Slager, Susan L; Macon, William R.; Habermann, Thomas Matthew; Karp, Judith E.; Gore, Steven D.; Kay, Neil Elliot; Jelinek, Diane F; Witzig, Thomas Elmer; Nowakowski, Grzegorz S; Kaufmann, Scott H.

In: Blood, Vol. 125, No. 4, 22.01.2015, p. 658-667.

Research output: Contribution to journalArticle

Correia, Cristina ; Schneider, Paula A. ; Dai, Haiming ; Dogan, Ahmet ; Maurer, Matthew J. ; Church, Amy K. ; Novak, Anne J ; Feldman, Andrew L ; Wu, Xiaosheng ; Ding, Husheng ; Meng, X. Wei ; Cerhan, James R ; Slager, Susan L ; Macon, William R. ; Habermann, Thomas Matthew ; Karp, Judith E. ; Gore, Steven D. ; Kay, Neil Elliot ; Jelinek, Diane F ; Witzig, Thomas Elmer ; Nowakowski, Grzegorz S ; Kaufmann, Scott H. / BCL2 mutations are associated with increased risk of transformation and shortened survival in follicular lymphoma. In: Blood. 2015 ; Vol. 125, No. 4. pp. 658-667.
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abstract = "Follicular lymphoma (FL), an indolent neoplasm caused by a t(14;18) chromosomal translocation that juxtaposes the BCL2 gene and immunoglobulin locus, has a variable clinical course and frequently undergoes transformation to an aggressive lymphoma. Although BCL2 mutations have been previously described, their relationship to FL progression remains unclear. In this study, we evaluated the frequency and nature of BCL2 mutations in 2 independent cohorts of grade 1 and 2 FLs, along with the correlation between BCL2 mutations, transformation risk, and survival. The prevalence of BCL2 coding sequence mutations was 12{\%} in FL at diagnosis and 53{\%} at transformation (P < .0001).The presence of these BCL2 mutations at diagnosis correlated with an increased risk of transformation (hazard ratio 3.6; 95{\%} CI, 2.0-6.2; P < .0001) and increased risk of death due to lymphoma (median survival of 9.5 years with BCL2 mutations vs 20.4 years without; P = .012). In a multivariate analysis, BCL2 mutations and high FL international prognostic index were independent risk factors for transformation and death due to lymphoma. Some mutant Bcl-2 proteins exhibited enhanced antiapoptotic capacity in vitro. Accordingly, BCL2 mutations can affect antiapoptotic Bcl-2 function, are associated with increased activation-induced cytidine deaminase expression, and correlate with increased risk of transformation and death due to lymphoma.",
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T1 - BCL2 mutations are associated with increased risk of transformation and shortened survival in follicular lymphoma

AU - Correia, Cristina

AU - Schneider, Paula A.

AU - Dai, Haiming

AU - Dogan, Ahmet

AU - Maurer, Matthew J.

AU - Church, Amy K.

AU - Novak, Anne J

AU - Feldman, Andrew L

AU - Wu, Xiaosheng

AU - Ding, Husheng

AU - Meng, X. Wei

AU - Cerhan, James R

AU - Slager, Susan L

AU - Macon, William R.

AU - Habermann, Thomas Matthew

AU - Karp, Judith E.

AU - Gore, Steven D.

AU - Kay, Neil Elliot

AU - Jelinek, Diane F

AU - Witzig, Thomas Elmer

AU - Nowakowski, Grzegorz S

AU - Kaufmann, Scott H

PY - 2015/1/22

Y1 - 2015/1/22

N2 - Follicular lymphoma (FL), an indolent neoplasm caused by a t(14;18) chromosomal translocation that juxtaposes the BCL2 gene and immunoglobulin locus, has a variable clinical course and frequently undergoes transformation to an aggressive lymphoma. Although BCL2 mutations have been previously described, their relationship to FL progression remains unclear. In this study, we evaluated the frequency and nature of BCL2 mutations in 2 independent cohorts of grade 1 and 2 FLs, along with the correlation between BCL2 mutations, transformation risk, and survival. The prevalence of BCL2 coding sequence mutations was 12% in FL at diagnosis and 53% at transformation (P < .0001).The presence of these BCL2 mutations at diagnosis correlated with an increased risk of transformation (hazard ratio 3.6; 95% CI, 2.0-6.2; P < .0001) and increased risk of death due to lymphoma (median survival of 9.5 years with BCL2 mutations vs 20.4 years without; P = .012). In a multivariate analysis, BCL2 mutations and high FL international prognostic index were independent risk factors for transformation and death due to lymphoma. Some mutant Bcl-2 proteins exhibited enhanced antiapoptotic capacity in vitro. Accordingly, BCL2 mutations can affect antiapoptotic Bcl-2 function, are associated with increased activation-induced cytidine deaminase expression, and correlate with increased risk of transformation and death due to lymphoma.

AB - Follicular lymphoma (FL), an indolent neoplasm caused by a t(14;18) chromosomal translocation that juxtaposes the BCL2 gene and immunoglobulin locus, has a variable clinical course and frequently undergoes transformation to an aggressive lymphoma. Although BCL2 mutations have been previously described, their relationship to FL progression remains unclear. In this study, we evaluated the frequency and nature of BCL2 mutations in 2 independent cohorts of grade 1 and 2 FLs, along with the correlation between BCL2 mutations, transformation risk, and survival. The prevalence of BCL2 coding sequence mutations was 12% in FL at diagnosis and 53% at transformation (P < .0001).The presence of these BCL2 mutations at diagnosis correlated with an increased risk of transformation (hazard ratio 3.6; 95% CI, 2.0-6.2; P < .0001) and increased risk of death due to lymphoma (median survival of 9.5 years with BCL2 mutations vs 20.4 years without; P = .012). In a multivariate analysis, BCL2 mutations and high FL international prognostic index were independent risk factors for transformation and death due to lymphoma. Some mutant Bcl-2 proteins exhibited enhanced antiapoptotic capacity in vitro. Accordingly, BCL2 mutations can affect antiapoptotic Bcl-2 function, are associated with increased activation-induced cytidine deaminase expression, and correlate with increased risk of transformation and death due to lymphoma.

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