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

• Published in: Blood Vol. 125; no. 4; pp. 658 - 667
• Main Authors: 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 M., Karp, Judith E., Gore, Steven D., Kay, Neil E., Jelinek, Diane F., Witzig, Thomas E., Nowakowski, Grzegorz S., Kaufmann, Scott H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.01.2015; American Society of Hematology
• Subjects: Adult; Age Factors; Aged; Aged, 80 and over; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Chromosomes, Human, Pair 14 - genetics; Chromosomes, Human, Pair 14 - metabolism; Chromosomes, Human, Pair 18 - genetics; Chromosomes, Human, Pair 18 - metabolism; Cohort Studies; Cytidine Deaminase - biosynthesis; Cytidine Deaminase - genetics; Disease-Free Survival; Female; Gene Expression Regulation, Enzymologic - genetics; Gene Expression Regulation, Neoplastic - drug effects; Humans; Immunoglobulins - genetics; Immunoglobulins - metabolism; Lymphoid Neoplasia; Lymphoma, Follicular - genetics; Lymphoma, Follicular - metabolism; Lymphoma, Follicular - mortality; Male; Middle Aged; Mutation; Prevalence; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Risk Factors; Survival Rate
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2014-04-571786

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. •BCL2 mutations in FL correlate with activation-induced cytidine deaminase expression and frequently alter the amino acid sequence of the protein.•Mutations in the BCL2 coding sequence at diagnosis are associated with shortened time to transformation and earlier death due to lymphoma.