title: BCL2 mutations are associated with increased risk of transformation and shortened survival in follicular lymphoma.
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.
authors.affiliation: Division of Oncology Research, Department of Oncology.
authors.forename: Cristina
authors.initials: C
authors.lastname: Correia
authors.affiliation: Division of Oncology Research, Department of Oncology.
authors.forename: Paula A
authors.initials: PA
authors.lastname: Schneider
authors.affiliation: Division of Oncology Research, Department of Oncology.
authors.forename: Haiming
authors.initials: H
authors.lastname: Dai
authors.affiliation: Division of Hematopathology, Department of Laboratory Medicine and Pathology.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Dogan
authors.affiliation: Division of Biomedical Statistics and Bioinformatics, Department of Health Sciences Research.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Maurer
authors.affiliation: Division of Hematology, Department of Medicine.
authors.forename: Amy K
authors.initials: AK
authors.lastname: Church
authors.affiliation: Division of Hematology, Department of Medicine.
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Novak
authors.affiliation: Division of Hematopathology, Department of Laboratory Medicine and Pathology.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Feldman
authors.affiliation: Department of Immunology, and.
authors.forename: Xiaosheng
authors.initials: X
authors.lastname: Wu
authors.affiliation: Division of Oncology Research, Department of Oncology.
authors.forename: Husheng
authors.initials: H
authors.lastname: Ding
authors.affiliation: Division of Oncology Research, Department of Oncology.
authors.forename: X Wei
authors.initials: XW
authors.lastname: Meng
authors.affiliation: Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN; and.
authors.forename: James R
authors.initials: JR
authors.lastname: Cerhan
authors.affiliation: Division of Biomedical Statistics and Bioinformatics, Department of Health Sciences Research.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Slager
authors.affiliation: Division of Hematopathology, Department of Laboratory Medicine and Pathology.
authors.forename: William R
authors.initials: WR
authors.lastname: Macon
authors.affiliation: Division of Hematology, Department of Medicine.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Habermann
authors.affiliation: Division of Hematological Malignancies, Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, MD.
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
authors.affiliation: Division of Hematological Malignancies, Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, MD.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Gore
authors.affiliation: Division of Hematology, Department of Medicine.
authors.forename: Neil E
authors.initials: NE
authors.lastname: Kay
authors.affiliation: Division of Hematology, Department of Medicine, Department of Immunology, and.
authors.forename: Diane F
authors.initials: DF
authors.lastname: Jelinek
authors.affiliation: Division of Hematology, Department of Medicine.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Witzig
authors.affiliation: Division of Hematology, Department of Medicine.
authors.forename: Grzegorz S
authors.initials: GS
authors.lastname: Nowakowski
authors.affiliation: Division of Oncology Research, Department of Oncology, Division of Hematology, Department of Medicine.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics / Q000378:metabolism; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D003564:Cytidine Deaminase / Q000096:biosynthesis / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism; D008224:Lymphoma, Follicular / Q000235:genetics* / Q000378:metabolism / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015995:Prevalence; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D015996:Survival Rate
chemical_list: D007136:Immunoglobulins; D019253:Proto-Oncogene Proteins c-bcl-2; D003564:Cytidine Deaminase