title: BCL2 mutations in diffuse large B-cell lymphoma.
abstract: BCL2 is deregulated in diffuse large B-cell lymphoma (DLBCL) by the t(14;18) translocation, gene amplification and/or nuclear factor-κB signaling. RNA-seq data have recently shown that BCL2 is the most highly mutated gene in germinal center B-cell (GCB) DLBCL. We have sequenced BCL2 in 298 primary DLBCL biopsies, 131 additional non-Hodgkin lymphoma biopsies, 24 DLBCL cell lines and 51 germline DNAs. We found frequent BCL2 mutations in follicular lymphoma (FL) and GCB DLBCL, but low levels of BCL2 mutations in activated B-cell DLBCL, mantle cell lymphoma, small lymphocytic leukemia and peripheral T-cell lymphoma. We found no BCL2 mutations in GC centroblasts. Many mutations were non-synonymous; they were preferentially located in the flexible loop domain, with few in BCL2-homology domains. An elevated transition/transversions ratio supports that the mutations result from somatic hypermutation. BCL2 translocations correlate with, and are likely important in acquisition of, additional BCL2 mutations in GCB DLBCL and FL. DLBCL mutations were not independently associated with survival. Although previous studies of BCL2 mutations in FL have reported mutations to result in pseudo-negative BCL2 protein expression, we find this rare in de-novo DLBCL.
authors.affiliation: Canada's Michael Smith Genome Sciences Center, BC Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: J M
authors.initials: JM
authors.lastname: Schuetz
authors.forename: N A
authors.initials: NA
authors.lastname: Johnson
authors.forename: R D
authors.initials: RD
authors.lastname: Morin
authors.forename: D W
authors.initials: DW
authors.lastname: Scott
authors.forename: K
authors.initials: K
authors.lastname: Tan
authors.forename: S
authors.initials: S
authors.lastname: Ben-Nierah
authors.forename: M
authors.initials: M
authors.lastname: Boyle
authors.forename: G W
authors.initials: GW
authors.lastname: Slack
authors.forename: M A
authors.initials: MA
authors.lastname: Marra
authors.forename: J M
authors.initials: JM
authors.lastname: Connors
authors.forename: A R
authors.initials: AR
authors.lastname: Brooks-Wilson
authors.forename: R D
authors.initials: RD
authors.lastname: Gascoyne
mesh_terms: D020732:Cytogenetic Analysis; D006801:Humans; D007124:Immunoenzyme Techniques; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000378:metabolism; D016411:Lymphoma, T-Cell, Peripheral / Q000235:genetics* / Q000378:metabolism; D008479:Mediastinal Neoplasms / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2