title: Genetic profiling ofMYCandBCL2in diffuse large B-cell lymphoma determines cell-of-origin-specific clinical impact.
abstract: The clinical significance ofMYCandBCL2genetic alterations in diffuse large B-cell lymphoma (DLBCL), apart from translocations, has not been comprehensively investigated using high-resolution genetic assays. In this study, we profiledMYCandBCL2genetic alterations using next-generation sequencing and high-resolution SNP array in 347 de novo DLBCL cases treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) at the British Columbia Cancer Agency. Cell-of-origin (COO) subtype was determined by Lymph2Cx digital gene expression profiling. We showed that the incidence ofMYC/BCL2genetic alterations and their clinical significance were largely dependent on COO subtypes. It is noteworthy that the presence ofBCL2gain/amplification is significantly associated with poor outcome in activated B-cell-like andBCL2translocation with poor outcome in germinal center B-cell subtypes, respectively. Both have prognostic significance independent of MYC/BCL2 dual expression and the International Prognostic Index (IPI). Furthermore, the combination ofBCL2genetic alterations with IPI identifies markedly worse prognostic groups within individual COO subtypes. Thus, high-resolution genomic assays identify extremely poor prognostic groups within each COO subtype on the basis ofBCL2genetic status in this large, uniformly R-CHOP-treated population-based cohort of DLBCL. These results suggest COO subtype-specific biomarkers based onBCL2genetic alterations can be used to risk-stratify patients with DLBCL treated with immunochemotherapy.
authors.affiliation: Centre for Lymphoid Cancer.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ennishi
authors.affiliation: Centre for Lymphoid Cancer.
authors.forename: Anja
authors.initials: A
authors.lastname: Mottok
authors.affiliation: Centre for Lymphoid Cancer.
authors.forename: Susana
authors.initials: S
authors.lastname: Ben-Neriah
authors.affiliation: Centre for Lymphoid Cancer.
authors.forename: Hennady P
authors.initials: HP
authors.lastname: Shulha
authors.affiliation: Centre for Lymphoid Cancer.
authors.forename: Pedro
authors.initials: P
authors.lastname: Farinha
authors.affiliation: Centre for Lymphoid Cancer.
authors.forename: Fong Chun
authors.initials: FC
authors.lastname: Chan
authors.affiliation: Centre for Lymphoid Cancer.
authors.forename: Barbara
authors.initials: B
authors.lastname: Meissner
authors.affiliation: Centre for Lymphoid Cancer.
authors.forename: Merrill
authors.initials: M
authors.lastname: Boyle
authors.affiliation: Centre for Lymphoid Cancer.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Hother
authors.affiliation: Centre for Lymphoid Cancer.
authors.forename: Robert
authors.initials: R
authors.lastname: Kridel
authors.affiliation: Molecular Oncology, and.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lai
authors.affiliation: Molecular Oncology, and.
authors.forename: Saeed
authors.initials: S
authors.lastname: Saberi
authors.affiliation: Molecular Oncology, and.
authors.forename: Ali
authors.initials: A
authors.lastname: Bashashati
authors.affiliation: Molecular Oncology, and.
authors.forename: Sohrab P
authors.initials: SP
authors.lastname: Shah
authors.affiliation: Genome Science Centre, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Morin
authors.affiliation: Genome Science Centre, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
authors.affiliation: Centre for Lymphoid Cancer.
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Savage
authors.affiliation: Centre for Lymphoid Cancer.
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Sehn
authors.affiliation: Centre for Lymphoid Cancer.
authors.forename: Christian
authors.initials: C
authors.lastname: Steidl
authors.affiliation: Centre for Lymphoid Cancer.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Connors
authors.affiliation: Centre for Lymphoid Cancer.
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.affiliation: Centre for Lymphoid Cancer.
authors.forename: David W
authors.initials: DW
authors.lastname: Scott
mesh_terms: D056915:DNA Copy Number Variations / Q000235:genetics; D018450:Disease Progression; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc