title: Cell of origin of transformed follicular lymphoma.
abstract: Follicular lymphoma (FL) is an indolent disease but transforms in 2% to 3% of patients per year into aggressive, large cell lymphoma, a critical event in the course of the disease associated with increased lymphoma-related mortality. Early transformation cannot be accurately predicted at the time of FL diagnosis and the biology of transformed FL (TFL) is poorly understood. Here, we assembled a cohort of 126 diagnostic FL specimens including 40 patients experiencing transformation (<5 years) and 86 patients not experiencing transformation for at least 5 years. In addition, we assembled an overlapping cohort of 155 TFL patients, including 114 cases for which paired samples were available, and assessed temporal changes of routinely available biomarkers, outcome after transformation, as well as molecular subtypes of TFL. We report that the expression of IRF4 is an independent predictor of early transformation (Hazard ratio, 13.3; P < .001). We also show that composite histology at the time of transformation predicts favorable prognosis. Moreover, applying the Lymph2Cx digital gene expression assay for diffuse large B-cell lymphoma (DLBCL) cell-of-origin determination to 110 patients with DLBCL-like TFL, we demonstrate that TFL is of the germinal-center B-cell-like subtype in the majority of cases (80%) but that a significant proportion of cases is of the activated B-cell-like (ABC) subtype (16%). These latter cases are commonly negative for BCL2 translocation and arise preferentially from BCL2 translocation-negative and/or IRF4-expressing FLs. Our study demonstrates the existence of molecular heterogeneity in TFL as well as its relationship to the antecedent FL.
authors: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, and.
authors: Robert
authors: R
authors: Kridel
authors: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, and.
authors: Anja
authors: A
authors: Mottok
authors: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, and.
authors: Pedro
authors: P
authors: Farinha
authors: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada;
authors: Susana
authors: S
authors: Ben-Neriah
authors: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada;
authors: Daisuke
authors: D
authors: Ennishi
authors: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada;
authors: Yvonne
authors: Y
authors: Zheng
authors: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada;
authors: Elizabeth A
authors: EA
authors: Chavez
authors: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada;
authors: Hennady P
authors: HP
authors: Shulha
authors: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada;
authors: King
authors: K
authors: Tan
authors: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada;
authors: Fong Chun
authors: FC
authors: Chan
authors: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada;
authors: Merrill
authors: M
authors: Boyle
authors: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada;
authors: Barbara
authors: B
authors: Meissner
authors: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada;
authors: Adele
authors: A
authors: Telenius
authors: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada; Department of Medicine, University of British Columbia, Vancouver, BC, Canada;
authors: Laurie H
authors: LH
authors: Sehn
authors: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; and.
authors: Marco A
authors: MA
authors: Marra
authors: Department of Pathology and Laboratory Medicine, and Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada.
authors: Sohrab P
authors: SP
authors: Shah
authors: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, and.
authors: Christian
authors: C
authors: Steidl
authors: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada; Department of Medicine, University of British Columbia, Vancouver, BC, Canada;
authors: Joseph M
authors: JM
authors: Connors
authors: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada; Department of Medicine, University of British Columbia, Vancouver, BC, Canada;
authors: David W
authors: DW
authors: Scott
authors: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, and.
authors: Randy D
authors: RD
authors: Gascoyne
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics; D051925:CD79 Antigens / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D005260:Female; D018858:Germinal Center / Q000378:metabolism / Q000473:pathology; D006162:Guanylate Cyclase / Q000235:genetics; D006801:Humans; D008224:Lymphoma, Follicular / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*
chemical_list: C000595707:BCL2 protein, human; D053468:CARD Signaling Adaptor Proteins; D051925:CD79 Antigens; C497883:CD79B protein, human; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D019253:Proto-Oncogene Proteins c-bcl-2; C426242:CARD11 protein, human; D006162:Guanylate Cyclase