title: Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation.
abstract: Follicular lymphoma (FL) is incurable with conventional therapies and has a clinical course typified by multiple relapses after therapy. These tumors are genetically characterized by B-cell leukemia/lymphoma 2 (BCL2) translocation and mutation of genes involved in chromatin modification. By analyzing purified tumor cells, we identified additional novel recurrently mutated genes and confirmed mutations of one or more chromatin modifier genes within 96% of FL tumors and two or more in 76% of tumors. We defined the hierarchy of somatic mutations arising during tumor evolution by analyzing the phylogenetic relationship of somatic mutations across the coding genomes of 59 sequentially acquired biopsies from 22 patients. Among all somatically mutated genes, CREBBP mutations were most significantly enriched within the earliest inferable progenitor. These mutations were associated with a signature of decreased antigen presentation characterized by reduced transcript and protein abundance of MHC class II on tumor B cells, in line with the role of CREBBP in promoting class II transactivator (CIITA)-dependent transcriptional activation of these genes. CREBBP mutant B cells stimulated less proliferation of T cells in vitro compared with wild-type B cells from the same tumor. Transcriptional signatures of tumor-infiltrating T cells were indicative of reduced proliferation, and this corresponded to decreased frequencies of tumor-infiltrating CD4 helper T cells and CD8 memory cytotoxic T cells. These observations therefore implicate CREBBP mutation as an early event in FL evolution that contributes to immune evasion via decreased antigen presentation.
authors.affiliation: Division of Oncology, Center for Cancer Systems Biology, arasha@stanford.edu michael.green@unmc.edu.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Green
authors.affiliation: Division of Oncology.
authors.forename: Shingo
authors.initials: S
authors.lastname: Kihira
authors.affiliation: Division of Oncology.
authors.forename: Chih Long
authors.initials: CL
authors.lastname: Liu
authors.affiliation: Division of Oncology, Division of Radiology.
authors.forename: Ramesh V
authors.initials: RV
authors.lastname: Nair
authors.affiliation: Department of Computer Science, and.
authors.forename: Raheleh
authors.initials: R
authors.lastname: Salari
authors.affiliation: Center for Cancer Systems Biology, Division of Radiology.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Gentles
authors.affiliation: Division of Oncology.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Irish
authors.affiliation: Stanford Cancer Institute, Department of Medicine, Stanford University, Stanford, CA 94305;
authors.forename: Henning
authors.initials: H
authors.lastname: Stehr
authors.affiliation: Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, Campus M. de Unamuno s/n, Consejo Superior de Investigaciones Cientificas/Universidad de Salamanca, Salamanca 37007, Spain; Institute of Biomedical Research of Salamanca, Salamanca 37007, Spain; and.
authors.forename: Carolina
authors.initials: C
authors.lastname: Vicente-Dueñas
authors.affiliation: Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, Campus M. de Unamuno s/n, Consejo Superior de Investigaciones Cientificas/Universidad de Salamanca, Salamanca 37007, Spain; Institute of Biomedical Research of Salamanca, Salamanca 37007, Spain; and.
authors.forename: Isabel
authors.initials: I
authors.lastname: Romero-Camarero
authors.affiliation: Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, Campus M. de Unamuno s/n, Consejo Superior de Investigaciones Cientificas/Universidad de Salamanca, Salamanca 37007, Spain; Institute of Biomedical Research of Salamanca, Salamanca 37007, Spain; and.
authors.forename: Isidro
authors.initials: I
authors.lastname: Sanchez-Garcia
authors.affiliation: Center for Cancer Systems Biology, Division of Radiology.
authors.forename: Sylvia K
authors.initials: SK
authors.lastname: Plevritis
authors.affiliation: Department of Pathology, Stanford University, Stanford, CA 94305.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Arber
authors.affiliation: Department of Computer Science, and.
authors.forename: Serafim
authors.initials: S
authors.lastname: Batzoglou
authors.affiliation: Division of Oncology, Center for Cancer Systems Biology, Stanford Cancer Institute, Department of Medicine, Stanford University, Stanford, CA 94305;
authors.forename: Ronald
authors.initials: R
authors.lastname: Levy
authors.affiliation: Division of Oncology, Center for Cancer Systems Biology, Stanford Cancer Institute, Department of Medicine, Stanford University, Stanford, CA 94305; arasha@stanford.edu michael.green@unmc.edu.
authors.forename: Ash A
authors.initials: AA
authors.lastname: Alizadeh
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology*; D050882:CREB-Binding Protein / Q000235:genetics; D002843:Chromatin / Q000378:metabolism; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D008224:Lymphoma, Follicular / Q000235:genetics* / Q000276:immunology; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000473:pathology*; D016133:Polymerase Chain Reaction
chemical_list: D002843:Chromatin; D000949:Histocompatibility Antigens Class II; D050882:CREB-Binding Protein; C494363:CREBBP protein, human
keywords: CREBBP; antigen presentation; exome; hierarchy; lymphoma