title: Integrative analysis reveals an outcome-associated and targetable pattern of p53 and cell cycle deregulation in diffuse large B cell lymphoma.
abstract: Diffuse large B cell lymphoma (DLBCL) is a clinically and biologically heterogeneous disease with a high proliferation rate. By integrating copy number data with transcriptional profiles and performing pathway analysis in primary DLBCLs, we identified a comprehensive set of copy number alterations (CNAs) that decreased p53 activity and perturbed cell cycle regulation. Primary tumors either had multiple complementary alterations of p53 and cell cycle components or largely lacked these lesions. DLBCLs with p53 and cell cycle pathway CNAs had decreased abundance of p53 target transcripts and increased expression of E2F target genes and the Ki67 proliferation marker. CNAs of the CDKN2A-TP53-RB-E2F axis provide a structural basis for increased proliferation in DLBCL, predict outcome with current therapy, and suggest targeted treatment approaches.
authors.affiliation: Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Monti
authors.forename: Bjoern
authors.initials: B
authors.lastname: Chapuy
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Takeyama
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.forename: Yansheng
authors.initials: Y
authors.lastname: Hao
authors.forename: Kelly T
authors.initials: KT
authors.lastname: Yeda
authors.forename: Haig
authors.initials: H
authors.lastname: Inguilizian
authors.forename: Craig
authors.initials: C
authors.lastname: Mermel
authors.forename: Treeve
authors.initials: T
authors.lastname: Currie
authors.forename: Ahmet
authors.initials: A
authors.lastname: Dogan
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Habermann
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Shipp
mesh_terms: D002453:Cell Cycle / Q000235:genetics*; D049109:Cell Proliferation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D056915:DNA Copy Number Variations; D050684:E2F Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D020869:Gene Expression Profiling; D019942:Genes, p16; D016158:Genes, p53; D006801:Humans; D019394:Ki-67 Antigen / Q000096:biosynthesis; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008969:Molecular Sequence Data; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D050684:E2F Transcription Factors; D019394:Ki-67 Antigen; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53