title: The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma.
abstract: We used gene expression profiling to establish a molecular diagnosis of mantle cell lymphoma (MCL), to elucidate its pathogenesis, and to predict the length of survival of these patients. An MCL gene expression signature defined a large subset of MCLs that expressed cyclin D1 and a novel subset that lacked cyclin D1 expression. A precise measurement of tumor cell proliferation, provided by the expression of proliferation signature genes, identified patient subsets that differed by more than 5 years in median survival. Differences in cyclin D1 mRNA abundance synergized with INK4a/ARF locus deletions to dictate tumor proliferation rate and survival. We propose a quantitative model of the aberrant cell cycle regulation in MCL that provides a rationale for the design of cell cycle inhibitor therapy in this malignancy.
authors.affiliation: The Lymphoma/Leukemia Molecular Profiling Project, National Cancer Institute/NIH, Bethesda, MD, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: George
authors.initials: G
authors.lastname: Wright
authors.forename: Adrian
authors.initials: A
authors.lastname: Wiestner
authors.forename: Wing C
authors.initials: WC
authors.lastname: Chan
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Connors
authors.forename: Elias
authors.initials: E
authors.lastname: Campo
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Grogan
authors.forename: H Konrad
authors.initials: HK
authors.lastname: Muller-Hermelink
authors.forename: Erlend B
authors.initials: EB
authors.lastname: Smeland
authors.forename: Michael
authors.initials: M
authors.lastname: Chiorazzi
authors.forename: Jena M
authors.initials: JM
authors.lastname: Giltnane
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Hurt
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Lauren
authors.initials: L
authors.lastname: Averett
authors.forename: Sarah
authors.initials: S
authors.lastname: Henrickson
authors.forename: Liming
authors.initials: L
authors.lastname: Yang
authors.forename: John
authors.initials: J
authors.lastname: Powell
authors.forename: Wyndham H
authors.initials: WH
authors.lastname: Wilson
authors.forename: Elaine S
authors.initials: ES
authors.lastname: Jaffe
authors.forename: Richard
authors.initials: R
authors.lastname: Simon
authors.forename: Richard D
authors.initials: RD
authors.lastname: Klausner
authors.forename: Emilio
authors.initials: E
authors.lastname: Montserrat
authors.forename: Francesc
authors.initials: F
authors.lastname: Bosch
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Greiner
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Weisenburger
authors.forename: Warren G
authors.initials: WG
authors.lastname: Sanger
authors.forename: Bhavana J
authors.initials: BJ
authors.lastname: Dave
authors.forename: James C
authors.initials: JC
authors.lastname: Lynch
authors.forename: Julie
authors.initials: J
authors.lastname: Vose
authors.forename: James O
authors.initials: JO
authors.lastname: Armitage
authors.forename: Richard I
authors.initials: RI
authors.lastname: Fisher
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Miller
authors.forename: Michael
authors.initials: M
authors.lastname: LeBlanc
authors.forename: German
authors.initials: G
authors.lastname: Ott
authors.forename: Stein
authors.initials: S
authors.lastname: Kvaloy
authors.forename: Harald
authors.initials: H
authors.lastname: Holte
authors.forename: Jan
authors.initials: J
authors.lastname: Delabie
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
mesh_terms: D020727:ADP-Ribosylation Factors / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D019938:Cyclin D1 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D004268:DNA-Binding Proteins; D005260:Female; D020869:Gene Expression Profiling; D052138:Genes, Neoplasm / Q000235:genetics*; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D020506:Untranslated Regions / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D020506:Untranslated Regions; D019938:Cyclin D1; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D020727:ADP-Ribosylation Factors