title: Point mutations and genomic deletions in CCND1 create stable truncated cyclin D1 mRNAs that are associated with increased proliferation rate and shorter survival.
abstract: A gene expression signature of tumor proliferation rate in mantle cell lymphoma (MCL) is an overriding molecular predictor of the length of survival following diagnosis. Many strongly proliferative MCL tumors have exceptionally high cyclin D1 mRNA levels and preferentially express short cyclin D1 mRNA isoforms. We demonstrate here that these short mRNAs are cyclin D1a isoforms with truncated 3'UTRs, not alternatively spliced cyclin D1b mRNA isoforms. Among 15 MCL tumors with truncated cyclin D1 mRNAs, 7 had genomic deletions in the CCND1 3'UTR region. In 3 others, CCND1 contained point mutations that created premature polyadenylation signals, giving rise to 1.5-kb mRNAs lacking most of the 3'UTR. Both types of genomic alteration created transcripts lacking mRNA destabilization elements present in the wild-type cyclin D1a mRNA. Premature polyadenylation due to a 3'UTR mutation also was present in the Z-138 MCL cell line, which expressed both truncated and full-length cyclin D1a mRNAs. In these cells, the half-life of the short cyclin D1a mRNA was much longer than that of the full-length mRNA. We conclude that alterations of CCND1 3'UTR structure can significantly increase its oncogenic effect and worsen the clinical course of MCL patients.
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Wiestner
authors.forename: Mahsa
authors.initials: M
authors.lastname: Tehrani
authors.forename: Michael
authors.initials: M
authors.lastname: Chiorazzi
authors.forename: George
authors.initials: G
authors.lastname: Wright
authors.forename: Federica
authors.initials: F
authors.lastname: Gibellini
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Nakayama
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: H Konrad
authors.initials: HK
authors.lastname: Muller-Hermelink
authors.forename: German
authors.initials: G
authors.lastname: Ott
authors.forename: Wing C
authors.initials: WC
authors.lastname: Chan
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Greiner
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Weisenburger
authors.forename: Julie
authors.initials: J
authors.lastname: Vose
authors.forename: James O
authors.initials: JO
authors.lastname: Armitage
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Connors
authors.forename: Elias
authors.initials: E
authors.lastname: Campo
authors.forename: Emilio
authors.initials: E
authors.lastname: Montserrat
authors.forename: Francesc
authors.initials: F
authors.lastname: Bosch
authors.forename: Erlend B
authors.initials: EB
authors.lastname: Smeland
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: Richard I
authors.initials: RI
authors.lastname: Fisher
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Grogan
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Miller
authors.forename: Wyndham H
authors.initials: WH
authors.lastname: Wilson
authors.forename: Elaine S
authors.initials: ES
authors.lastname: Jaffe
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
mesh_terms: D020413:3' Untranslated Regions; D000970:Antineoplastic Agents / Q000494:pharmacology; D049109:Cell Proliferation; D056741:Cyclin D; D016213:Cyclins / Q000235:genetics* / Q000502:physiology*; D003609:Dactinomycin / Q000494:pharmacology; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000401:mortality*; D009154:Mutation; D017354:Point Mutation; D026723:Polyadenylation; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D020413:3' Untranslated Regions; D000970:Antineoplastic Agents; D056741:Cyclin D; D016213:Cyclins; D020033:Protein Isoforms; D012333:RNA, Messenger; D003609:Dactinomycin