Originally published as JCO Early Release 10.1200/JCO.2005.01.3870 on August 29 2005

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Molecular Classification of Multiple Myeloma: A Distinct Transcriptional Profile Characterizes Patients Expressing CCND1 and Negative for 14q32 Translocations

Luca Agnelli, Silvio Bicciato, Michela Mattioli, Sonia Fabris, Daniela Intini, Donata Verdelli, Luca Baldini, Fortunato Morabito, Vincenzo Callea, Luigia Lombardi, Antonino Neri

From the Unita Operativa (UO) Ematologia 2 and UO Ematologia 1—Centro Trapianti di Midollo, Dipartimento di Scienze Mediche, Ospedale Maggiore Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Università degli Studi di Milano, Milano; Dipartimento di Processi Chimici dell'Ingegneria, Università degli Studi di Padova, Padova; and the Divisione di Ematologia e Centro Trapianto di Midollo, Azienda Ospedaliera Bianchi-Melacrinò-Morelli, Reggio Calabria, Italy

Address reprint requests to Antonino Neri, MD, UO Ematologia 2, Centro G. Marcora, Ospedale Maggiore Policlinico IRCCS, Dipartimento Scienze Mediche, Università degli Studi di Milano, Via Francesco Sforza 35, 20122 Milano, Italy; e-mail: neri.a{at}policlinico.mi.it.

PURPOSE: The deregulation of CCND1, CCND2 and CCND3 genes represents a common event in multiple myeloma (MM). A recently proposed classification grouped MM patients into five classes on the basis of their cyclin D expression profiles and the presence of the main translocations involving the immunoglobulin heavy chain locus (IGH) at 14q32. In this study, we provide a molecular characterization of the identified translocations/cyclins (TC) groups.

MATERIALS AND METHODS: The gene expression profiles of purified plasma cells from 50 MM cases were used to stratify the samples into the five TC classes and identify their transcriptional fingerprints. The cyclin D expression data were validated by means of real-time quantitative polymerase chain reaction analysis; fluorescence in situ hybridization was used to investigate the cyclin D loci arrangements, and to detect the main IGH translocations and the chromosome 13q deletion.

RESULTS: Class-prediction analysis identified 112 probe sets as characterizing the TC1, TC2, TC4 and TC5 groups, whereas the TC3 samples showed heterogeneous phenotypes and no marker genes. The TC2 group, which showed extra copies of the CCND1 locus and no IGH translocations or the chromosome 13q deletion, was characterized by the overexpression of genes involved in protein biosynthesis at the translational level. A meta-analysis of published data sets validated the identified gene expression signatures.

CONCLUSION: Our data contribute to the understanding of the molecular and biologic features of distinct MM subtypes. The identification of a distinctive gene expression pattern in TC2 patients may improve risk stratification and indicate novel therapeutic targets.

Supported by a grant from the Associazione Italiana Ricerca sul Cancro (AIRC) to A.N. and by the Fondazione Assistenza e Studio Malati Ematologici and the Italian Ministry of Health; by Fondo per gli Investimeni della Ricerca de Base Ministero Istruzione Università e Ricerca Grants No. RBNE01TZZ8 and RBAU01935A to S.B.

L.A. and S.B. contributed equally to this study.

Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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