 Leukemia & Lymphoma, 2013; Early Online: 1–7 © 2013 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2013.764416 * hese authors contributed equally to this manuscript. Correspondence: Roman Hajek, Kamenice 5, 62500 Brno, Czech Republic. Tel: + 420773242892. Fax: +420549494340. E-mail: roman.hajek@fno.cz (Received 26 July 2012; revised 3 December 2012; accepted 2 January 2013) ORIGINAL ARTICLE: CLINICAL Molecular heterogeneity and centrosome-associated genes in multiple myeloma Fedor Kryukov 1 * , Pavel Nemec 1 * , Elena Dementyeva 1 * , Lenka Kubiczkova 1 , Ivana Ihnatova 2 , Eva Budinska 2 , Jiri Jarkovsky 1,2 , Sabina Sevcikova 1,5 , Petr Kuglik 1,3 & Roman Hajek 1,4,5 1 Babak Myeloma Group, Department of Pathological Physiology and 2 Institute of Biostatistics and Analyses, Faculty of Medicine, Masaryk University, Brno, Czech Republic, 3 Integrated Laboratory of Molecular Cytogenetics, Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic, and 4 Department of Internal Medicine – Hematooncology and 5 Department of Clinical Hematology, University Hospital Brno, Czech Republic Introduction Multiple myeloma (MM) is an incurable plasma cell malig- nancy, a heterogeneous disorder with incompletely under- stood molecular defects and variable clinical manifestations. he genome of malignant plasma cells is extremely unstable, characterized by a combination of complex structural and numerical abnormalities. hese abnormalities serve as the background for a large variability in the clinical course and outcome of patients with MM [1]. he presence of these genetic and clinical heterogeneities can be explained by a multistep process of malignant trans- formation, which is acknowledged to be associated with cell cycle deregulation. A large number of cancer-associated proteins involved in the cell cycle, DNA repair, chaperoning and nucleocytoplasmic transport, etc. are involved in the control of centrosome number, duplication and centrosome formation, and have been implicated as the origin of cen- trosome abnormalities in cancer [2]. Centrosome abnor- malities, of which centrosome ampliication (CA) is the most prominent, frequently occur in various malignancies [3]. Centrosomes are small cell organelles composed of two cylindrically shaped centrioles surrounded by pericentriolar material in a normal mitotic cell. he centrosome function is to direct mitotic bipolar spindles in a process that is essential for accurate chromosome segregation during mitosis. Cen- trosomes duplicate once per cell cycle, and each daughter cell receives one centrosome upon cytokinesis [4,5]. How- ever, loss of mechanisms controlling numerical integrity of centrosomes leads to centrosome ampliication (presence of more than two centrosomes), primarily via overduplication or fragmentation of centrosomes, resulting in defective mito- sis and consequential chromosome instability [6]. CA is common in all stages of plasma cell neoplasia [7]. Centrosome ampliication is therefore an early event in MM and can serve as a source of genomic instability [8,9]. We assume that centrosome-related genes can reveal the molecular background of clinical heterogeneity and further allow us to stratify patients with MM into groups with divergent prognoses. his complex genetic screening will make it possi- ble to reveal the reason for heterogeneity within already estab- lished risk stratiication groups. In this study, we performed gene expression proiling, focusing on centrosome-related genes in order to determine the molecular heterogeneity characteristics for patients with MM. Design and methods Patients and sample preparation A total of 73 patients with MM enrolled in University Hospital Brno, Czech Republic, University Hospital Olomouc, Czech Abstract In multiple myeloma (MM), biologic complexity originates from complex oncogenic processes involving somatic acquisition of myriad mutations coupled with genetic variability within the host. This pathogenically determined molecular heterogeneity predetermines clinical intricacy. In this study, we performed gene expression proiling (GEP) focusing on centrosome-related genes to determine the molecular heterogeneity for centrosome- associated genes in patients with MM. We identiied the gene pattern with an impact on myeloma pathogenesis. According to expression tendency, three subgroups of patients were established. The revealed molecular signature is related to overall survival as well as to clinical parameters and the International Staging System. Associations with integral clinical parameters allow us to proclaim the impact of the revealed functional gene set in MM genesis. We believe that future investigation of this molecular heterogeneity will help to reine the broad prognoses ofered by present-day established systems and even sub-stratify them. Keywords: Multiple myeloma, centrosome abnormalities, gene expression proile Leuk Lymphoma Downloaded from informahealthcare.com by University of Southern California on 02/27/13 For personal use only.