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Integrative genomic analysis reveals distinct transcriptional and genetic features associated with chromosome 13 deletion in multiple myeloma

From the Centro di Genetica Molecolare ed Espressione Genica, U.O. Ematologia 1, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano, Italy (LA, SF, DI, DV, LL, AN); Dipartimento dei Processi Chimici dell’Ingegneria, Università degli Studi, Padova, Italy (SB, AC); Dipartimento di Scienze Mediche, Università degli Studi di Milano, Italy (LB, GL-D, AN); U.O. Ematologia, A.O. "Annunziata", Cosenza, Italy (FM): Laboratory of Experimental Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland (FB)

Correspondence: Antonino Neri, M.D., Centro di Genetica Molecolare ed Espressione Genica, Padiglione "G. Marcora", Fondazione IRCCS Ospedale Policlinico, via Francesco Sforza 35, 20122 Milan, Italy. E-mail neri.a{at}policlinico.mi.it

Background and Objectives: The chromosome 13 deletion (¹³) is one of the most frequent chromosomal alterations in multiple myeloma (MM). ¹³ is associated with an unfavorable prognosis, although there is increasing agreement that its prognostic relevance must be related to the ploidy status and the presence of different chromosomal translocations. The aim of this study was to provide a comprehensive analysis of the transcriptional features of ¹³ in MM.

Design and Methods: Highly purified plasma cells from 80 newly diagnosed MM patients were characterized by means of fluorescence in situ hybridization (FISH) and high-density oligonucleotide microarray for gene expression profiling and chromosomal alterations.

Results: We identified 67 differentially expressed genes in the patients with and without the chromosome 13 deletion, all of which were downregulated in the cases with ¹³: 44 mapped along the whole chromosome 13, seven on chromosome 11 and three on chromosome 19. Functional analyses of the selected genes indicated their involvement in protein biosynthesis, ubiquitination and transcriptional regulation. An integrative genomic approach based on regional analyses of the gene expression data identified distinct chromosomal regions whose global expression modulation could differentiate ¹³-positive cases, in particular the upregulation of 1q21-1q42 and the downregulation of 19p and almost the entire chromosome 11. FISH analyses confirmed the close relationship between ¹³-positivity and the presence of extra copies of 1q21-1q42 (p=6 x 10^–4) or the absence of chromosome 11 and 19 trisomy (p=5 x 10^–4).

Interpretation and Conclusions: Our results indicate that distinct types of chromosomal aberrations are closely related to the transcriptional profiles of ¹³-positive cases, suggesting that the contribution of ¹³ to the malignancy should be considered together with associated abnormalities.

Key words: multiple myeloma, chromosome 13 deletion, gene expression profiling, genome wide profiling, integrative genomics.