Upregulation of translational machinery and distinct genetic subgroups characterise hyperdiploidy in multiple myeloma.
Karyotypic instability, including numerical and structural chromosomal aberrations, represents a distinct feature of multiple myeloma (MM). About 40-50% of patients display hyperdiploidy, defined by recurrent trisomies of non-random chromosomes. To molecularly characterise hyperdiploid (H) and nonhyperdiploid (NH) MM, we analysed the gene expression profiles of 66 primary tumours, and used fluorescence in situ hybridisation to investigate the major chromosomal alterations. The differential expression of 225 genes mainly involved in protein biosynthesis, transcriptional machinery and oxidative phosphorylation distinguished the 28 H-MM from the 38 NH-MM cases. The 204 upregulated genes in H-MM mapped mainly to the chromosomes involved in hyperdiploidy, and the 29% upregulated genes in NH-MM mapped to 16q. The identified transcriptional fingerprint was robustly validated on a publicly available gene expression dataset of 64 MM cases; and the global expression modulation of regions on the chromosomes involved in hyperdiploidy was verified using a self-developed non-parametric statistical method. H-MM could be further divided into two distinct molecular and transcriptional entities, characterised by the presence of trisomy 11 and 1q-extracopies/chromosome 13 deletion respectively. These data reinforce the importance of combining molecular cytogenetics and gene expression profiling to define a genomic framework for the study of MM pathogenesis and clinical management.
Agnelli
Luca
L
Centro di Genetica Molecolare ed Espressione Genica, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy.
Fabris
Sonia
S
Bicciato
Silvio
S
Basso
Dario
D
Baldini
Luca
L
Morabito
Fortunato
F
Verdelli
Donata
D
Todoerti
Katia
K
Lambertenghi-Deliliers
Giorgio
G
Lombardi
Luigia
L
Neri
Antonino
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000782:Aneuploidy; D002869:Chromosome Aberrations; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D014176:Protein Biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic; D015854:Up-Regulation
D009363:Neoplasm Proteins