Summary
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.
Pediatric acute lymphoblastic leukemia (ALL) comprises genetically distinct subtypes. However, 25% of cases still lack defined genetic hallmarks. To identify genomic aberrancies in childhood ALL patients nonclassifiable by conventional methods, we performed a single nucleotide polymorphisms (SNP) array-based genomic analysis of leukemic cells from 29 cases. The vast majority of cases analyzed (19/24, 79%) showed genomic abnormalities; at least one of them affected either genes involved in cell cycle regulation or in B-cell development. The most relevant abnormalities were CDKN2A/9p21 deletions (7/24, 29%), ETV6 (TEL)/12p13 deletions (3/24, 12%), and intrachromosomal amplifications of chromosome 21 (iAMP21) (3/24, 12%). To identify variation in expression of genes directly or indirectly affected by recurrent genomic alterations, we integrated genomic and gene expression data generated by microarray analyses of the same samples. SMAD1 emerged as a down-regulated gene in CDKN2A homozygous deleted cases compared with nondeleted. The JAG1 gene, encoding the Jagged 1 ligand of the Notch receptor, was among a list of differentially expressed (up-regulated) genes in ETV6-deleted cases. Our findings demonstrate that integration of genomic analysis and gene expression profiling can identify genetic lesions undetected by routine methods and potential novel pathways involved in B-progenitor ALL pathogenesis.
Abnormalities of chromosome 1 are among the mostfrequent chromosomal alterations in multiple myeloma(MM), being found in up to 45% of patients.1,2 It has beenreported that the short arm of chromosome 1 is preferentiallyinvolved in deletions, whereas the long arm is associatedwith amplification. The gain of 1q (1q/gain) can occur asisochromosomes, duplications or jumping translocations. Ithas been widely reported that 1q/gain MM patients arecharacterized by complex karyotypes and aggressive disease,and a close association with poor-risk genetic features, suchas chromosome 13q deletion (D13) and the t(4;14) translocationhas also been described.1 It has been recentlydemonstrated that gains/amplification of 1q21 increase asthe condition goes from smoldering to overt MM, thussuggesting that these regions contain critical genes for diseaseprogression.2 These findings along with the limited informationconcerning specific transcriptional profiles prompted us tomolecularly characterize 1q/gain MMs by FISH and microarrayanalyses
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