Integrative genomics analyses reveal molecularly distinct subgroups of B-cell chronic lymphocytic leukemia patients with 13q14 deletion.
OBJECTIVE
Chromosome 13q14 deletion occurs in a substantial number of chronic lymphocytic leukemia (CLL) patients and it is believed to play a pathogenetic role. The exact mechanisms involved in this lesion have not yet been fully elucidated because of its heterogeneity and the imprecise knowledge of the implicated genes. This study was addressed to further contribute to the molecular definition of this lesion in CLL.


METHODS
We applied single-nucleotide polymorphism (SNP)-array technology and gene expression profiling data to investigate the 13q14 deletion occurring in a panel of 100 untreated, early-stage (Binet A) patients representative of the major genetics, molecular, and biological features of the disease.


RESULTS
Concordantly with FISH analysis, SNP arrays identified 44 patients with del(13)(q14) including 11 cases with a biallelic deletion. The shorter monoallelic deletion was 635-kb long. The loss of the miR-15a/16-1 cluster occurred in all del(13)(q14) cases except in 2 patients with a monoallelic deletion, who retained both copies. MiR-15a/16 expression was significantly downregulated only in patients with the biallelic loss of the miRNA cluster compared to 13q normal cases. Finally, the natural grouping of SNP profiles by nonnegative matrix factorization algorithm showed that patients could be classified into 2 separate clusters, mainly characterized by short/biallelic versus wide/monoallelic 13q14 deletions. Supervised analyses of expression data showed that specific transcriptional profiles are correlated with these 2 genomic subgroups.


CONCLUSIONS
Overall, our data highlight the presence of 2 distinct molecular types of 13q14 deletions, which may be of clinical relevance in CLL.
Dipartimento di Scienze Mediche, Università di Milano, U.O. Ematologia 1, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Laura
L
Mosca
Sonia
S
Fabris
Marta
M
Lionetti
Katia
K
Todoerti
Luca
L
Agnelli
Fortunato
F
Morabito
Giovanna
G
Cutrona
Adrian
A
Andronache
Serena
S
Matis
Francesco
F
Ferrari
Massimo
M
Gentile
Mauro
M
Spriano
Vincenzo
V
Callea
Gianluca
G
Festini
Stefano
S
Molica
Giorgio Lambertenghi
GL
Deliliers
Silvio
S
Bicciato
Manlio
M
Ferrarini
Antonino
A
Neri
D002872:Chromosome Deletion; D002882:Chromosomes, Human, Pair 13; D016000:Cluster Analysis; D018450:Disease Progression; D023281:Genomics / Q000379:methods*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000145:classification* / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics; D046228:Microarray Analysis / Q000379:methods; D025202:Molecular Diagnostic Techniques / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D018511:Systems Integration
D035683:MicroRNAs