Integrative genomics analyses reveal molecularly distinct subgroups of B-cell chronic lymphocytic leukemia patients with 13q14 deletion

Purpose: 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. Experimental Design: We applied 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 two patients with a monoallelic deletion who retained both copies. MiR-15a/16 expression was significantly down-regulated only in patients with the biallelic loss of the miRNA cluster compared to 13q normal cases. Finally, the natural grouping of SNP profiles by means of non-negative matrix factorization algorithm, showed that patients could be classified into two separate clusters mainly characterized by short/biallelic vs. wide/monoallelic 13q14 deletions. Supervised analyses of expression data demonstrated that specific transcriptional profiles are correlated with these two genomic subgroups. Conclusions: Overall, our data highlight the presence of two distinct molecular types of 13q14 deletions which may be of clinical relevance in CLL.