Genetic Imbalances in Progressed B-Cell Chronic Lymphocytic Leukemia and Transformed Large-Cell Lymphoma (Richter's Syndrome)

Abstract

Chromosomal imbalances were examined by comparative genomic hybridization in 30 cases of B-cell chronic lymphocytic leukemia (CLL) at diagnosis, in sequential samples from 17 of these patients, and in 6 large B-cell lymphomas transformed from CLL [Richter's syndrome (RS)] with no available previous sample. The most common imbalances in CLL at diagnosis were gains in chromosome 12 (30%), and losses in chromosomes 13 (17%), 17p (17%), 8p (7%), 11q (7%), and 14q (7%). The analysis of sequential samples showed an increased number of chromosomal imbalances in 6 of 10 (60%) patients with clinical progression and in 2 patients with stable stage C disease. No karyotypic evolution was observed in four cases with stable stage A disease and in one RS clonally unrelated to the previous CLL. Gains of 2pter, and 7pter, and losses of 8p, 11q, and 17p were recurrent alterations associated with karyotype progression. RS showed a higher number of gains, losses, total alterations, and losses of 8p and chromosome 9 than CLL at diagnosis. 17p losses were associated with p53 gene mutations and with a significantly higher number of chromosomal imbalances than tumors with normal chromosome 17 profile. However, no relationship was observed between 9p deletions and p16(INK4a) gene alterations. Losses of 17p and an increased number of losses at diagnosis were significantly associated with a shorter survival. These findings indicate that CLL has frequent chromosomal imbalances, which may increase during the progression of the disease and transformation into large cell lymphoma. Genetic alterations detected by comparative genomic hybridization may also be of prognostic significance.

Richter syndrome: molecular insights and clinical perspectives

“…Lack of involvement of 14q32 translocations in RS development suggests that RS pathogenesis differs from that of other aggressive B-cell non-Hodgkin lymphomas, including de novo DLBCL, in which proto-oncogene deregulation by juxtaposition to IG loci is a relatively common mechanism [31,59,60]. Molecular cytogenetic studies have shown that RS associates with a higher degree of genomic complexity compared to CLL, although none of the genetic lesions reported to date appear to be specific for RS [61].…”

Novel genomic alterations and clonal evolution in chronic lymphocytic leukemia revealed by representational oligonucleotide microarray analysis (ROMA)

“…It includes the 2 newly identified regions, as well as recurrent regions, which are narrower as the result of our higher resolution. [32][33][34][35][36] Novel regions, highlighted in yellow, are a 3.6-Mb deletion at 8p21.2-p12 and a 587-kb deletion at 2q37.1, including genes TRIM35 and SP100/110/140, respectively. Of the refined regions, a 249-kb region at 9p21.3 spanning the CDKN2A (p16 ϪINK4 ) and a 156-kb region at 18q23 containing NFATC1 are particularly interesting.…”

The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation

“…[6][7][8][9] Conversely, the pattern of genetic lesions acquired by RS on transformation is scarcely known, and available evidence is limited to small case series. [10][11][12][13][14][15][16][17][18] Cytogenetic and molecular studies have shown that RS is associated with a higher degree of genomic complexity than is CLL, suggesting that transformation to RS might result from accumulation of novel genetic lesions that drive clinicopathologic shift and change the course of the disease. [10][11][12][13][14][15][16][17][18] The conventional definition of RS is currently based on clinicopathologic grounds and does not take into account the immunogenetic heterogeneity of the disease.…”