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Background: A major conclusion drawn from the accumulated cytogenetic data on solid tumors and some hematologic malignancies is that tumors progress by the acquisition of chromosomal changes, as reflected by more aggressive tumors containing a larger number of chromosomal abnormalities. An additional observation is that some chromosomal changes appear early in the disease progression, and some others appear late., Material and Methods: On the basis of this information, a model for karyotypic evolution in chronic lymphocytic leukemia (CLL) is presented. The Mitelman Database of Chromosomes in Cancer was searched, and 1749 abnormal karyotypes were assessed. The main clones were analyzed, and chromosomal gains and losses were used to design a model of genetic acquisition based on the calculation of a variable called time to occurrence (TO)., Results: Our comprehensive study of genetic abnormalities in a large number of CLL karyotypes revealed that most CLL has 2 chromosomal aberrations at diagnosis. Moreover, the temporal analysis suggests that trisomy 12 is an early event in the biological evolution of CLL., Conclusion: These results highlight the possibility of targeted therapies affecting the genes located on this chromosome (cyclin D, cyclin D2, cyclin-dependent kinase 2, and cyclin-dependent kinase 4)., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Waldenström's macroglobulinemia (WM) is a distinct clinicobiological entity defined as a B-cell neoplasm characterized by a lymphoplasmacytic infiltrate in bone marrow (BM) and IgM paraprotein production. Cytogenetic analyses were historically limited by difficulty in obtaining tumor metaphases, and the genetic basis of the disease remains poorly defined. Here, we performed a comprehensive analysis in 42 WM patients by using a high-resolution, array-based comparative genomic hybridization approach to unravel the genetic mechanisms associated with WM pathogenesis. Overall, 83% of cases have chromosomal abnormalities, with a median of three abnormalities per patient. Gain of 6p was the second most common abnormality (17%), and its presence was always concomitant with 6q loss. A minimal deleted region, including MIRN15A and MIRN16-1, was delineated on 13q14 in 10% of patients. Of interest, we reported biallelic deletions and/or inactivating mutations with uniparental disomy in tumor necrosis factor (TNF) receptor-associated factor 3 and TNFalpha-induced protein 3, two negative regulators of the nuclear factor-kappaB (NF-kappaB) signaling pathway. Furthermore, we confirmed the association between TRAF3 inactivation and increased transcriptional activity of NF-kappaB target genes. Mutational activation of the NF-kappaB pathway, which is normally activated by ligand receptor interactions within the BM microenvironment, highlights its biological importance, and suggests a therapeutic role for inhibitors of NF-kappaB pathway activation in the treatment of WM.

Cytogenetic analyses have been historically limited in Waldenström's macroglobulinemia (WM) by the difficulty to obtain tumor metaphases. Thus, few recurrent karyotypic abnormalities have been reported and the molecular consequences of these imbalances are largely unknown. We used an array-based comparative genomic hybridization approach to better characterize the recurrent chromosome abnormalities associated with WM pathogenesis and to compare them with the publicly available findings in other B-cell neoplasias. The majority of the recurrent chromosome abnormalities identified in WM were shared with marginal zone lymphomas (MZL), as deletions of 6q23 and 13q14 and gains of 3q13-q28, 6p and 18q. On the other hand, gains of 4q and 8q were recurrently identified in WM but have not been described as being common abnormalities in MZL. The genetic consequences of these specific abnormalities remain elusive and further studies are critical to refine the search and to precise the molecular pathways affected by these abnormalities.

Fluorescence in situ hybridisation (FISH) is an effective technique for the cytogenetic analysis of Waldenström macroglobulinemia (WM), but the potential impact of molecular cytogenetics on disease evolution and as a prognostic marker is still unknown. Deletion of the long arm of chromosome 6 (6q-) is the most frequent cytogenetic abnormality in WM. This study analysed the prevalence of this aberration in 102 WM patients, and correlated it with disease characteristics. The incidence of 6q21 deletion was 7% by conventional cytogenetics and 34% when analysed by FISH (54% when cytoplasmic immunoglobulin M-FISH was used). Patients with deletion of 6q displayed features of adverse prognosis, such as higher levels of beta2-microglobulin and monoclonal paraprotein and a greater tendency to display anaemia and hypoalbuminemia. Interestingly, there was a correlation between the presence of 6q deletion and the International Staging System prognostic index (incidence of 6q- among patients stratified in stages 1, 2 and 3 was 24%, 42% and 67% respectively). Those patients diagnosed with smouldering WM who displayed the abnormality showed a trend to an earlier requirement of treatment. Finally, the survival analysis did not show differences between the two groups of patients, probably due to the short follow up of our series.

Waldenström macroglobulinemia (WM) is a B-cell malignancy characterized by the ability of the B-cell clone to differentiate into plasma cells. Although the clinical syndrome and the pathologic characteristics are well defined, little is known about its biology and controversy still exists regarding its cell of origin. In this gene-expression study, we compared the transcription profiles of WM with those of other malignant B cells including (chronic lymphocytic leukemia [CLL] and multiple myeloma [MM]) as well as normal cells (peripheral-blood B cells and bone marrow plasma cells). We found that WM has a homogenous gene expression regardless of 6q deletion status and clusters with CLL and normal B cells on unsupervised clustering with very similar expression profiles. Only a small gene set has expression profiles unique to WM compared to CLL and MM. The most significantly up-regulated gene is IL6 and the most significantly associated pathway for this set of genes is MAPK signaling. Thus, IL6 and its downstream signaling may be of biologic importance in WM. Further elucidation of the role of IL-6 in WM is warranted as this may offer a potential therapeutic avenue.

IgM monoclonal gammopathy of undetermined significance (IgM MGUS) and Waldenström macroglobulinemia (WM) are sometimes clinically difficult to distinguish. In our previous study, deletion of the long arm of chromosome 6 (6q) was found in about half of WM patients. To further clarify the area of minimal deletion at 6q (6q-) and to address the issue of whether 6q- occurs in IgM MGUS, 12 IgM MGUS and 38 WM patients were studied by fluorescence in situ hybridization using probes targeting different chromosomal segments of 6q. No 6q deletions were found in IgM MGUS samples. Of 38 successfully studied WM patients, 21 (55%) showed a deletion of 6q. The area of minimal deletion was between 6q23 and 6q24.3, but the deletion usually encompassed a large fragment of the 6q arm. These results indicate that 6q- can distinguish WM from IgM MGUS and is likely to be a secondary event.

Waldenstrom's macroglobulinemia (WM) is a clonal B-cell disorder characterized by the production of a monoclonal paraprotein and lymphoplasmacytic clonal expansion. The genetic basis of this disorder is poorly understood. We have recently found that the genetic makeup of WM cells is different from that commonly reported for multiple myeloma (MM), follicular lymphoma, and B-cell chronic lymphocytic leukemia. Translocations involving the immunoglobulin heavy chain locus (IgH) translocations could not be detected in any case, and a molecular analysis showed that the IgH locus switch mu retained its germline configuration. Aneuploidy was not detected using chromosome enumeration probes. The only recurrent chromosome abnormality found was deletion of 6q21. The lack of legitimate of illegitimate rearrangements at the IgH locus suggests that other mechanisms are involved in the pathogenesis of the disorder. Given the clear evidence of a familial form of WM and the currently presumed genomic stability of the clonal cells, it is likely that a single gene defect may be responsible for disease pathogenesis. Having found deletions of the long arm of chromosome 6 as the only recurrent aberration, we speculate that a gene involved in B-cell maturation or survival at this locus may be inactivated as a cause of WM., (Copyright 2003 Elsevier Inc. All rights reserved.)

Lymphoplasmacytic lymphoma (LPL) is characterized by t(9;14)(p13;q32) in 50% of patients who lack paraproteinemia. Waldenström macroglobulinemia (WM), which has an immunoglobulin M (IgM) paraproteinemia, is classified as an LPL. Rare reports have suggested that WM sometimes is associated with 14q23 translocations, deletions of 6q, and t(11;18)(q21;q21). We tested for these abnormalities in the clonal cells of WM patients. We selected patients with clinicopathologic diagnosis of WM (all had IgM levels greater than 1.5 g/dL). Southern blot assay was used to detect legitimate and illegitimate IgH switch rearrangements. In addition to conventional cytogenetic (CC) and multicolor metaphase fluorescence in situ hybridization (M-FISH) analyses, we used interphase FISH to screen for t(9;14)(p13;q32) and other IgH translocations, t(11;18)(q21;q21), and 6q21 deletions. Genomic stability was also assessed using chromosome enumeration probes for chromosomes 7, 9, 11, 12, 15, and 17 in 15 patients. There was no evidence of either legitimate or illegitimate IgH rearrangements by Southern blot assay (n = 12). CC (n = 37), M-FISH (n = 5), and interphase FISH (n = 42) failed to identify IgH or t(11;18) translocations. Although tumor cells from most patients were diploid for the chromosomes studied, deletions of 6q21 were observed in 42% of patients. In contrast to LPL tumors that are not associated with paraproteinemia and that have frequent t(9;14)(p13;q32) translocations, IgH translocations are not found in WM, a form of LPL tumor distinguished by IgM paraproteinemia. However, WM tumor cells, which appear to be diploid or near diploid, often have deletions of 6q21.

Waldenström macroglobulinemia (WM) is a plasma cell dyscrasia characterized by a monoclonal IgM paraproteinemia. Deletions of 17p13.1 and 13q14 are associated with tumor progression and worsened outcome in multiple myeloma (MM), and we thus investigated WM patients for their presence. Patients (n = 40) were required to have a > or = 1.5 g/dl serum IgM paraproteinemia and a monoclonal lymphoplasmacytic infiltrate. We used interphase fluorescence in situ hybridization (FISH) with probes that localized to 17p13.1(LSI p53/CEP 17) and 13q14 (D13S319 and LSI 13 Rb). Of 40 successfully studied patients for 17p13.1(p53) deletions, 6 were abnormal, consistent with hemizygous deletion (15%). Of 37 cases successfully studied for the 13q14 deletions, 6 were also abnormal with one pair of signals deleted (16%). Patients with deletions were more likely to be later in the course of the disease. No obvious clinical associations were noted with the exception that patients with 17p13.1(p53) deletions had a higher percent involvement of clonal cells in the bone marrow. Deletions of these two regions are uncommon in WM, being more common in the late stages of the disease, thus unlikely playing a role in primary disease pathogenesis.

In B-cell lymphomas, loss of human leukocyte antigen (HLA) class I and II molecules might contribute to immune escape from CD8(+) and CD4(+) cytotoxic T cells, especially because B cells can present their own idiotype. Loss of HLA expression and the possible underlying genomic alterations were studied in 28 testicular, 11 central nervous system, and 21 nodal diffuse large B-cell lymphomas (DLCLs), the first two sites are considered as immune-privileged sites. The analysis included immunohistochemistry, loss of heterozygosity analysis, and fluorescent in situ hybridization (FISH) on interphase cells and isolated DNA fibers. Total loss of HLA-A expression was found in 60% of the extranodal cases and in 10% of the nodal cases (P <.01), whereas loss of HLA-DR expression was found in 56% and 5%, respectively (P <.01). This was accompanied by extensive loss of heterozygosity within the HLA region in the extranodal DLCLs. In 3 cases, retention of heterozygosity for D6S1666 in the class II region suggested a homozygous deletion. This finding was confirmed by interphase FISH that showed homozygous deletions in the class II genes in 11 of the 18 extranodal lymphomas but in none of the 7 nodal DLCLs (P <.001). Mapping by fiber FISH showed variable deletions that always included HLA-DQ and HLA-DR genes. Hemizygous deletions and mitotic recombinations often involving all HLA genes were found in 13 of 18 extranodal and 2 of 7 nodal lymphomas. In conclusion, a structural loss of HLA class I and II expression might help the B-cell lymphoma cells to escape from immune attack.