Evolutionary sequence of cytogenetic aberrations during the oncogenesis of plasma cell disorders. Direct evidence at single cell level

Nagy, Zsófia; Kajtár, Béla; Jaksó, Pál; Dávid, M.; Kosztolányi, Szabolcs; Hermesz, Judit; Kereskai, László; Pajor, László; Alpár, Donát

doi:10.1016/j.leukres.2011.02.010

Cited by 5 publications

(6 citation statements)

References 6 publications

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“…2,3 In this context our results strongly support recently published single cell level FISH data questioning the initiating role of recurrent IGH translocations. 33 In addition, our results are also similar to those reported by Fonseca et al 7 in a series of 23 MGUS patients who had t(14q32), most of whom [15/23 (65%)] had a significant proportion (>15%) of clonal Ig-light chain-restricted PC without t(14q32) coexisting with the t(14q32)-positive cells.…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nsupporting

confidence: 92%

Cytogenetic profiles in multiple myeloma and monoclonal gammopathy of undetermined significance: a study in highly purified aberrant plasma cells

et al. 2012

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Cytogenetic studies in clonal plasma cell disorders have mainly been done in whole bone marrow or CD138 + microbead-enriched plasma cells and suggest that recurrent immunoglobulin heavy chain translocations -e.g. t(4;14) -are primary oncogenetic events. The aim of this study was to determine cytogenetic patterns of highly purified aberrant plasma cells (median purity ≥98%) in different clonal plasma cell disorders. We analyzed aberrant plasma cells from 208 patients with multiple myeloma (n=148) and monoclonal gammopathy of undetermined significance (n=60) for the presence of del(13q14), del(17p13) and t(14q32) using multicolor interphase fluorescence in situ hybridization. Additionally, immunoglobulin heavy chain gene arrangements were analyzed and complementarity determining region 3 was sequenced in a subset of patients and combined multicolor interphase fluorescence in situ hybridization/immunofluorescent protein staining analyses were performed in selected cases to confirm clonality and cytogenetic findings. At diagnosis, 96% of cases with multiple myeloma versus 77% of monoclonal gammopathy of undetermined significance cases showed at least one cytogenetic alteration and/or hyperdiploidy. The cytogenetic heterogeneity of individual cases reflected coexistence of cytogenetically-defined aberrant plasma cell clones, and led to the assumption that karyotypic alterations were acquired stepwise. Cases of multiple myeloma and monoclonal gammopathy of undetermined significance frequently showed different but related cytogenetic profiles when other cytogenetic alterations such as deletions/gains of the immunoglobulin heavy chain or the fibroblast growth factor receptor 3 were additionally considered. Interestingly, in 24% of multiple myeloma versus 62% of monoclonal gammopathy of undetermined significance patients with an immunoglobulin heavy chain translocation, aberrant plasma cells with and without t(14q32) coexisted in the same patient. Our data suggest that recurrent immunoglobulin heavy chain translocations might be absent in the primordial plasma cell clone in a significant proportion of patients with clonal plasma cell disorders carrying these cytogenetic alterations.

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Section: © F E R R a T A S T O R T I F O U N D A T I O Nsupporting

confidence: 92%

Cytogenetic profiles in multiple myeloma and monoclonal gammopathy of undetermined significance: a study in highly purified aberrant plasma cells

et al. 2012

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“…I‐FISH signals had fluorescence intensity sufficiently high for reliable analysis and considering the performance of the labeling procedure, significant inter‐sample variability was not observed. The lowest signal‐to‐noise ratio was observed at the probe set visualizing TP53 , which is in accordance with our previous observation (Nagy et al, ). The LSI IgH/MAF DC DF probe set produced very robust signals allowing efficient and specific detection of t(14;16) translocation with dual‐fusion strategy.…”

Section: Resultssupporting

confidence: 92%

“…All the t(4;14) and t(14;16) positive cases harbored D13 as well, in line with previously published data. In 1990s, D13 was thought to be associated with shorter survival (Tricot et al, 1995;P erez-Sim on et al, 1998;Zojer et al, 2000) but later it turned out that a strong association with the adverse prognostic markers mentioned above mislead the interpretation regarding its clinical importance (Guti errez et al, 2007;Fonseca et al, 2009). Although, the number of analyzed patients with t(14;16) was low in our study, loss of 1p and gain 1q were commonly observed in this group.…”

Section: Discussionmentioning

confidence: 50%

Multiplex ligation‐dependent probe amplification and fluorescence in situ hybridization are complementary techniques to detect cytogenetic abnormalities in multiple myeloma

Alpár

Jong

Holczer-Nagy

et al. 2013

Genes Chromosomes & Cancer

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Multiple myeloma (MM) is a genetically heterogeneous disease with diverse clinical outcomes. Interphase fluorescence in situ hybridization (i-FISH) is the most commonly used approach to detect recurrent cytogenetic abnormalities in this malignancy. We aimed to assess the performance of multiplex ligation-dependent probe amplification (MLPA) to reveal copy number abnormalities (CNAs) in MM. Diagnostic bone marrow samples from 81 patients were analyzed using 42 MLPA probes for the following regions: 1p32-31, 1p21, 1q21.3, 1q23.3, 5q31.3, 12p13.31, 13q14, 16q12, 16q23, and 17p13. All samples were also screened by i-FISH for the presence of hyperdiploidy, deletion/monosomy of chromosome 13, deletion of TP53, disruption of the immunoglobulin heavy-chain gene, t(4;14), t(11;14), t(14;16), t(8;14), gain of 5q and abnormalities of chromosome 1. A total of 245 alterations were detected in 79 cases (98%). Investigating the same aberrations, the two methods showed a congruency of higher than 90%. A low proportion of cells with the relevant abnormality, focal CNAs and unmatched probes were responsible for the discrepancies. MLPA revealed 95 CNAs not detected by i-FISH providing additional information in 53 cases (65%). Scrutiny of CNAs on chromosome 1, using more than 20 probes, revealed significant heterogeneity in size and location, and variable intra-chromosomal and intra-clonal rates of loss or gain. Our results suggest that MLPA is a reliable high-throughput technique to detect CNAs in MM. Since balanced aberrations are key to prognostic classification of this disease, MLPA and i-FISH should be applied as complementary techniques in diagnostic pathology.

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“…This model is in agreement with other temporal analyses of hyperdiploid myeloma where trisomies were shown to precede translocations and monosomies or deletions 20,44 and cytogenetic studies of myeloma and monoclonal gammopathy of undetermined significance where patients had 14q32 translocations, but these were absent in the primordial aberrant myeloma clone. 45,46 Therefore, hyperdiploidy may occur earlier in the B-cell development but simply confer a slight proliferative cell advantage that will be further enhanced by the acquisition of additional genetic lesions, such as an IGH translocation, loss of 13q or 17p, or RAS mutations, during the course of clonal evolution and disease progression. The presence of hyperdiploidy and its favorable prognostic value is not an exclusive event of myeloma and has been seen in other hematologic malignancies such as acute myeloid leukemias 47 and childhood B-acute lymphoblastic leukemia, 42,48,49 where hyperdiploidy involves Figure 2 for an additional case study with hyperdiploidy preceding IGH translocation.…”

Section: Discussionmentioning

confidence: 99%

Coexistent hyperdiploidy does not abrogate poor prognosis in myeloma with adverse cytogenetics and may precede IGH translocations

Pawlyn

Melchor

Murison

et al. 2015

Blood

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Key Points• Coexistent hyperdiploidy or t(11;14) does not abrogate the poor prognosis associated with adverse cytogenetics in myeloma patients.• Single-cell analysis reveals that hyperdiploidy may precede IGH translocation in the clonal history of a proportion of patients with both.The acquisition of the cytogenetic abnormalities hyperdiploidy or translocations into the immunoglobulin gene loci are considered as initiating events in the pathogenesis of myeloma and were often assumed to be mutually exclusive. These lesions have clinical significance; hyperdiploidy or the presence of the t(11;14) translocation is associated with a favorable outcome, whereas t(4;14), t(14;16), and t(14;20) are unfavorable. Poor outcomes are magnified when lesions occur in association with other high-risk features, del17p and 11q. Some patients have coexistence of both good and poor prognostic lesions, and there has been no consensus on their risk status. To address this, we have investigated their clinical impact using cases in the Myeloma IX study (ISRCTN68454111) and shown that the coexistence of hyperdiploidy or t(11;14) does not abrogate the poor prognosis associated with adverse molecular lesions, including translocations. We have also used single-cell analysis to study cases with coexistent translocations and hyperdiploidy to determine how these lesions cosegregate within the clonal substructure, and we have demonstrated that hyperdiploidy may precede IGH translocation in a proportion of patients. These findings have important clinical and biological implications, as we conclude patients with coexistence of adverse lesions and hyperdiploidy should be considered high risk and treated accordingly. (Blood. 2015;125(5):831-840)

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Evolutionary sequence of cytogenetic aberrations during the oncogenesis of plasma cell disorders. Direct evidence at single cell level

Cited by 5 publications

References 6 publications

Cytogenetic profiles in multiple myeloma and monoclonal gammopathy of undetermined significance: a study in highly purified aberrant plasma cells

Cytogenetic profiles in multiple myeloma and monoclonal gammopathy of undetermined significance: a study in highly purified aberrant plasma cells

Multiplex ligation‐dependent probe amplification and fluorescence in situ hybridization are complementary techniques to detect cytogenetic abnormalities in multiple myeloma

Coexistent hyperdiploidy does not abrogate poor prognosis in myeloma with adverse cytogenetics and may precede IGH translocations

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