Both IGH translocations and chromosome 13q deletions are early events in monoclonal gammopathy of undetermined significance and do not evolve during transition to multiple myeloma

Abstract

Molecular and genetic events associated with the transition from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) are still poorly characterized. We investigated serial bone marrow specimens from 11 patients with MGUS who eventually progressed to MM (MM post-MGUS) by interphase fluorescence in situ hybridization for immunoglobulin heavy-chain gene (IgH) translocations and chromosome 13q deletions (del(13q)). In nine patients, IgH translocations were present both in MGUS and MM post-MGUS plasma cells, including three t(11;14)(q13;q32) and one t(4;14)(p16;q32), which was observed already 92 months prior to MM. Similarly, all five MM patients with del(13q) had this aberration already at the MGUS stage. Two patients without IgH translocation and del(13q) had chromosomal gains suggesting hyperdiploidy, but IgH translocations and/or del(13q) did not emerge at MM post-MGUS. IgH translocations and del(13q) are early genetic events in monoclonal gammopathies, suggesting that additional events are required for the transition from stable MGUS to progressive MM.

SNP-based mapping arrays reveal high genomic complexity in monoclonal gammopathies, from MGUS to myeloma status

“…7,8 Cytogenetic studies using fluorescence in situ hybridization (FISH) have demonstrated that most genetic lesions typical of MM are already present in MGUS stage. [9][10][11] We recently have shown that a major difference between these three entities is the number of PC with genetic abnormalities, which increases from MGUS to SMM and to MM. 12 It demonstrates that the progression from MGUS to SMM, and eventually to MM, involves a clonal expansion of genetically abnormal PC.…”

“…The only five cases with no CNA were from asymptomatic entities (two MGUS and three SMM patients), whereas all MM patients showed at least one CNA. Overall, a total of 703 DNA copy number changes were detected with a median of 8 imbalances per abnormal case (range, 1-32 imbalances): 374 gains with a median of 4 per abnormal case (range, [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] and 329 losses with a median of 3 (range . A detailed description of the most frequent aberrations is shown in Supplementary Table 2.…”

“…PC bearing CNA increase from MGUS to SMM and to MM We observed at least one minor subclone (o50% of PC) carrying a CNA more frequently in MGUS (75% of cases; median of 3.5 of subclones/case, range 1-12) than in SMM (30% of cases; median of 1, range [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] and MM (56% of cases; median of 1/case, range 1-16) (P ¼ 0.017 in the comparison of MGUS vs SMM þ MM). When we compared the presence of minor and major subclones for a particular CNA, we observed that the minor subclones predominated in MGUS, whereas in MM patients (both symptomatic and asymptomatic disease) the major subpopulation was the predominant one.…”

Molekulare Pathologie von Plasmazellneoplasien

“…2 aufgeführten häufigen Partnerloci nachweisen. Insgesamt zeigen etwa 50-70% der MM eine Translokation von 14q32, wobei der ge- [12,17]. Als relativ häufige sekundäre Translokationen finden sich Alterationen des C-MYC-Locus, die in etwa 10-15% unselektierter MM zu finden sind, aber in 50% der Fälle mit plasmablastischer Morphologie sowie häufig in Plasmazellleukämien [2].…”

“…Eine häufige numerische Aberration insbesondere bei MM mit Ig-Translokationen sind Deletionen von 13q bzw. die Monosomie 13, die in früheren Studien einen prognostisch ungünstigen Faktor darstellten [13,17]. Eine zweite große Gruppe von MM zeigt einen hyperdiploiden Chromosomensatz mit zusätzlichen Kopien vor allem der Chromosomen 3, 5, 7, 9, [14].…”