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Molecular genetic aberrations in the pathogenesis of multiple myeloma

Ivyna Pau Ni Bong
Ivyna Pau Ni Bong
 et 
Ezalia Esa
Ezalia Esa
   | 18 oct. 2023
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Article Category: Review
Publié en ligne: 18 oct. 2023
Pages: 152 - 162
DOI: https://doi.org/10.2478/abm-2023-0056
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© 2023 Ivyna Pau Ni Bong et al., published by Sciendo
This work is licensed under the Creative Commons Attribution 4.0 International License.

Figure 1.

Primary and secondary oncogenic events in the molecular pathogenesis of MM. MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; SMM, smoldering multiple myeloma.
Primary and secondary oncogenic events in the molecular pathogenesis of MM. MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; SMM, smoldering multiple myeloma.

Figure 2.

Recurrent gene aberrations and their frequency in MM. MM, Multiple myeloma.
Recurrent gene aberrations and their frequency in MM. MM, Multiple myeloma.

Figure 3.

Main clonal evolution models in multiple myeloma. Each color represents a single subclone.
Main clonal evolution models in multiple myeloma. Each color represents a single subclone.

Figure 4.

Complex chromosomal rearrangements in multiple myeloma: chromothripsis and chromoplexy.
Complex chromosomal rearrangements in multiple myeloma: chromothripsis and chromoplexy.

Common primary and secondary chromosomal abnormalities and their prognostic outcomes in MM

Chromosomal abnormality Genes/chromosomes affected Frequency (%) Risk stratification Prognosis Remarks References
Primary oncogenic events
Hyperdiploidy Trisomies of odd-numbered chromosomes 50–60 Standard risk FavorablePositive impact on OS and PFS Trisomy 21-negative impact on OSTrisomy 3 or 5-positive impact on OS [12,13,14,15,16,17]
IgH translocations 60 Occur as early as the MGUS stageCaused by errors in CSR (90%) and SHM (10%) [12, 18, 19]
t(4;14)(p16;q32) FGFR3/ MMSET 15 High risk Unfavorable/neutralNegative impact on OS and PFS Commonly developed from errors in CSRIncreases rate of relapseCo-occurrence with trisomy 3 or 5 might improve prognosis [10, 17, 20,21,22,23,24,25]
t(14;16)(q32;q23) c-MAF 5–7 High risk Unfavorable [14, 19, 20, 26]
t(14;20)(q32;q11) MAFB 1–2 High risk Unfavorable [14, 20, 27]
t(11;14)(q13;q32) CCND1 15–20 Standard risk Favorable/neutral Commonly caused by SHM40% RRMM response to VenetoclaxHigh MCL1causes resistance to Venetoclax [10, 28,29,30]
Others:
t(12;14)(p13;q32) CCND2 <1 Standard risk Favorable/neutral [19]
t(6;14)(p21;q32) CCND3 2 Standard risk Favorable/neutral
t(8;14)(q24.3;q32) MAFA <1 High risk Unfavorable
Secondary oncogenic events
del(1p) CDKN2C/ FAM46C/ FaF1 30 High risk UnfavorableNegative impact on OS and PFS 1p21 and 1p32 are the most frequently deleted regions [31,32,33]
Gain (1q21) CKS1B/ PSMD4 40 High risk UnfavorableNegative impact on OS and PFS Rarely found in MGUSInvolves in disease progressionInduces bortezomib resistanceWorsens prognosis in cases with copy numbers ≥4 [34,35,36,37]
Monosomy 13/ del(13q) DIS3/ RB1 50 Neutral 85% are monosomy; 15% are partial deletionResponds well to first-line therapy [8, 32, 38,39,40]
del(17p) TP53 5–10 NDMM40 advanced MM High risk UnfavorableNegative impact on OS and PFS Late event in pathogenesisMight be resistant to standard therapy [11, 41, 42]
MYC translocation MYC/ IgK/ IgL/ IgH/ FOXO3/ FAM46C/ TXNDC5/ BMP6 15 early-stage MM50 advanced MM Unfavorable/neutralNegative impact on OS and PFS IgH/MYC or IgK/MYC are commonly associated with disease progressionIgL/MYC adverse prognosis in NDMMIncreases risk of progression from SMM to MM [11, 12, 42,43,44,45,46,47,48,49]
Others
del(11q) BIRC2/3 7 [12, 32, 50, 51]
del(16q) WWOX/ CYLD 35 Unfavorable
del(14q) TRAF3 38 Unfavorable
del(12p) CDKN1B Unfavorable
del(8p) TRAIL Unfavorable
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