Molecular genetic aberrations in the pathogenesis of multiple myeloma

Ivyna Pau Ni Bong; Ezalia Esa

doi:10.2478/abm-2023-0056

Figures & Tables

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

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

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

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

Molecular genetic aberrations in the pathogenesis of multiple myeloma

Figures & Tables

Figure 1.

Figure 2.

Figure 3.

Figure 4.

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

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