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Sadaf et al. J Transl Genet Genom 2022;6:63-83 https://dx.doi.org/10.20517/jtgg.2021.36 Page 67

Translocation t(14;16) (q32.3;q23)
The translocation t(14;16) shows up in 5%-10% MM patients . This translocation is associated with a poor
[1]
prognosis; however, a large retrospective analysis of 1003 patients with t(14;16) revoked its prognostic
significance . The t(14;16) gives rise to over-expression of the MAF gene splice variant c-MAF, which is a
[49]
transcription factor that up-regulates a couple of genes, including CCND2, by directly binding to its
[50]
promoter . MAF up-regulates the expression of APOBEC3A and APOBEC3B, two DNA-editing enzymes,
in MM tumors carrying t(14;16). This leads to a mutational pattern termed as APOBEC signature with a
[51]
high mutation rate .

Translocation t(14;20) (q32;q12)
The translocation t(14;20) is the rarest of 5 major translocations detected in only 1% MM patients, and has a
poor prognosis. However, paradoxically, long-term stable disease is found in the MGUS and SMM
[52]
[53]
stages . It results in over-expression of the MAF gene paralog - MAFB . Mutant MAFB is seen in 25% of
patients with MM harboring t(14;20) . Microarray studies have shown that MAFB over-expression results
[54]
in CCND2 deregulation like c-MAF . Tumors with t(14;20) have the APOBEC mutational signature, which
[47]
is induced by the up-regulated APOBEC4 .
[51]
Secondary translocation affecting MYC
Secondary translocations are independent of class-switch recombination and occur later in the disease .
[14]
The c-MYC proto-oncogenes at 8q24 is the key target of secondary translocations. c-MYC over-expression
[55]
is associated with poor prognosis and has a robust correlation to high levels of serum β microglobulin .
2
The most common secondary translocation in MM is t(8;14), involving the IGH at 14q32.3 . The other
[56]
partner loci in the remaining 40% MYC translocations include IGL at 22q11.2, IGK at 2p11.2, FAM46C at
1p12, FOXO3 at 6q21, and BMP6 at 6p24.3 . Importantly, all these translocations are unbalanced and
[51]
associated with kataegis, which is a pattern of localized hypermutation linked with the deregulation of
APOBEC activity near the translocation breakpoints. As APOBEC works on single-stranded DNA exposed
around the translocation locate, kataegis occurs next to the point of chromosomal rearrangements .
[1]

COPY NUMBER VARIATIONS
CNVs involve either gain or loss of DNA. It comprises focal deletions/amplification, chromosomal arm
loss/gain, and hyperdiploidy. CNVs contribute to genomic instability either via over-expression of proto-
oncogenes or loss of tumor suppression genes. Therefore, CNVs act as important driver events in MM
development and progression [1,3,57] .

Hyperdiploidy
HRD is defined by a chromosome count greater than the diploid number of chromosomes (> 46). In MM,
HRD involves trisomies of the odd-numbered chromosomes (3, 5, 7, 9, 11, 15, 19, and 21) and is noticed in
approximately 50% of MM cases [51,58,59] . The underlying mechanism for HRD is unknown, but one
hypothesis suggests that single disastrous mitosis causes the gain of all chromosomes rather than their serial
gathering over time . However, the contribution of HRD to myelomagenesis is unknown. In addition to
[60]
the dysfunction of cyclin D genes, GEP studies have validated the involvement of many protein synthesis
[61]
genes in hyperdiploid tumors. These include MYC, NF-κB, and MAPK signaling pathways . From a
prognostic perspective, HRD is associated with more favorable survival outcomes than hypodiploidy .
[62]
Furthermore, patients harboring trisomy 3 and trisomy 5 have better overall survival in comparison to
[63]
trisomy 21 . In contrast, HRD MM with co-existent cytogenetic lesions like del(17p) t(4;14) and gain of 1q
[64]
has a poor prognosis compared to HRD MM alone .