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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 65

4.25-fold risk of MM in first-degree relatives (95%CI: 1.81-8.41) that was observed in the 1961-2003 Swedish
[18]
national cancer registry data . Similarly, among the first-degree relatives observed in Minnesota and Mayo
Clinic cohorts exhibited the increased risk of MGUS (RR = 3.3; 95%CI: 2.1-4.8) and MM (RR = 2.0; 95%CI:
[19]
1.4-2.8) . While the familial clustering of MM indicates a genetic predisposition to the disease, only
recently (2012) has GWAS identified single-nucleotide polymorphisms associated with MM risk . In
[20]
addition to identifying multiple risk loci, GWAS has provided innovative insights into genetic-related
risk . Inherited variations at loci 2p23.3, 3p22.1, and 7p15.3 are associated with a genetic predisposition to
[20]
MGUS and involves gene pairs 2p: DNMT3A and DTNB, 3p: ULK4 and TRAK1, and 7p: DNAH11 and
CDCA7L [21,22] . Chubb et al. verified that the seven common variant loci 2p23.3, 3p22.1, 3q26.2, 6p21.33,
[23]
7p15.3, 17p11.2, and 22q13.1 may account for 13% of the familial risk of MM. Further studies have
confirmed more candidate loci summarized in Table 1. Additionally, rare variants such as LSD1/KDM1A,
KIF18A, USP45, ARDID1A, CDKN2A, and DIS3 may be contributed to missing heritability . The reliable
[16]
identification of these susceptible risk variants would be an important advancement in the early detection of
MM. Furthermore, it could postulate potential personalized treatments or gene knockdown to limit
progression to MM in the future.

The African American (AA) population has a higher prevalence of MGUS and MM than Caucasian
[32]
Americans (CA) of European ancestry [30,31] . A study by Costa et al. reported a 2.24-fold higher incidence
of MM in AA men compared to CA men. Also, MM occurs in the AA population at an early age of 65.8
compared to age 69.8 in the CA population . When considering polygenic risk scores (PRS), people of
[33]
African ancestry in the top 10% PRS had a 1.82-fold (95%CI: 1.56-2.11) increased risk for MM compared to
those with an average risk . Although the confounding factors of healthcare inequalities, lifestyle, and
[34]
environmental factors are significant, racial genetics is crucial in the etiology of MM in the AA
population .
[20]

A study involving GWAS analysis revealed a stronger association between the 7p15.3 (rs4487645) locus and
MM in AA . The expression quantitative trait locus analysis on the biological function of the 7p15.3
[35]
(rs4487645) risk locus showed that the C risk allele is linked to elevated CDCA7L (cell division cycle-
associated 7 like) . The elevated CDCA7L attributes to the emergence of an IRF4 binding site on the
[36]
7p15.3 enhancer , hence, connecting the germline risk of MM to a genetic pathway IRF4-MYC.
[37]

Similarly, an NGS study about acquired somatic mutations in MMmyeloma has underlined new insights
into racial differences between AA and CA patients. It demonstrated higher mutation frequency in genes
ABI3BP, ANKRD26, AUTS2, BCL7A, BRWD3, DDX17, GRM7, IRF4, MYH13, PARP4, PLD1, PTCHD3,
RPL10, RYR1, SPEF2, STXBP4, and TP53 among AA than in CA myeloma patients . Besides, myeloma
[3]
MM-associated translocations t(11;14), t(14;16), and t(14;20) also play a critical role in racial AA vs. CA
disparity .
[38]

TRANSLOCATIONS IN MYELOMA
Translocation (4;14) (p16.3;q32.3)
The translocaton t(4;14) is seen in 15% of MM cases and has a poor prognosis [39,40] . This translocation results
in the over-expression of two genes: FGFR3 (70% of cases) and MMSET (all cases) [41,42] . FGFR3 up-
[43]
regulation results in the ectopic expression of the FGFR3 tyrosine kinase receptor types . MMSET is a
methyltransferase protein. Its up-regulation leads to enhanced methylation of histone H3K36, which
modulates the expression of several genes. MMSET also regulates the methylation of histone H4K20,
subsequently affecting the recruitment of tumor protein p53binding protein 1 (TP53BP1) at the site of DNA
damage . Both MMSET and FGFR3 over-expression up-regulate CCND2 and in some instances CCND1
[44]