Page 149 - Read Online

Page 68 Sadaf et al. J Transl Genet Genom 2022;6:63-83 https://dx.doi.org/10.20517/jtgg.2021.36

Gain of 1q
The gain of 1q arm is present in 30 to 40% of MM cases and is associated with a poor prognosis . The
[14]
amplification process involves 1q12 pericentromeric region instability due to hypomethylation and jumping
translocation of the whole 1q arm . Gene studies have shown a minimally amplified region between 1q21.1
[65]
and 1q23.3 carrying candidate oncogenes including CKS1B, ANP32E, BCL9, PDZK1, ADAR1, PSMD4,
ILF2, IL6R, and MCL1 [1,66] . The protein phosphatase 2A inhibitor ANP32E involved in chromatin
remodeling and transcriptional regulation is independently associated with short survival . The identified
[67]
specific inhibitors of the candidate genes and pathways may help in the treatment of patients with 1q
gain .
[14]

Loss of 1p
Loss of 1p is present in 30% of MM cases and may involve whole arm deletion or interstitial deletion. 1p loss
correlates to poor prognosis . 1p12 and 1p32.3 are two important regions involved in myelomagenesis .
[68]
[1]
Both these regions experience hemizygous or homozygous deletions . Tumor suppressor gene FAM46C is
[14]
located on 1p12, and its expression has been verified as positively correlated with ribosomal proteins,
eukaryotic initiation, and elongation factors involved in protein translation . Similarly, FAF1 and CDKN2C
[7]
[1]
are located on 1p32.3 . The protein encoded by FAF1 is involved in apoptosis initiation via the Fas
pathway, while CDKN2C is a cyclin-dependent kinase 4 (CDK4) inhibitor which negatively regulates the
cell cycle . 1p32.3 deletion correlates to a poor prognosis in MM patients undertaking an autologous stem
[1]
cell transplantation (ASCT) and a neutral prognosis in those receiving non-intensive treatment .
[68]
Loss of chromosome 13/13q
Loss of chromosome 13 is present in 45%-50% of MM cases, and primarily in non-HRD tumors. 85% of
cases involve whole 13q arm deletion whereas 15% encompass interstitial deletions . The minimal deleted
[14]
region located between 13q14.11 and 13q14.3 also contains some genes related to MM progression,
including RB1, RCBTB2, RNASEH2B, EBPL, mir15a, and mir161. The under-expression of RB1, a tumor
[57]
suppressor gene, results in negative cell cycle regulation . In 90% of cases, del(13/13q) occurs concurrently
with t(4;14) as determined by conventional cytogenetic studies and is linked with poor prognosis . In the
[69]
absence of concurrent lesion, del(13/13q) lacks prognostic significance. Hence, the correlation between
del(13/13q) and poor prognosis can only be seen in some patients with other high-risk genetic lesions .
[70]

17p deletion
The chromosome 17 deletion is a late disease event. It is hemizygous and involves the whole p arm . The
[14]
most common gene deregulated in 17p deletion is the tumor suppressor gene TP53 . GEP has shown that
[71]
monoallelic 17p deletions in MM samples exhibit remarkably lower TP53 compared to non-deleted
samples . TP53 influences DNA repair, cell cycle arrest, and apoptosis in response to DNA damage as a
[57]
transcriptional regulator . In MM, 17p deletion is related to more extramedullary involvement, an
[14]
aggressive disease phenotype, and a shortened life span. It is hypothesized that PCL is the main
consequence of TP53 dysfunction [72,73] .

Miscellaneous chromosomal gains & losses
Focal CNVs have extracted the list of potential driver genes affected by these changes. Gain of 8q24.21 can
be discovered in 14% MM patients and disturbs MYC genes . A gain of 11q13.2 is found in 15% of patients
[1]
and involves the oncogene CCND1. CCND1 is also affected by chromosomal translocations and somatic
[1]
mutations . 11q deletion is detected in 7% MM cases and downregulates tumor suppressor genes BIRC2
and BIRC3 . Deletion of 14q occurs in 38% of cases and involves TRAF3 (tumor suppressor gene) . 16q
[1]
[57]
deletion is another common event (in 35% myeloma cases) and reduces the expression of the tumor
suppressor genes CYLD and WWOX (implicated in apoptosis) . Del(8p) and del(12p) are independent
[57]