Gain/Amplification of Chromosome Arm 1q21 in Multiple Myeloma

Abstract

Multiple myeloma (MM), a plasma cell neoplasm, is an incurable hematological malignancy characterized by complex genetic and prognostic heterogeneity. Gain or amplification of chromosome arm 1q21 (1q21+) is the most frequent adverse chromosomal aberration in MM, occurring in 40% of patients at diagnosis. It occurs in a subclone of the tumor as a secondary genomic event and is more amplified as the tumor progresses and a risk factor for the progression from smoldering multiple myeloma to MM. It can be divided into either 1q21 gain (3 copies) or 1q21 amplification (≥4 copies), and it has been suggested that the prognosis is worse in cases of amplification than gain. Trisomy of chromosome 1, jumping whole-arm translocations of chromosome1q, and tandem duplications lead to 1q21+ suggesting that its occurrence is not consistent at the genomic level. Many studies have reported that genes associated with the malignant phenotype of MM are situated on the 1q21 amplicon, including CKS1B, PSMD4, MCL1, ANP32E, and others. In this paper, we review the current knowledge regarding the clinical features, prognostic implications, and the speculated pathology of 1q21+ in MM, which can provide clues for an effective treatment approach to MM patients with 1q21+.

Systems medicine dissection of chr1q-amp reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma

“…First, by combining WGS and 3D genome data we found that genetic amplification disrupts a large proportion of the chromatin structure throughout the chr1q arm. This level of disruption likely reflects contribution of multiple mechanisms to structural changes in chr1q 46 , including isochromosome formation 47 , hypoxia-driven tandem duplications 48 , jumping translocations 4 , chromothripsis 49 , chromoplexy 50 , and combination of the above 51 . Nevertheless, we detected four main blocks of co-amplification (hyper-domains) which are the product of distinct amplification patterns and retain their overall chromatin structure across MM patients.…”

Systems medicine dissection of chromosome 1q amplification reveals oncogenic regulatory circuits and informs targeted therapy in cancer

“…First, by combining WGS and 3D genome data we found that genetic amplification disrupts a large proportion of the chromatin structure throughout the chr1q arm. This level of disruption likely reflects contribution of multiple mechanisms to structural changes in chr1q (31), including isochromosome formation (32), hypoxia-driven tandem duplications (33), jumping translocations (5), chromothripsis and chromoplexy (34), and combination of the above (35). Nevertheless, we detected four main blocks of co-amplification (hyper-domains) which are the product of distinct amplification patterns and retain their overall chromatin structure across MM patients.…”

Anaplastic multiple myeloma with MYC rearrangement

“…However, it should be noted that many other genes at the 1q21 locus could be associated with poor prognosis and resistance to chemotherapy [14] . 1q21+ is also observed in non-anaplastic MM and is likely to be associated with the disease progression of MM [15] . Moreover, it was recently reported that 1q21+ is strongly associated with MYC rearrangement, which is associated with poor prognosis in MM [ 16 , 17 ].…”