Gain of 1q21 in multiple myeloma: from bad to worse?

Comment on Hanamura et al, page 1724

Recurrent chromosomal aberrations occur in the majority of multiple myeloma cases and may have strong clinical implications. In this issue of Blood, Hanamura and colleagues describe the frequent gain of chromosome 1q21, which is associated with poor-prognosis multiple myeloma.

The genome of clonal multiple myeloma (MM) plasma cells is characterized by recurrent chromosomal translocations. While the mechanism of initiation of plasma cell dyscrasias is unknown, myeloma is thought to develop through a multistep process in which clonal selection and additional mutations are relevant for disease progression. Deletion of chromosome 13 as well as hypodiploidy and t(4;14) with dysregulated expression of MMSET/FGFR3 can be recognized as disease entities and they are associated with a poor prognosis.¹  As in many other cancers, rearrangements and changes of chromosome 1 are prevalent in multiple myeloma, and deletions of 1p and gains of 1q are frequently observed.

Comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) have revealed chromosomal gains of 1q, which may occur as iso-chromosomes, duplications, or jumping translocations. In addition, single-nucleotide polymorphism (SNP)-based mapping arrays have identified copy number changes of 1q at the submegabase level and loss of heterozygosity.²  In many cases, loss of heterozygosity is a major mechanism leading to expression of mutant genes. The DNA sequence and biologic annotation of chromosome 1 were recently published.³  Since chromosome 1 has 3141 genes, is one of the largest chromosomes, and has many overlapping coding sequences, it is a likely candidate for genetic events that lead to malignant transformation.

In this issue of Blood, Hanamura and colleagues demonstrate that the frequency of 1q21 amplifications is low in monoclonal gammopathy of undetermined significance (MGUS) and increases to 43% in the transition to overt multiple myeloma and 72% at relapse. Amplifications of 1q21 are concurrent with dysregulated expression of c-MAF, MMSET/FGFR3, or Del13 and are associated with a more aggressive clinical course of the disease. Their findings suggest that myeloma cells with more than 4 copies of 1q21 are associated with a drug-resistant phenotype. A recently presented analysis of the patients in the French Intergroupe Francophone du Myélome (IFM) trials did however not find an independent prognostic impact of 1q gains.⁴  The clinical translation of this finding is as yet questionable, since patients with amplifications of 1q21 do not benefit from alternative therapeutic strategies such as thalidomide.

The cellular and molecular mechanisms of 1q21 amplifications are not well understood. Previous studies suggested that CKS1B, BCL-9, or RAB25 may be crucial genes in 1q21-amplified cases, which could not be confirmed by others.²  The same investigators have suggested that CKS1B, which regulates proteolysis of the cyclin-dependent kinase inhibitor p27KIP1, is a candidate gene for myeloma progression.⁵ 

Finally, these data indicate the relevance of karyotypic and molecular analysis in patients with multiple myeloma. If indeed amplifications of 1q21 represent an independent unfavorable prognostic factor, new treatments are needed, since these patients do not benefit from recent improvements such as adding thalidomide to high-dose treatment. Since 1q21 amplification occurs in almost 50% of the patients, its relevance should then be evaluated in clinical trials with new antimyeloma drugs. ▪