Concurrent Amplification of MYC and 1q21 in Multiple Myeloma: Focal and Segmental Jumping Translocations of MYC

Abstract

IntroductionMultiple myeloma (MM) is characterized by an accumulation of secondary chromosome aberrations which lead to cytogenetically heterogeneous subpopulations of cells in the subclonal progression of this disease. Copy number aberrations (CNAs) represent a large proportion of these aberrations and include both numerical and structural chromosome aberrations which involve unbalanced translocations, amplifications, insertions, and deletions.Secondary MYC translocations are thought to play a role in driving the transition from MGUS to MM, and during tumor progression additional secondary CNAs of both MYC (8q24) and 1q21 are found in relapsed patients. When CNAs are taken into account the percentage of myeloma cases where MYC is deregulated is 55%, making it the most common genetic event in MM (Walker B. et al., Nature Comm, 2015). In fact, high resolution SNP arrays have shown that somatic CNAs of MYC and 1q21 are two of the top ten CNAs in all cancers (Beroukhim R. et al., Nature, 2010). Two types of amplification predominate by SNPs array, either large arm-length amplifications (25% of the genome) or small focal CNAs (10% of the genome). Unfortunately, the origins of the complex structural chromosomal aberrations which underlie these types CNAs have not been well characterized in MM.To better understand the possible relationship between MYC and 1q21 CNAs we undertook a comprehensive metaphase cytogenetic analysis of 26 diagnostic specimens showing concurrent MYC and 1q21 CNAs by G-banding.MethodsLocus specific FISH probes and Spectral karyotyping were used to define and follow the progression of aberrations occurring in these two regions. Locus specific FISH probes for selected regions of chromosomes 1 and 8 pericentromeric regions and the regions surrounding 1q21 and 8q24 were utilized.ResultsThree primary aberration patterns were observed:The most frequent pattern involved copy number gains in both regions, apparently occurring independently of each other (sixteen patients).The second most frequent pattern showed unbalanced segmental jumping translocations (SJTs) of 8q and the MYC locus to different receptor chromosomes. These unbalanced translocations of MYC were found in seven patients involving varying sized segments of 8q, and included both intra and inter-chromosomal translocations. Surprisingly, three patients in this group showed clones with the co-amplification of MYC and 1q21 on the same derivative chromosome, where 8q and MYC were in essence piggybacking on jumping translocations of 1q12 (JT1q12) to receptor chromosomes.Finally, the third and most complex structural aberration pattern involved the breakage-fusion-bridge cycle mechanism, which results in focal amplifications of genes. This mechanism typically results from telomere shortening and loss and subsequent formation of dicentric chromosomes. Evidence of dicentric chromosomes 8 and the breakage fusion break amplification of MYC was identified in three patients and, strikingly, in one case was found to be initiated by a JT1q12 to 8qter. Therefore, this case identifies a novel alternative mechanism for the focal amplification of the MYC locus whereby the JT1q12 initiates sister chromatid fusion at 8q24.ConclusionWe demonstrate for the first time the mechanistic coupling of MYC and 1q21 amplifications involving sequential jumping translocations of 8q and JT1q12s. These findings provide evidence for the origin of both arm-length and focal amplifications of MYC, and that these aberrations can co-evolve in the same clones. The concurrent amplification of MYC and 1q21 suggests pericentromeric instability, and to a lesser extent telomeric instability, play a role in driving CNAs of both of these genomic lesions in MM. DisclosuresDavies:Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Morgan:Univ of AR for Medical Sciences: Employment; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Bristol Meyers: Consultancy, Honoraria; Janssen: Research Funding.