Chromosome 1q12 Instability Drives Both 1q21 Amplification and Arm-Length Deletions in Multiple Myeloma

Abstract Introduction Chromosome instability is a driver of copy number aberrations (CNAs) in cancer, and is a factor leading to tumor heterogeneity and resistance to therapy. In multiple myeloma (MM) CNAs involving 1q21 and p53 are high-risk secondary aberrations identified in increasing frequency in relapsed and refractory patients. The 1q21 region contains a large number of possible candidate genes which show amplification (amp) and/or deregulated expression important in myeloma pathogenesis; these genes include MCL1, MUC1, IL6R, BCL9, CKS1B, ANP32E, PSMD4 and ILF2, among others. Given that 1q21 copy number gains are one of the most frequent CNAs in all cancers, the mechanisms for the accumulation of CNAs of 1q21 in MM have important implications in cancer genomics. The most common mechanisms for CNAs of 1q21 in MM are direct and inverted duplications of 1q21, focal amplification of 1q12-23 by breakage-fusion-bridge (BFB) cycles, and unbalanced jumping translocations of 1q12 (JT1q12s) pericentromeric heterochromatin. JT1q12s translocate the entire 1q to the pericentromeric or telomeric regions of non-homologous receptor chromosomes (RCs). Unfortunately, in addition to an increase of 1q21 CNAs, collateral damage involving concomitant losses of arm-length segments of the RCs occurs in the unbalanced pericentromeric translocations. This type of loss may be an underappreciated mechanism for the accumulation of haploinsufficiency and loss of tumor suppressor genes in MM, which have been reported in other malignancies. In our cytogenetic database the most frequent losses of RCs associated with JT1q12 gains are losses of 16q, 19q, 1p, 6q, and 17p, respectively. Methods To investigate the cytogenetic impact and progression of these arm-level deletions in RCs we performed a comprehensive metaphase analysis of 50 patients showing segmental aneuploidies with 4 or more copies of 1q21. G-banding, metaphase FISH, and spectral karyotyping were used to identify the key transient and clonal structural aberrations of 1q12 resulting in concomitant segmental aneuploidies in RCs. Results The losses of 16q (8 patients), 19q (7 patients), and 17p (3 patients), were associated with whole-arm JT1q12s to the pericentromeric regions of these RCs. Losses of 6q (6 patients) were associated with a spectrum of JT1q12s aberrations which included the entire 6q from 6q10 through 6q27. Strikingly, isochromosome 1q (i1q) formation, which results in the deletion of 1p and gain of 1q (14 patients) showed the highest range CNAs for 1q21 (4-10). The higher copy number of 1q21 in the i1q patients resulted from BFB cycles of the 1q12-23 amplicon involving sister chromatid fusions (SCFs) at 1q12 breakpoints in these patients. Segmental amplifications of regions harboring MYC and MET were identified hitchhiking on JT1q12s, resulting in cryptic insertions in non-homologous RCs. Unexpectedly, BFB cycle amp of MYC involving SCFs at 1q12 breakpoints identified a novel mechanism for the amp of MYC in MM. Conclusion In this study the unbalanced pericentromeric translocation of 1q12 involving RCs 16q, 19q, 6q, and 17p provides evidence for recurring arm-length deletions in the cytogenetic progression of MM. Importantly, loss of 17p is currently recognized as a high risk-stratification marker by interphase FISH (iFISH), and has previously been shown to result from JT1q12s in a subset of patients. We suggest that the accumulation of other concomitant copy number gains of 1q21 and losses of RCs such as 16q, 19q, and 6q may provide new risk stratification markers in myeloma. Disclosures Davies: Seattle Genetics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Bristol-Myers: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Morgan: Takeda: Consultancy, Honoraria; Bristol Myers: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding.