Frequent occurrence of large duplications at reciprocal genomic rearrangement breakpoints in multiple myeloma and other tumors

Abstract

Using a combination of array comparative genomic hybridization, mate pair and cloned sequences, and FISH analyses, we have identified in multiple myeloma cell lines and tumors a novel and recurrent type of genomic rearrangement, i.e. interchromosomal rearrangements (translocations or insertions) and intrachromosomal inversions that contain long (1–4000 kb; median ∼100 kb) identical sequences adjacent to both reciprocal breakpoint junctions. These duplicated sequences were generated from sequences immediately adjacent to the breakpoint from at least one—but sometimes both—chromosomal donor site(s). Tandem duplications had a similar size distribution suggesting the possibility of a shared mechanism for generating duplicated sequences at breakpoints. Although about 25% of apparent secondary rearrangements contained these duplications, primary IGH translocations rarely, if ever, had large duplications at breakpoint junctions. Significantly, these duplications often contain super-enhancers and/or oncogenes (e.g. MYC) that are dysregulated by rearrangements during tumor progression. We also found that long identical sequences often were identified at both reciprocal breakpoint junctions in six of eight other tumor types. Finally, we have been unable to find reports of similar kinds of rearrangements in wild-type or mutant prokaryotes or lower eukaryotes such as yeast.

Multiple myeloma immunoglobulin lambda translocations portend poor prognosis

“…1d, right, e.g., WHSC1 , MAF , and MAFB ). These data indicate that IgH translocations are mostly clonal whereas non-IgH translocations occur at sub-clonal frequencies, which is consistent with previous reports indicating IgH translocations are primary events whereas MYC translocations represent complex secondary events, and are often accompanied by duplications immediately adjacent to the translocation breakpoint 20,21 .…”

“…Indeed, 85% of cases that harbored MYC translocations also contained a MYC CNA, and these were primarily amplifications that abutted the translocation breakpoint. These amplifications are reported to result from large inversions at reciprocal translocation breakpoints 20 . Both amplifications and translocations resulted in commensurate upregulation of MYC as compared to other myelomas, but even those without a MYC structural variant, expressed MYC at a substantial level, supporting the notion that MYC overexpression is a common feature of myeloma 13 .…”

Microhomology-mediated end joining drives complex rearrangements and over-expression of MYC and PVT1 in multiple myeloma

“…Tandem-duplication breakpoints were enriched at the second hotspot (69.0% of breakpoints), Figure 5 and Supplementary Figures 7-8, as have been noted in MM cell lines previously. 34 Conversely, deletion breakpoints were enriched at the first hotspot (30.5%) and at an additional hotspot centromeric of MYC (chr8:126.3-126.4 Mb). Inversion breakpoints were equally spread across all three hotspots.…”

Functions and Clinical Significance of Super-Enhancers in Bone-Related Diseases

“…Diseases-related cells acquire SEs through various mechanisms, including (i)mutations and genomic alterations like deletions, duplications, translocations, insertions, inversions (Mansour et al, 2014;Oldridge et al, 2015;Zhang et al, 2019); (ii) single-nucleotide polymorphisms (SNPs) (Zhu et al, 2018); (iii) chromosomal rearrangements (Affer et al, 2014;Gröschel et al, 2014;Demchenko et al, 2016); and (iv) 3D genome structural changes (Furlong and Levine, 2018). Once the SEs originated through the above mechanisms, resulting in the dysregulation of nearby SEs-target genes, which ultimately accelerates the deterioration of diseases.…”