Fig. 4: A schematic view of the mechanisms behind gain and amplification of MDM2 in lipomatous tumors.

a The initial event is duplication of one or more large (often >10 Mb) segments from chromosome arm 12q (oval circles represent centromeres; horizontal bars represent telomeres). b These duplicated segments can, after more or less extensive reorganization, either be (top) inserted in one of the two homologs of Chr12, as exemplified by Case 2, or (middle) translocated to one or more other chromosomes, as exemplified by Case 3; in both scenarios the gained 12q segments end up in a chromosome with intact telomeres, providing relative mitotic stability. The third option (bottom) involves circularization of the gained segments in a ring chromosome, which subsequently develops a neocentromere (beige oval circle); the structural variants, as well as the copy number data in Case 16, suggest that gain of 12q precedes co-amplification with other chromosomes. Due to mitotic instability, the ring chromosome will experience extensive copy number alterations, resulting in amplification of some segments. c The ring will occasionally break up to form a rod-shaped structure (see Fig. 1d) and fuse with material from other chromosomes, notably Chr1. d The consistent finding of structural variants fusing the most telomeric sequences of the gained sequences from Chr12 and co-amplified chromosomes, as seen in Cases 5, 16, 20, and 21, strongly suggests that the newly formed rod-shaped chromosome is dicentric. e After breakage-fusion-bridge cycles, the dicentric chromosome will break and form a new ring chromosome. f After further cycles of breaking up and recircularization, the amplified structure will eventually capture telomeres from other chromosomes and become relatively stable.