Structural variant evolution after telomere crisis

Telomere crisis contributes to cancer genome evolution, yet only a subset of cancers display breakage-fusion-bridge (BFB) cycles and chromothripsis, hallmarks of previous experimental telomere crisis studies. We examine the spectrum of SVs instigated by natural telomere crisis. Spontaneous post-crisis clones from prior studies had both complex and simple SVs without BFB cycles or chromothripsis. In contrast, BFB cycles and chromothripsis occurred in clones that escaped from telomere crisis after CRISPR-controlled telomerase activation in MRC5 fibroblasts. This system revealed convergent evolutionary lineages altering one allele of 12p, where a short telomere likely predisposed to fusion. Remarkably, the 12p chromothripsis and BFB events were stabilized by independent fusions to 21. Telomere crisis can therefore generate a wide spectrum of SVs, and lack of BFB patterns and chromothripsis does not indicate absence of past crisis.