Abstract
Telomere crisis contributes to cancer genome evolution, yet only a subset of cancers display breakage-fusion-bridge (BFB) cycles and chromothripsis, hallmarks of experimental telomere crisis identified in previous studies. We examine the spectrum of structural variants (SVs) instigated by natural telomere crisis. Eight spontaneous post-crisis clones did not show prominent patterns of BFB cycles or chromothripsis. Their crisis-induced genome rearrangements varied from infrequent simple SVs to more frequent and complex SVs. In contrast, BFB cycles and chromothripsis occurred in MRC5 fibroblast clones that escaped telomere crisis after CRISPR-controlled telomerase activation. This system revealed convergent evolutionary lineages altering one allele of chromosome 12p, where a short telomere likely predisposed to fusion. Remarkably, the 12p chromothripsis and BFB events were stabilized by independent fusions to chromosome 21. The data establish that telomere crisis can generate a wide spectrum of SVs implying that a lack of BFB patterns and chromothripsis in cancer genomes does not indicate absence of past telomere crisis.
Highlights
Telomere crisis contributes to cancer genome evolution, yet only a subset of cancers display breakage-fusion-bridge (BFB) cycles and chromothripsis, hallmarks of experimental telomere crisis identified in previous studies
In order to determine the structural variants (SVs) in post-telomere crisis genomes, we examined nine SV40 large T-transformed cell lines that had undergone spontaneous telomerase activation after passage into telomere crisis (Supplementary Table 1 and Supplementary Fig. 1A)
We have described the first whole-genome profiles of cells emerging from natural telomere crisis, both in the setting of spontaneous and controlled telomerase activation
Summary
Telomere crisis contributes to cancer genome evolution, yet only a subset of cancers display breakage-fusion-bridge (BFB) cycles and chromothripsis, hallmarks of experimental telomere crisis identified in previous studies. Eight spontaneous post-crisis clones did not show prominent patterns of BFB cycles or chromothripsis Their crisis-induced genome rearrangements varied from infrequent simple SVs to more frequent and complex SVs. In contrast, BFB cycles and chromothripsis occurred in MRC5 fibroblast clones that escaped telomere crisis after CRISPR-controlled telomerase activation. BFB cycles and chromothripsis occurred in MRC5 fibroblast clones that escaped telomere crisis after CRISPR-controlled telomerase activation This system revealed convergent evolutionary lineages altering one allele of chromosome 12p, where a short telomere likely predisposed to fusion. SVs (including chromothripsis, breakage-fusion-bridge (BFB) cycles, and double minutes), identify novel event classes, and study the rearranged structure of aneuploid alleles[3]. Telomere crisis, which is thought to occur at an early stage of carcinogenesis before a telomere maintenance mechanism is activated[15], has been suggested as a cause of cancer genome SVs
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