Structural variant evolution after telomere crisis

Sally M. Dewhurst, Xiaotong Yao, Joel Rosiene, Huasong Tian, Julie Behr, Nazario Bosco, Kaori K. Takai, Titia de Lange () and Marcin Imieliński ()
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Sally M. Dewhurst: Rockefeller University
Xiaotong Yao: Weill Cornell Medicine
Joel Rosiene: Weill Cornell Medicine
Huasong Tian: Weill Cornell Medicine
Julie Behr: Weill Cornell Medicine
Nazario Bosco: Rockefeller University
Kaori K. Takai: Rockefeller University
Titia de Lange: Rockefeller University
Marcin Imieliński: Weill Cornell Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21933-7

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