Laboratory of Cell Biology and Genetics, Rockefeller University, New York, NY, USA.
Tri-Institutional Ph.D. Program in Computational Biology and Medicine, Weill Cornell Medicine, New York, NY, USA.
Nat Commun. 2021 Apr 7;12(1):2093. doi: 10.1038/s41467-021-21933-7.
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.
端粒危机导致癌症基因组进化，但只有一部分癌症表现出断裂-融合-桥接（BFB）循环和染色体重排，这是先前研究中确定的实验性端粒危机的标志。我们研究了由自然端粒危机引发的结构变异（SV）谱。8 个自发的危机后克隆没有表现出明显的 BFB 循环或染色体重排模式。它们由危机引起的基因组重排从罕见的简单 SV 到更频繁和复杂的 SV 不等。相比之下，BFB 循环和染色体重排发生在 MRC5 成纤维细胞克隆中，这些克隆在 CRISPR 控制的端粒酶激活后逃脱了端粒危机。该系统揭示了趋同进化谱系，改变了 12p 染色体的一个等位基因，其中短端粒可能容易融合。值得注意的是，12p 染色体重排和 BFB 事件通过与 21 号染色体的独立融合得到稳定。这些数据表明，端粒危机可以产生广泛的 SV，这意味着癌症基因组中缺乏 BFB 模式和染色体重排并不表明过去没有端粒危机。
