Structural variant evolution after telomere crisis.

Area of Science:

• Genomics
• Cancer Biology
• Cellular Stress Response

Background:

• Telomere crisis is a known driver of cancer genome evolution.
• Breakage-fusion-bridge (BFB) cycles and chromothripsis are hallmarks of experimental telomere crisis.
• The spectrum of genome rearrangements from natural telomere crisis is not fully understood.

Purpose of the Study:

• To investigate the range of structural variants (SVs) arising from natural telomere crisis.
• To compare genome rearrangements in spontaneous post-crisis clones versus experimentally induced crisis.

Main Methods:

• Analysis of structural variants in eight spontaneous post-crisis clones.
• Induction of telomere crisis in MRC5 fibroblast clones using CRISPR-controlled telomerase activation.
• Examination of genome rearrangements, including BFB cycles and chromothripsis, in experimental clones.

Main Results:

• Spontaneous post-crisis clones exhibited varied SVs, from simple to complex, without prominent BFB or chromothripsis.
• CRISPR-induced telomere crisis led to BFB cycles and chromothripsis, particularly involving chromosome 12p.
• Convergent evolution was observed in 12p rearrangements, with stabilization via fusion to chromosome 21.

Conclusions:

• Telomere crisis can generate a broad spectrum of structural variants.
• The absence of BFB patterns and chromothripsis in cancer genomes does not rule out past telomere crisis.
• Understanding the full spectrum of crisis-induced rearrangements is crucial for cancer genome evolution studies.