Topoisomerase IIb binding delineates localized mutational processes and driver mutations in cancer genomes

Area of Science:

• Genomics
• Molecular Biology
• Cancer Research

Background:

• Topoisomerases are crucial for DNA topology, with Type-II topoisomerases creating double-strand breaks.
• Topoisomerases are chemotherapy targets, but TOP2B's unique role in non-dividing cells and sensitivity to poisons warrants further investigation.
• Understanding TOP2B's function is key to deciphering its impact on mutagenesis and cancer development.

Purpose of the Study:

• To map DNA-binding sites of TOP2B, CTCF, and RAD21 in human cancer samples.
• To analyze these binding sites for driver mutations and mutational processes across a large cancer genome cohort.
• To elucidate TOP2B's role in maintaining genome integrity and its implications for cancer genomics.

Main Methods:

• Generated DNA-binding maps of TOP2B, CTCF, and RAD21.
• Analyzed 6500 whole cancer genomes for driver mutations and mutational processes.
• Investigated TOP2B-bound elements, including non-coding regions, for functional impact.

Main Results:

• TOP2B-CTCF-RAD21 and TOP2B-RAD21 sites are significantly enriched in somatic mutations and structural variants.
• Enrichment of mutations occurs at evolutionarily conserved, highly transcribed, and long-range chromatin interaction sites.
• TOP2B binds to key cancer driver genes (TP53, MYC, FOXA1, VHL) and frequently mutated non-coding regions, including an RMRP element driving tumor growth in vivo.

Conclusions:

• TOP2B plays a critical role in safeguarding genome integrity in cancer.
• TOP2B binding sites serve as markers for mutational processes and hotspots within the cancer genome.
• These findings have significant implications for cancer genomics research and understanding therapy-related genotoxicity.