Using TOP2B binding maps and sequencing data from over 6,000 cancer genomes, researchers focus on non-coding regions and identify hundreds of potential cancer-driving mutations, highlighting non-coding RNA gene RMRP as a key player in tumor initiation and growth.

The findings point to new genetic underpinnings of cancers and raise implications for treatment, including risks tied to existing topoisomerase-targeting chemotherapies that can affect TOP2B and potentially promote treatment-related cancers.

Overall, the study expands understanding of how genome topology and non-coding regions shape cancer mutational landscapes and may inform future diagnostics and therapies.

Co-authors stress the need to couple computational analyses with experimental validation and propose CRISPR-based exploration of similar non-coding sites to uncover additional hidden cancer drivers.

Led by Dr. Juri Reimand at the Ontario Institute for Cancer Research, the work links TOP2B’s normal cellular role to the accumulation of mutations in cancer, including non-coding driver mutations.

The research casts TOP2B as a double-edged sword, active in regions shaping gene expression and chromosome structure, which can become mutation hotspots and offer new ways to identify driver mutations before and after chemotherapy.

Mapping TOP2B binding during DNA untangling reveals mutations cluster at these sites, with dozens of established cancer-driving mutations identified there.

Functional genomics and mouse model studies validate that RMRP drives cancer initiation and progression, reinforcing its role alongside TOP2B-bound regions.