Therapy-associated mutagenesis at CTCF binding sites is shaped by chromatin context and DNA repair capacity

Area of Science:

• Genomics
• Cancer Biology
• Epigenetics

Background:

• Genotoxic cancer therapies induce DNA damage, leading to somatic mutations in tumor cells.
• The impact of these mutations on crucial regulatory elements like CTCF binding sites (CBS) is not well understood.

Purpose of the Study:

• To investigate whether cancer treatments increase mutagenesis at CTCF binding sites (CBS).
• To analyze the association between specific therapies and mutation enrichment at CBS across various cancer types.

Main Methods:

• Analysis of 4,870 whole-genome sequences from metastatic tumors across 17 cancer types.
• Examination of mutation patterns at CTCF binding sites (CBS) in relation to 45 different therapies.
• Correlation of mutation enrichment with genomic context (motif presence, expression levels, replication timing) and DNA damage response gene alterations.

Main Results:

• Radiotherapy and trifluridine exposure in metastatic colorectal cancer showed increased mutation enrichment at CBS.
• Mutation enrichment was more pronounced at motif-containing CBS and in specific genomic contexts (low-expression, late-replicating).
• Alterations in DNA damage response genes, such as BRCA2, were linked to higher CBS mutation rates after radiotherapy.

Conclusions:

• Therapy-induced mutagenesis affects CTCF binding sites, impacting genome regulatory architecture.
• The extent of mutagenesis at CBS is influenced by chromatin context and the tumor's DNA repair capacity.
• These findings highlight how cancer treatments can reshape the regulatory landscape of the genome.