Cancer histone mutations impact protein binding and DNA repair with possible links to genomic instability.

Histones are key epigenetic factors that regulate the accessibility and compaction of eukaryotic genomes, affecting DNA replication and repair, and gene expression. Recent studies have demonstrated that histone missense mutations can perturb normal histone function, promoting the development of phenotypically distinguishable cancers. However, most histone mutations observed in cancer patients remain enigmatic in their potential to promote cancer development. To assess the oncogenic potential of histone missense mutations, we have gathered whole-exome sequencing data for the tumors of about 12 000 patients. Histone mutations occurred in about 16% of cancer patients, although specific cancer types showed substantially higher rates. Using genomic, structural, and biophysical analyses, we found several predominant modes of action by which histone mutations may alter function. Namely, cancer missense mutations primarily affected histone acidic patch residues and protein-binding interfaces in a cancer-specific manner and targeted interaction interfaces with specific DNA repair proteins. Consistent with this finding, we observed a high tumor mutational burden in patients with histone mutations affecting interactions with proteins involved in maintaining genome integrity. We identified potential cancer driver mutations in several histone genes, including mutations on histone H4-a highly conserved histone without previously documented driver mutations.