The expanding landscape of ‘oncohistone’ mutations in human cancers

Mutations in epigenetic pathways are common oncogenic drivers. Histones, the fundamental substrate for chromatin-modifying and remodeling enzymes, are mutated in tumors including in gliomas, sarcomas, head and neck cancers, and carcinosarcomas. Classical ‘oncohistone’ mutations occur in the N-terminal tail of histone H3 and impact the function of Polycomb Repressor Complexes 1 and 2. However, the prevalence and function of histone mutations in additional tumor contexts is unknown. Here we show that somatic histone mutations conservatively occur in ~ 4% of tumors of diverse types and in critical regions of histone proteins. Mutations occur in all four core histones, in both the N-terminal tails and globular histone fold domains, and at or near residues that harbor important post-translational modifications. Many globular domain mutations are either homologous to yeast mutants that abrogate the need for SWI/SNF function, occur in the key regulatory ‘acidic patch’ of histone H2A and H2B, or are predicted to disrupt the H2B-H4 interface. The histone mutation dataset (https://bit.ly/2GXH5Ve) and the hypotheses presented herein on the impact of the mutations on important chromatin functions should serve as a resource and starting point for the chromatin and cancer biology fields in exploring an expanding role of histone mutations in cancer.