The expanding landscape of 'oncohistone' mutations in human cancers.

TitleThe expanding landscape of 'oncohistone' mutations in human cancers.
Publication TypeJournal Article
Year of Publication2019
AuthorsNacev, BA, Feng, L, Bagert, JD, Lemiesz, AE, Gao, JJ, Soshnev, AA, Kundra, R, Schultz, N, Muir, TW, C Allis, D
JournalNature
Volume567
Issue7749
Pagination473-478
Date Published2019 Mar
ISSN1476-4687
Abstract

Mutations in epigenetic pathways are common oncogenic drivers. Histones, the fundamental substrates for chromatin-modifying and remodelling enzymes, are mutated in tumours including gliomas, sarcomas, head and neck cancers, and carcinosarcomas. Classical 'oncohistone' mutations occur in the N-terminal tail of histone H3 and affect the function of polycomb repressor complexes 1 and 2 (PRC1 and PRC2). However, the prevalence and function of histone mutations in other tumour contexts is unknown. Here we show that somatic histone mutations occur in approximately 4% (at a conservative estimate) of diverse tumour types and in crucial 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 contain important post-translational modifications. Many globular domain mutations are homologous to yeast mutants that abrogate the need for SWI/SNF function, occur in the key regulatory 'acidic patch' of histones H2A and H2B, or are predicted to disrupt the H2B-H4 interface. The histone mutation dataset and the hypotheses presented here on the effect 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.

DOI10.1038/s41586-019-1038-1
Alternate JournalNature
PubMed ID30894748
PubMed Central IDPMC6512987
Grant ListT32 CA009512 / CA / NCI NIH HHS / United States
U24 CA220457 / CA / NCI NIH HHS / United States
P01 CA196539 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
F32 GM123659 / GM / NIGMS NIH HHS / United States