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Nature. 2019 Mar;567(7749):473-478. doi: 10.1038/s41586-019-1038-1. Epub 2019 Mar 20.

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

Author information

1
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
2
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY, USA.
3
Department of Chemistry, Princeton University, Princeton, NJ, USA.
4
Department of Chemistry, Princeton University, Princeton, NJ, USA. muir@princeton.edu.
5
Memorial Sloan Kettering Cancer Center, New York, NY, USA. alliscd@mail.rockefeller.edu.
6
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY, USA. alliscd@mail.rockefeller.edu.

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.

PMID:
30894748
PMCID:
PMC6512987
[Available on 2019-09-20]
DOI:
10.1038/s41586-019-1038-1

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