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Nat Genet. 2017 Feb;49(2):180-185. doi: 10.1038/ng.3757. Epub 2017 Jan 9.

Impaired H3K36 methylation defines a subset of head and neck squamous cell carcinomas.

Author information

1
Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
2
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, New York, USA.
3
Department of Pediatrics, McGill University and McGill University Heath Centre Research Institute, Montreal, Quebec, Canada.
4
Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
5
Department of Pathology, Montreal Neurological Hospital, McGill University, Montreal, Quebec, Canada.
6
Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
7
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
8
Department of Pathology, University Health Network, Toronto, Ontario, Canada.
9
Department of Otolaryngology and Department of Surgical Oncology, Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
10
Wisconsin Institute for Discovery and Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA.
11
Department of Otolaryngology-Head and Neck Surgery, University of Western Ontario, London, Ontario, Canada.
12
Department of Oncology, University of Western Ontario, London, Ontario, Canada.
13
Department of Pathology and Laboratory Medicine, University of Western Ontario, London, Ontario, Canada.
14
Department of Microbiology and Immunology, Oncology and Otolaryngology-Head and Neck Surgery, University of Western Ontario, London, Ontario, Canada.
15
London Regional Cancer Program and Lawson Health Research Institute, London, Ontario, Canada.

Abstract

Human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (HNSCCs) are deadly and common cancers. Recent genomic studies implicate multiple genetic pathways, including cell signaling, cell cycle and immune evasion, in their development. Here we analyze public data sets and uncover a previously unappreciated role of epigenome deregulation in the genesis of 13% of HPV-negative HNSCCs. Specifically, we identify novel recurrent mutations encoding p.Lys36Met (K36M) alterations in multiple H3 histone genes. histones. We further validate the presence of these alterations in multiple independent HNSCC data sets and show that, along with previously described NSD1 mutations, they correspond to a specific DNA methylation cluster. The K36M substitution and NSD1 defects converge on altering methylation of histone H3 at K36 (H3K36), subsequently blocking cellular differentiation and promoting oncogenesis. Our data further indicate limited redundancy for NSD family members in HPV-negative HNSCCs and suggest a potential role for impaired H3K36 methylation in their development. Further investigation of drugs targeting chromatin regulators is warranted in HPV-negative HNSCCs driven by aberrant H3K36 methylation.

PMID:
28067913
PMCID:
PMC5549104
DOI:
10.1038/ng.3757
[Indexed for MEDLINE]
Free PMC Article

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