title: Impaired H3K36 methylation defines a subset of head and neck squamous cell carcinomas.
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.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Simon
authors.identifier: http://orcid.org/0000-0002-0372-2266
authors.initials: S
authors.lastname: Papillon-Cavanagh
authors.affiliation: Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, New York, USA.
authors.forename: Chao
authors.identifier: http://orcid.org/0000-0003-0982-8122
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Tenzin
authors.initials: T
authors.lastname: Gayden
authors.affiliation: Department of Pediatrics, McGill University and McGill University Heath Centre Research Institute, Montreal, Quebec, Canada.
authors.forename: Leonie G
authors.initials: LG
authors.lastname: Mikael
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Denise
authors.initials: D
authors.lastname: Bechet
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Christina
authors.initials: C
authors.lastname: Karamboulas
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Laurie
authors.initials: L
authors.lastname: Ailles
authors.affiliation: Department of Pathology, Montreal Neurological Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Jason
authors.initials: J
authors.lastname: Karamchandani
authors.affiliation: Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Dylan M
authors.initials: DM
authors.lastname: Marchione
authors.affiliation: Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Garcia
authors.affiliation: Department of Pathology, University Health Network, Toronto, Ontario, Canada.
authors.forename: Ilan
authors.initials: I
authors.lastname: Weinreb
authors.affiliation: Department of Otolaryngology and Department of Surgical Oncology, Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Goldstein
authors.affiliation: Wisconsin Institute for Discovery and Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Lewis
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Octavia Maria
authors.identifier: http://orcid.org/0000-0003-2596-7843
authors.initials: OM
authors.lastname: Dancu
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Western Ontario, London, Ontario, Canada.|Department of Oncology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Dhaliwal
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Western Ontario, London, Ontario, Canada.
authors.forename: William
authors.initials: W
authors.lastname: Stecho
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Western Ontario, London, Ontario, Canada.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Howlett
authors.affiliation: Department of Microbiology and Immunology, Oncology and Otolaryngology-Head and Neck Surgery, University of Western Ontario, London, Ontario, Canada.|London Regional Cancer Program and Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: Joe S
authors.initials: JS
authors.lastname: Mymryk
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Western Ontario, London, Ontario, Canada.|Department of Oncology, University of Western Ontario, London, Ontario, Canada.|London Regional Cancer Program and Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: John W
authors.initials: JW
authors.lastname: Barrett
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Western Ontario, London, Ontario, Canada.|Department of Oncology, University of Western Ontario, London, Ontario, Canada.|London Regional Cancer Program and Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: Anthony C
authors.identifier: http://orcid.org/0000-0002-0760-980X
authors.initials: AC
authors.lastname: Nichols
authors.affiliation: Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, New York, USA.
authors.forename: C David
authors.initials: CD
authors.lastname: Allis
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Jacek
authors.identifier: http://orcid.org/0000-0003-3572-9558
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.|Department of Pediatrics, McGill University and McGill University Heath Centre Research Institute, Montreal, Quebec, Canada.
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
mesh_terms: D063646:Carcinogenesis / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics; D006258:Head and Neck Neoplasms / Q000235:genetics*; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D027383:Papillomaviridae / Q000472:pathogenicity; D030361:Papillomavirus Infections / Q000235:genetics; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C113272:NSD1 protein, human