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

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.

Indexed on Europe PMC as PubMed record 28067913 (DOI 10.1038/ng.3757). Its author list gives "Nichols AC" with the affiliation "Department of Otolaryngology-Head and Neck Surgery, University of Western Ontario, London, Ontario, Canada", which names Verspeeten Family Cancer Centre, London Health Sciences Centre; that is how the record was matched to Anthony C. Nichols, and no figure has been checked by an editor.