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

• Published in: Nature genetics Vol. 49; no. 2; pp. 180 - 185
• Main Authors: Papillon-Cavanagh, Simon, Lu, Chao, Gayden, Tenzin, Mikael, Leonie G, Bechet, Denise, Karamboulas, Christina, Ailles, Laurie, Karamchandani, Jason, Marchione, Dylan M, Garcia, Benjamin A, Weinreb, Ilan, Goldstein, David, Lewis, Peter W, Dancu, Octavia Maria, Dhaliwal, Sandeep, Stecho, William, Howlett, Christopher J, Mymryk, Joe S, Barrett, John W, Nichols, Anthony C, Allis, C David, Majewski, Jacek, Jabado, Nada
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2017; Nature Publishing Group
• Subjects: 631/208/212/177; 631/67/1536; Agriculture; analysis; Animal Genetics and Genomics; Biomedicine; Cancer Research; Carcinogenesis - genetics; Carcinoma, Squamous Cell - genetics; Care and treatment; Cell Differentiation - genetics; Deregulation; Development and progression; DNA methylation; DNA Methylation - genetics; Epigenesis, Genetic - genetics; Gene expression; Gene Function; Gene mutation; Genes; Genetic aspects; Head and neck cancer; Head and Neck Neoplasms - genetics; Health aspects; Histones; Histones - genetics; Human Genetics; Humans; Intracellular Signaling Peptides and Proteins - genetics; Mutation; Mutation - genetics; Nuclear Proteins - genetics; Papillomaviridae - pathogenicity; Papillomavirus Infections - genetics; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck; Studies
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.3757

Nada Jabado, Jacek Majewski and colleagues identify mutations in multiple histone H3 genes causing recurrent p.Lys36Met alterations in head and neck squamous cell carcinomas. They show that tumors with these p.Lys36Met alterations correspond to a specific DNA methylation cluster along with tumors harboring previously described mutations in NSD1 . 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.