Journal
NATURE GENETICS
Volume 49, Issue 2, Pages 180-185Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3757
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Funding
- US National Institutes of Health (NIH) [P01CA196539, K99CA212257, T32GM008275]
- Rockefeller University
- Wisconsin Institute for Discovery
- Greater Milwaukee Foundation
- Sidney Kimmel Foundation (Kimmel Scholar Award)
- Canadian Institutes for Health Research (CIHR) [MOP 142491, MOP 340674]
- Cedars Cancer Foundation
- Leukemia and Lymphoma Society Dr. Robert Arceci Scholar Award
- Genome Canada
- Genome Quebec
- Institute for Cancer Research of the CIHR
- McGill University
- Damon Runyon Cancer Research Foundation [DRG-2195-14]
- Fond de la Recherche du Quebec en Sante
- Canada Research Chair (tier 2)
- TD Trust/Montreal Children's Hospital Foundation
- CIHR
- Montreal Children's Hospital Foundation
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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.
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