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
Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, New York, USA.
Nat Genet. 2017 Feb;49(2):180-185. doi: 10.1038/ng.3757. Epub 2017 Jan 9.
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.
人乳头瘤病毒（HPV）阴性的头颈部鳞状细胞癌（HNSCC）是常见的致命癌症。最近的基因组研究表明，多种遗传途径，包括细胞信号传导、细胞周期和免疫逃逸，在其发展过程中发挥作用。在此，我们分析了公共数据集，发现表观基因组失调在13%的HPV阴性HNSCC发生过程中存在一个此前未被认识到的作用。具体而言，我们在多个H3组蛋白基因中鉴定出编码p.Lys36Met（K36M）改变的新型复发性突变。我们进一步在多个独立的HNSCC数据集中验证了这些改变的存在，并表明，与先前描述的NSD1突变一起，它们对应于一个特定的DNA甲基化簇。K36M替代和NSD1缺陷共同作用，改变组蛋白H3在K36（H3K36）位点的甲基化，随后阻断细胞分化并促进肿瘤发生。我们的数据进一步表明，在HPV阴性的HNSCC中，NSD家族成员的冗余性有限，并提示H3K36甲基化受损在其发展过程中可能发挥的作用。对于由异常H3K36甲基化驱动的HPV阴性HNSCC，有必要进一步研究针对染色质调节剂的药物。
