A Clinically Distinct and ‘Atypical’ Subgroup of Head and Neck Cancers Positive for a CpG Island Methylator Phenotype

The current era of genomic medicine has greatly increased our un2) Stem-like smoking, 3) CIMP-Atypical, 4) Non-CIMP-Atypical and 5) derstanding of the inter-connectedness of genetic, epigenetic, transcriptomic and proteomic profiles of human health and disease, none more evident than in human cancer. While human cancer genomics has primarily focused on genetic mutations and copy number alterations, epigenetic changes, namely DNA methylation and chromatin modifications are highly prevalent in every cancer type, occur more frequently than genetic alterations in human cancers (Schuebel et al., 2007) and can result in gene expression modulation. Human cancers are characterized by global DNA hypomethylation of repetitive elements and CpG-poor regions together with gene-specific, promoter CpG island DNA hypermethylation. DNA methylation changes may result in tumor suppressor gene silencing and the activation of oncogenes. This aspect of cancer epigenetics is compelling, as unlike somatic mutations and copy number alterations, cancer-specific DNA methylation changes can be reversed by treatmentwith DNAmethylation inhibitors, such as 5-aza-cytidine (5-Aza-CR) and 5-aza-2′-deoxycytidine (5-AzaCdR), which have been used in treatment of human cancers (reviewed in Raynal and Issa (2016)). DNA methylation-based subgroups of human cancers have been identified that show clinical utility. Evidence of a CpG IslandMethylator Phenotype (CIMP) was first described in colorectal cancer as DNA hypermethylation of a subset of CpG islands in a subset of tumors (reviewed in Weisenberger (2014)). CIMP status is also identified in glioblastoma, gastric cancer, endometrial and breast cancers (reviewed inWeisenberger (2014)). Colorectal CIMPwas further shown to strongly correlate with a point mutation in the BRAF gene, older patient age and female gender (Weisenberger et al., 2006). Overall, CIMPs generally do not present with a consistent genomic profile, suggesting that CIMPs can result from multiple and unique sets of aberrations (Weisenberger, 2014). In the accompanying report, Brennan and colleagues (Brennan et al., 2017-in this issue) describe a CIMP for head and neck squamous cell carcinomas (HNSCCs) after meta analyses of TCGA DNA methylation and gene expression datasets (The Cancer Genome Atlas Network, 2015). There arefive HNSCC subgroups based on human papillomavirus infection (HPV+), CIMP status and smoking history: 1) NSD1-smoking,