Identification of an atypical etiological head and neck squamous carcinoma subtype featuring the CpG island methylator phenotype

Abstract

Head and neck squamous cell carcinoma (HNSCC) is broadly classified into HNSCC associated with human papilloma virus (HPV) infection, and HPV negative HNSCC, which is typically smoking-related. A subset of HPV negative HNSCCs occur in patients without smoking history, however, and these etiologically ‘atypical’ HNSCCs disproportionately occur in the oral cavity, and in female patients, suggesting a distinct etiology.To investigate the determinants of clinical and molecular heterogeneity, we performed unsupervised clustering to classify 528 HNSCC patients from The Cancer Genome Atlas (TCGA) into putative intrinsic subtypes based on their profiles of epigenetically (DNA methylation) deregulated genes.HNSCCs clustered into five subtypes, including one HPV positive subtype, two smoking-related subtypes, and two atypical subtypes. One atypical subtype was particularly genomically stable, but featured widespread gene silencing associated with the ‘CpG island methylator phenotype’ (CIMP).Further distinguishing features of this ‘CIMP-Atypical’ subtype include an antiviral gene expression profile associated with pro-inflammatory M1 macrophages and CD8+ T cell infiltration, CASP8 mutations, and a well-differentiated state corresponding to normal SOX2 copy number and SOX2OT hypermethylation. We developed a gene expression classifier for the CIMP-Atypical subtype that could classify atypical disease features in two independent patient cohorts, demonstrating the reproducibility of this subtype. Taken together, these findings provide unprecedented evidence that atypical HNSCC is molecularly distinct, and postulates the CIMP-Atypical subtype as a distinct clinical entity that may be caused by chronic inflammation.

VirTect: a computational method for detecting virus species from RNA-Seq and its application in head and neck squamous cell carcinoma

“…Although only two patients had detectable HPV33 fragments, this is consistent with the report that HPV33 rarely induces HNSCC (45).…”

“…For example, human papillomavirus (HPV) comprises a group of more than 200 related viruses, and some HPV subtypes were found to be associated with specific types of cancers such as cervical, vaginal, vulvar, anal, penile, and head and neck squamous cell carcinomas (HNSCC) (16)(17)(18). The oncogenic HPV subtypes (e.g., subtypes 16,18,31,33,35,39,45, 51, 52, 56, 58, 59 and 68) are sexually transmitted viruses (19)(20)(21)(22). Importantly, the proportion of HNSCCs that are HPVpositive increased from 18% in 1973 to 32% in 2005 in the USA, representing an unprecedented and dramatic epidemiologic spike (23).…”

Detection of human papillomavirus in cases of head and neck squamous cell carcinoma by RNA‐seq and VirTect

“…Also, the cervical cancer high‐risk strain HPV18 was not detected in any of the tested samples, but HPV33 was detected. Although only two patients had detectable HPV33 fragments, this is consistent with the report that HPV33 rarely induces HNSCC (Brennan et al ., ).…”

Somatic mutations and promotor methylation of the ryanodine receptor 2 is a common event in the pathogenesis of head and neck cancer

“…In addition to genomic mutations, the accumulation of epigenetic alterations has been identified as a hallmark of HNSCC. Epigenetic alterations and in particular aberrant DNA methylation of CpG units in the proximity of predicted transcription start sites (TSS) are common features of HNSCC and often result in gene expression silencing and signaling pathway deregulation . In many cancers, epigenetic events linked to tumor suppressor gene inactivation through promoter hypermethylation are even more frequent than somatic mutations and could drive neoplastic initiation and malignant progression .…”

“…Epigenetic alterations and in particular aberrant DNA methylation of CpG units in the proximity of predicted transcription start sites (TSS) are common features of HNSCC and often result in gene expression silencing and signaling pathway deregulation. [18][19][20] In many cancers, epigenetic events linked to tumor suppressor gene inactivation through promoter hypermethylation are even more frequent than somatic mutations and could drive neoplastic initiation and malignant progression. 21 So far, only a limited number of studies conducted an integrative approach considering both somatic mutations and gene promoter methylation to unravel new key regulators in the pathogenesis of HNSCC.…”