Stratification of HPV‐associated and HPV‐negative oropharyngeal squamous cell carcinomas based on DNA methylation epigenotypes

Abstract

While the incidence of oropharyngeal squamous cell carcinoma (OPSCC) has been increasing in these two decades, primarily due to human papillomavirus (HPV), stratification of OPSCC into molecular subgroups showing different clinicopathological features has not been fully investigated. We performed DNA methylome analysis using Infinium 450k for 170 OPSCC cases, including 89 cases in our cohort and 81 cases reported by The Cancer Genome Atlas, together with targeted exon sequencing analysis. We stratified OPSCC by hierarchical clustering analysis using methylome data. Methylation levels of classifier markers were validated quantitatively using pyrosequencing, and area under the curve (AUC) values of receiver operating characteristics (ROC) curves were calculated. OPSCC was stratified into four epigenotypes: HPV(+) high‐methylation (OP1), HPV(+) intermediate‐methylation (OP2), HPV(−) intermediate‐methylation (OP3) and HPV(−) low‐methylation (OP4). Ten methylation marker genes were generated: five to classify HPV(+) cases into OP1 and OP2, and five to classify HPV(−) cases into OP3 and OP4. AUC values of ROC curves were 0.969 and 0.952 for the two marker panels, respectively. While significantly higher TP53 mutation and CCND1 copy number gains were observed in HPV(−) than in HPV(+) groups (p < 0.01), no significant difference of genomic aberrations was observed between OP1 and OP2, or OP3 and OP4. The four epigenotypes showed significantly different prognosis (p = 0.0006), distinguishing the most favorable OPSCC subgroup (OP1) among generally favorable HPV(+) cases, and the most unfavorable OPSCC subgroup (OP3) among generally unfavorable HPV(−) cases. HPV(+) and HPV(−) OPSCC are further divided into distinct DNA methylation epigenotypes, showing significantly different prognosis.

Identification of novel methylation markers in HPV-associated oropharyngeal cancer: genome-wide discovery, tissue verification and validation testing in ctDNA

“…The incidence of human papilloma virus (HPV)-associated oropharyngeal cancer (OPC) has increased in recent decades and is now the most prevalent HPV-related cancer in developed countries [4]. An estimated 70-80% of OPCs are now attributed to HPV in the United States, western Europe and Japan [5]. Compared with smoking-related or alcohol-related OPC, HPV positivity is associated with a better prognosis [6].…”

G Protein-Coupled Receptor Genes, PTGDR1, PTGDR2, and PTGIR, Are Candidate Epigenetic Biomarkers and Predictors for Treated Patients with HPV-Associated Oropharyngeal Cancer

“…Cervical cancer is the most common HPV-associated cancer among women, and oropharyngeal cancers (OPC) are the most common among men [ 8 ]. It is characterized with a few genomic alterations in TP53 and p16 but may also exhibit phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha ( PIK3CA ) alterations, copy-number gains in TNF receptor-associated factor 3 and E2F transcription factor 1 (E2F1), and lack of cyclin D1 ( CCND1 ) amplification as compared to HPV-negative cancers [ 9 ]. Studies have revealed the correlation between DNA methylation and several cancer types, especially virus-associated cancers [ 10 ].…”

Long interspersed nuclear element 1 hypomethylation has novel prognostic value and potential utility in liquid biopsy for oral cavity cancer

“…Current pre-and post-treatment surveillance for HNSCC patients involve clinical evaluation combined with flexible endoscopy and conventional imaging [3]. HNSCC is a heterogeneous disease, and although molecular studies have been used in distinguishing HPV-positive from HPV-negative HNSCC, validated molecular characterizations have not yet been established [4][5][6].…”