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- Title
Stratification of HPV‐associated and HPV‐negative oropharyngeal squamous cell carcinomas based on DNA methylation epigenotypes.
- Authors
Nakagawa, Takuya; Matsusaka, Keisuke; Misawa, Kiyoshi; Ota, Satoshi; Fukuyo, Masaki; Rahmutulla, Bahityar; Kunii, Naoki; Sakurai, Daiju; Hanazawa, Toyoyuki; Matsubara, Hisahiro; Okamoto, Yoshitaka; Kaneda, Atsushi
- 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. What's new? Infection with human papilloma virus (HPV) generally lowers risk of death for patients with oropharyngeal squamous cell carcinoma but 20% of patients do not "benefit" from HPV infection in this sense. Here the authors used DNA methylome analysis to further subdivide HPV+ and HPV‐ cancer patients, successfully recapitulating the distinct prognosis. They also generated classifier markers to accurately distinguish between subtypes based on epigenome analysis, but not genomic mutations, thus potentially aiding with clinical treatment decisions in the future.
- Subjects
SQUAMOUS cell carcinoma; DNA methylation; HIERARCHICAL clustering (Cluster analysis); RECEIVER operating characteristic curves; PAPILLOMAVIRUSES
- Publication
International Journal of Cancer, 2020, Vol 146, Issue 9, p2460
- ISSN
0020-7136
- Publication type
Article
- DOI
10.1002/ijc.32890