HPV infection-specific hypermethylated genes in oropharyngeal squamous cell carcinomas

Background: HPV-positive oropharyngeal squamous cell carcinomas (OPSCCs) are sensitive to chemo-radiation therapy and have favorable survival outcomes compared with HPV-negative cancers. These tumors are usually not related to tobacco and alcohol exposure. Therefore, it is crucial to diagnose HPV-positive OPSCCs for the appropriate management of the disease, and no suitable markers are available for HPV-positive tumors. In this study, we attempt to find HPV-specific epigenetic biomarkers for OPSCCs. Methods A total of 127 surgical samples were analyzed for HPV positivity and promoter methylation of a panel of genes. HPV detection was performed by PCR detection of HPV E6 and E7 viral oncoproteins. In addition, promoter methylation of a total of 8 genes ( DAPK , FHIT , RASSF1A , TIMP3 AGTR1 , CSGALNACT2 , GULP1 and VGF ) was analyzed by quantitative-methylation specific PCR (QMSP), and their associations with HPV positivity or RB/p16 expressions were evaluated. Results AGTR1 and FHIT were frequently methylated in HPV positive OPSCC samples with a good area under the curve (AUC over 0.70). In addition, these genes promoter methylation significantly associated with p16 positive and RB negative cases, which were the characteristics of OPSCC cases with favorable survival outcomes. Either of AGTR1 and FHIT methylated cases were significantly associated with HPV-positive cancers with 92.0% sensitivity (P < 0.001). Also, they had significantly better overall survival (P = 0.047) than both unmethylated cases. Conclusions A combination of AGTR1 and FHIT methylation demonstrated a suitable detection marker of OPSCCs derived from the HPV-infected field, which were familiar with p16-positive and RB-negative phenotypes.