TY - JOUR
T1 - High-risk HPV infection-associated hypermethylated genes in oropharyngeal squamous cell carcinomas
AU - Inokawa, Yoshikuni
AU - Hayashi, Masamichi
AU - Begum, Shahnaz
AU - Noordhuis, Maartje G.
AU - Sidransky, Daivd
AU - Califano, Joseph
AU - Koch, Wayne
AU - Brait, Mariana
AU - Westra, William H.
AU - Hoque, Mohammad O.
N1 - Funding Information:
This work was supported by a career development award to M. O. Hoque from the Specialized Program of Research Excellence and P50 CA098252 (T-C Wu) National Institutes of Health (NIH)/National Cancer Institute (NCI). The funders had no role in study design, data collection and analysis, publication decisions, or manuscript preparation.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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, diagnosing HPV-positive OPSCCs for the appropriate disease management is crucial, and no suitable markers are available for detecting early malignancies in HPV-infected tissues. 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 was significantly associated with p16 positive and RB negative cases, which were the characteristics of OPSCC cases with favorable survival outcomes. Either AGTR1 or 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, familiar with p16-positive and RB-negative phenotypes.
AB - 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, diagnosing HPV-positive OPSCCs for the appropriate disease management is crucial, and no suitable markers are available for detecting early malignancies in HPV-infected tissues. 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 was significantly associated with p16 positive and RB negative cases, which were the characteristics of OPSCC cases with favorable survival outcomes. Either AGTR1 or 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, familiar with p16-positive and RB-negative phenotypes.
KW - AGTR1
KW - HPV
KW - Methylation
KW - Oropharyngeal SCC
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U2 - 10.1186/s12885-022-10227-w
DO - 10.1186/s12885-022-10227-w
M3 - Article
C2 - 36344942
AN - SCOPUS:85141543873
SN - 1471-2407
VL - 22
JO - BMC cancer
JF - BMC cancer
IS - 1
M1 - 1146
ER -