. 2022 Nov 7;22(1):1146.

doi: 10.1186/s12885-022-10227-w.

High-risk HPV infection-associated hypermethylated genes in oropharyngeal squamous cell carcinomas

Yoshikuni Inokawa^#^{1

2}, Masamichi Hayashi^#^{1

2}, Shahnaz Begum^#³, Maartje G Noordhuis³, Daivd Sidransky¹, Joseph Califano⁴, Wayne Koch¹, Mariana Brait¹, William H Westra⁵, Mohammad O Hoque^{6

7

8

9}

Affiliations

¹ Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
³ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California San Diego, CA, San Diego, USA.
⁵ Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶ Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. mhoque1@jhmi.edu.
⁷ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. mhoque1@jhmi.edu.
⁸ Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. mhoque1@jhmi.edu.
⁹ Department of Otolaryngology and Head & Neck Surgery, Urology and Oncology, The Johns Hopkins University School of Medicine, 1550 Orleans Street, CRB II, 5M, Baltimore, MD, 21231, USA. mhoque1@jhmi.edu.

^# Contributed equally.

PMID: 36344942
PMCID: PMC9641857
DOI: 10.1186/s12885-022-10227-w

High-risk HPV infection-associated hypermethylated genes in oropharyngeal squamous cell carcinomas

Yoshikuni Inokawa et al. BMC Cancer. 2022.

. 2022 Nov 7;22(1):1146.

doi: 10.1186/s12885-022-10227-w.

Authors

Affiliations

¹ Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
³ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California San Diego, CA, San Diego, USA.
⁵ Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶ Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. mhoque1@jhmi.edu.
⁷ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. mhoque1@jhmi.edu.
⁸ Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. mhoque1@jhmi.edu.
⁹ Department of Otolaryngology and Head & Neck Surgery, Urology and Oncology, The Johns Hopkins University School of Medicine, 1550 Orleans Street, CRB II, 5M, Baltimore, MD, 21231, USA. mhoque1@jhmi.edu.

^# Contributed equally.

PMID: 36344942
PMCID: PMC9641857
DOI: 10.1186/s12885-022-10227-w

Abstract

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.

Keywords: AGTR1; HPV; Methylation; Oropharyngeal SCC.

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Conflict of interest statement

The authors declare no potential conflicts of interest.

Figures

**Fig. 1**
Scattered plots of QMSP values of tested genes in control samples (n = 33), HPV negative OPSCCs (n = 44) and HPV positive OPSCCs (n = 50)

See this image and copyright information in PMC

References

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High-risk HPV infection-associated hypermethylated genes in oropharyngeal squamous cell carcinomas

Affiliations

High-risk HPV infection-associated hypermethylated genes in oropharyngeal squamous cell carcinomas

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Research Materials