Discovery and development of differentially methylated regions in human papillomavirus-related oropharyngeal squamous cell carcinoma

Shuling Ren, Daria Gaykalova, Jennifer Wang, Theresa Guo, Liudmila V Danilova, Alexander Favorov, Elana Fertig, Justin Bishop, Zubair Khan, Emily Flam, Piotr T. Wysocki, Peter DeJong, Mizuo Ando, Chao Liu, Akihiro Sakai, Takahito Fukusumi, Sunny Haft, Sayed Sadat, Joseph A. Califano

Research output: Contribution to journalArticle

Abstract

Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) exhibits a different composition of epigenetic alterations. In this study, we identified differentially methylated regions (DMRs) with potential utility in screening for HPV-positive OPSCC. Genome wide DNA methylation was measured using methyl-CpG binding domain protein-enriched genome sequencing (MBD-seq) in 50 HPV-positive OPSCC tissues and 25 normal tissues. Fifty-one DMRs were defined with maximal methylation specificity to cancer samples. The Cancer Genome Atlas (TCGA) methylation array data was used to evaluate the performance of the proposed candidates. Supervised hierarchical clustering of 51 DMRs found that HPV-positive OPSCC had significantly higher DNA methylation levels compared to normal samples, and non-HPV-related head and neck squamous cell carcinoma (HNSCC). The methylation levels of all top 20 DNA methylation biomarkers in HPV-positive OPSCC were significantly higher than those in normal samples. Further confirmation using quantitative methylation specific PCR (QMSP) in an independent set of 24 HPV-related OPSCCs and 22 controls showed that 16 of the 20 candidates had significant higher methylation levels in HPV-positive OPSCC samples compared with controls. One candidate, OR6S1, had a sensitivity of 100%, while 17 candidates (KCNA3, EMBP1, CCDC181, DPP4, ITGA4, BEND4, ELMO1, SFMBT2, C1QL3, MIR129–2, NID2, HOXB4, ZNF439, ZNF93, VSTM2B, ZNF137P and ZNF773) had specificities of 100%. The prediction accuracy of the 20 candidates rang from 56.2% to 99.8% by receiver operating characteristic analysis. We have defined 20 highly specific DMRs in HPV-related OPSCC, which can potentially be applied to molecular-based detection tests and improve disease management.

Original languageEnglish (US)
JournalInternational Journal of Cancer
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Squamous Cell Carcinoma
Methylation
DNA Methylation
Genome
Atlases
Disease Management
Epigenomics
ROC Curve
Cluster Analysis
Neoplasms
Carrier Proteins
Biomarkers
Polymerase Chain Reaction

Keywords

  • differentially methylated regions
  • epigenetics
  • head and neck squamous cell carcinoma
  • human papillomavirus
  • oropharyngeal squamous cell carcinoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Discovery and development of differentially methylated regions in human papillomavirus-related oropharyngeal squamous cell carcinoma. / Ren, Shuling; Gaykalova, Daria; Wang, Jennifer; Guo, Theresa; Danilova, Liudmila V; Favorov, Alexander; Fertig, Elana; Bishop, Justin; Khan, Zubair; Flam, Emily; Wysocki, Piotr T.; DeJong, Peter; Ando, Mizuo; Liu, Chao; Sakai, Akihiro; Fukusumi, Takahito; Haft, Sunny; Sadat, Sayed; Califano, Joseph A.

In: International Journal of Cancer, 01.01.2018.

Research output: Contribution to journalArticle

Ren, Shuling ; Gaykalova, Daria ; Wang, Jennifer ; Guo, Theresa ; Danilova, Liudmila V ; Favorov, Alexander ; Fertig, Elana ; Bishop, Justin ; Khan, Zubair ; Flam, Emily ; Wysocki, Piotr T. ; DeJong, Peter ; Ando, Mizuo ; Liu, Chao ; Sakai, Akihiro ; Fukusumi, Takahito ; Haft, Sunny ; Sadat, Sayed ; Califano, Joseph A. / Discovery and development of differentially methylated regions in human papillomavirus-related oropharyngeal squamous cell carcinoma. In: International Journal of Cancer. 2018.
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AU - Favorov, Alexander

AU - Fertig, Elana

AU - Bishop, Justin

AU - Khan, Zubair

AU - Flam, Emily

AU - Wysocki, Piotr T.

AU - DeJong, Peter

AU - Ando, Mizuo

AU - Liu, Chao

AU - Sakai, Akihiro

AU - Fukusumi, Takahito

AU - Haft, Sunny

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