Epigenetic changes in the CDKN2A locus are associated with differential expression of P16INK4A and P14ARF in HPV-positive oropharyngeal squamous cell carcinoma

Nicolas F. Schlecht, Miriam Ben-Dayan, Nicole Anayannis, Roberto A. Lleras, Carlos Thomas, Yanhua Wang, Richard V. Smith, Robert D. Burk, Thomas M. Harris, Geoffrey J. Childs, Thomas J. Ow, Michael B. Prystowsky, Thomas J. Belbin

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is recognized as a distinct disease entity associated with improved survival. DNA hypermethylation profiles differ significantly by HPV status suggesting that a specific subset of methylated CpG loci could give mechanistic insight into HPV-driven OPSCC. We analyzed genome-wide DNA methylation of primary tumor samples and adjacent normal mucosa from 46 OPSCC patients undergoing treatment at Montefiore Medical Center, Bronx, NY using the Illumina HumanMethylation27 beadchip. For each matched tissue set, we measured differentially methylated CpG loci using a change in methylation level (M value). From these analyses, we identified a 22 CpG loci panel for HPV+ OPSCC that included four CDKN2A loci downstream of the p16(INK4A) and p14(ARF) transcription start sites. This panel was significantly associated with overall HPV detection (P <0.05; ROC area under the curve = 0.96, 95% CI: 0.91-1.0) similar to the subset of four CDKN2A-specific CpG loci (0.90, 95% CI: 0.82-0.99) with equivalence to the full 22 CpG panel. DNA hypermethylation correlated with a significant increase in alternative open reading frame (ARF) expression in HPV+ OPSCC primary tumors, but not to the other transcript variant encoded by the CDKN2A locus. Overall, this study provides evidence of epigenetic changes to the downstream region of the CDKN2A locus in HPV+ oropharyngeal cancer that are associated with changes in expression of the coded protein products.

Original languageEnglish (US)
Pages (from-to)342-353
Number of pages12
JournalCancer Medicine
Volume4
Issue number3
DOIs
StatePublished - Mar 1 2015

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Epigenomics
Squamous Cell Carcinoma
Open Reading Frames
Cyclin-Dependent Kinase Inhibitor p16
Oropharyngeal Neoplasms
Transcription Initiation Site
DNA
DNA Methylation
Methylation
Area Under Curve
Neoplasms
Mucous Membrane
Genome
Survival
Proteins

Keywords

  • Carcinoma
  • HPV
  • methylation
  • oropharynx
  • squamous

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Epigenetic changes in the CDKN2A locus are associated with differential expression of P16INK4A and P14ARF in HPV-positive oropharyngeal squamous cell carcinoma. / Schlecht, Nicolas F.; Ben-Dayan, Miriam; Anayannis, Nicole; Lleras, Roberto A.; Thomas, Carlos; Wang, Yanhua; Smith, Richard V.; Burk, Robert D.; Harris, Thomas M.; Childs, Geoffrey J.; Ow, Thomas J.; Prystowsky, Michael B.; Belbin, Thomas J.

In: Cancer Medicine, Vol. 4, No. 3, 01.03.2015, p. 342-353.

Research output: Contribution to journalArticle

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abstract = "Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is recognized as a distinct disease entity associated with improved survival. DNA hypermethylation profiles differ significantly by HPV status suggesting that a specific subset of methylated CpG loci could give mechanistic insight into HPV-driven OPSCC. We analyzed genome-wide DNA methylation of primary tumor samples and adjacent normal mucosa from 46 OPSCC patients undergoing treatment at Montefiore Medical Center, Bronx, NY using the Illumina HumanMethylation27 beadchip. For each matched tissue set, we measured differentially methylated CpG loci using a change in methylation level (M value). From these analyses, we identified a 22 CpG loci panel for HPV+ OPSCC that included four CDKN2A loci downstream of the p16(INK4A) and p14(ARF) transcription start sites. This panel was significantly associated with overall HPV detection (P <0.05; ROC area under the curve = 0.96, 95{\%} CI: 0.91-1.0) similar to the subset of four CDKN2A-specific CpG loci (0.90, 95{\%} CI: 0.82-0.99) with equivalence to the full 22 CpG panel. DNA hypermethylation correlated with a significant increase in alternative open reading frame (ARF) expression in HPV+ OPSCC primary tumors, but not to the other transcript variant encoded by the CDKN2A locus. Overall, this study provides evidence of epigenetic changes to the downstream region of the CDKN2A locus in HPV+ oropharyngeal cancer that are associated with changes in expression of the coded protein products.",
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AU - Anayannis, Nicole

AU - Lleras, Roberto A.

AU - Thomas, Carlos

AU - Wang, Yanhua

AU - Smith, Richard V.

AU - Burk, Robert D.

AU - Harris, Thomas M.

AU - Childs, Geoffrey J.

AU - Ow, Thomas J.

AU - Prystowsky, Michael B.

AU - Belbin, Thomas J.

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