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Speel, Ernst-Jan M.; Reuschenbach, Miriam; Huebbers, Christian U.; Prigge, Elena-Sophie; Bermejo, Justo L.; Kalteis, Simon; Preuss, Simon; Kolligs, Jutta; Olthof, Nadine C.; Kremer, Bernd; Wagner, Steffen; Klussmann, Jens P.; Vinokurova, Svetlana; von Knebel Doeberitz, Magnus

Abstract 828: Methylation status of HPV16 E2-binding sites identifies subtypes of HPV-associated oropharyngeal squamous cell carcinomas

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  • Media type: E-Article
  • Title: Abstract 828: Methylation status of HPV16 E2-binding sites identifies subtypes of HPV-associated oropharyngeal squamous cell carcinomas
  • Contributor: Speel, Ernst-Jan M.; Reuschenbach, Miriam; Huebbers, Christian U.; Prigge, Elena-Sophie; Bermejo, Justo L.; Kalteis, Simon; Preuss, Simon; Kolligs, Jutta; Olthof, Nadine C.; Kremer, Bernd; Wagner, Steffen; Klussmann, Jens P.; Vinokurova, Svetlana; von Knebel Doeberitz, Magnus
  • imprint: American Association for Cancer Research (AACR), 2015
  • Published in: Cancer Research
  • Language: English
  • DOI: 10.1158/1538-7445.am2015-828
  • ISSN: 1538-7445; 0008-5472
  • Keywords: Cancer Research ; Oncology
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title> <jats:p>Background: The viral E2 protein is a transcriptional repressor of the HPV oncogenes E6/E7 and loss of E2 function is considered a key step in carcinogenesis. Integration of HPV into the host genome may disrupt the E2 gene. Furthermore, methylation of CpG dinucleotides in E2 binding sites (E2BSs) in the HPV upstream regulatory region (URR) may interfere with transcriptional repression of E6 and E7 by the E2 protein. We hypothesized that CpG methylation of the E2BS is found in a proportion of HPV16-associated oropharyngeal squamous cell cancers (OPSCC) in association with E2 gene integrity and viral integration.</jats:p> <jats:p>Methods: Methylation of 10 CpGs within the URR, encompassing E2BSs 1, 2, 3 and 4, was quantitatively analyzed by bisulfite pyrosequencing in 57 HPV16-associated OPSCC. E2 status was analyzed by gene amplification and quantitative real-time RT-PCR. Viral integration was determined by integration-specific PCR methods.</jats:p> <jats:p>Results: Three subgroups with differential E2BSs3 and 4 methylation were identified: a) complete methylation (&amp;gt;80%) associated with presence of integrated HPV genomes with intact E2 gene, b) intermediate methylation levels (20-80%) with predominantly episomal HPV genomes with intact E2, and c) no methylation (&amp;lt;20%) with integrated HPV with disrupted E2. Patients with complete and without methylation had poor 5-year overall survival compared to patients with intermediate methylation (stage-adjusted hazard ratio 3.8 (95%CI 1.3-11.2) and 3.1 (95%CI 1.14-8.28); p = 0.03).</jats:p> <jats:p>Conclusions: E2BSs3 and 4 methylation in oropharyngeal cancers with episomal HPV and integrated HPV with intact E2 gene might explain deregulated viral oncogene expression in the presence of E2. The methylation level appears to be of prognostic significance for patients with HPV-associated OPSCC.</jats:p> <jats:p>Citation Format: Ernst-Jan M. Speel, Miriam Reuschenbach, Christian U. Huebbers, Elena-Sophie Prigge, Justo L. Bermejo, Simon Kalteis, Simon Preuss, Jutta Kolligs, Nadine C. Olthof, Bernd Kremer, Steffen Wagner, Jens P. Klussmann, Svetlana Vinokurova, Magnus von Knebel Doeberitz. Methylation status of HPV16 E2-binding sites identifies subtypes of HPV-associated oropharyngeal squamous cell carcinomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 828. doi:10.1158/1538-7445.AM2015-828</jats:p>
  • Access State: Open Access