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Molecular profile of nasopharyngeal carcinoma: analysing tumour suppressor gene promoter hypermethylation by multiplex ligation-dependent probe amplification
  1. Marc Ooft1,
  2. Jolique van Ipenburg2,
  3. Rob van Loo1,
  4. Rick de Jong1,
  5. Cathy Moelans1,
  6. Weibel Braunius3,4,
  7. Remco de Bree4,
  8. Paul van Diest1,
  9. Senada Koljenović2,
  10. Rob Baatenburg de Jong5,
  11. Jose Hardillo5,
  12. Stefan Willems1
  1. 1Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
  2. 2Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
  3. 3Department of Otorhinolaryngology, University Medical Center Utrecht, Utrecht, The Netherlands
  4. 4Department of Head and Neck Surgical Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands
  5. 5Department of Otorhinolaryngology and Head and Neck Surgery, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
  1. Correspondence to Dr Marc Ooft, Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, Utrech 3583CX, The Netherlands; m.l.ooft{at}umcutrecht.nl

Abstract

Aims To assess differences in methylation profiles, and thus pathogenesis, between Epstein-Barr virus (EBV)-positive and negative nasopharyngeal carcinomas (NPCs). Also, promoter hypermethylation is a common phenomenon in early carcinogenesis to inactivate tumour suppressor genes. Since epigenetic changes are reversible, the therapeutic application of methylation inhibitors could provide treatment options.

Methods We evaluated promoter hypermethylation profiles of 22 common tumour suppressor genes in 108 NPCs using methylation-specific multiplex ligation-dependent probe amplification. Correlation between methylation, clinicopathological features (including EBV) and survival was examined. Cluster analysis was also performed.

Results Hypermethylation of RASSF1A and ESR1 was significantly more frequent in EBV-positive NPC, while hypermethylation of DAPK1 was more frequent in EBV-negative NPC. In logistic regression, age, with EBV-positive NPC occurring at earlier age, and RASSF1, with RASSF1 hypermethylation being more frequent in EBV-positive NPC, remained significant. In EBV-positive NPC, hypermethylation of RASSF1A predicted worse overall survival (OS) (HR 3.058,95% CI 1.027 to 9.107). In EBV-negative NPC, hypermethylated adenomatous polyposis coli (APC) was a predictor of poor disease-free survival (DFS) (HR 6.868, 95% CI 2.142 to 22.022).

Conclusion There are important epigenetic differences between EBV-negative and EBV-positive NPCs, with EBV-negative NPC having a more similar hypermethylation profile to other head and neck squamous cell carcinomas than EBV-positive NPC. Hypermethylation of RASSF1A might contribute to worse OS in EBV-positive NPC, and may be an important event in the pathogenesis of EBV-infected NPC. Hypermethylation of APC might contribute to worse DFS in EBV-negative NPC.

  • tumour biology
  • tumour Virology
  • molecular oncology
  • molecular pathology
  • oncology

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Footnotes

  • Handling editor Runjan Chetty.

  • Contributors The authors have contributed to the conception and design of the work, and also to the acquisition, analysis and interpretation of data. The authors have given approval of the version to be published. The authors are in agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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