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Global hypomethylation identifies Loci targeted for hypermethylation in head and neck cancer

Graham M Poage1, E Andres Houseman, Brock C Christensen

  • 1Departments of Molecular Pharmacology and Physiology, Community Health-Center for Environmental Health and Technology, and Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, USA.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|April 21, 2011
PubMed
Abstract

Insights

Global hypomethylation and gene promoter hypermethylation are linked in head and neck cancers. These epigenetic changes correlate with tumor site and HPV status, suggesting coordinated processes influenced by clinical factors.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Genomics

Background:

  • The human epigenome undergoes significant alterations in cancer, characterized by global DNA hypomethylation and gene promoter hypermethylation.
  • The coordination between these widespread epigenetic changes in cancer development remains largely unclear.

Purpose of the Study:

  • To investigate the relationship between global hypomethylation and gene promoter methylation in head and neck squamous cell carcinomas (HNSCC).
  • To explore potential associations with clinical characteristics and exposures in HNSCC.

Main Methods:

  • Global methylation was assessed using the luminometric methylation assay (LUMA) and pyrosequencing of LINE-1 and AluYb8 repetitive elements.
  • Gene promoter methylation was analyzed using the Illumina HumanMethylation27 Microarray across over 27,000 CpG loci.
  • Statistical analyses included Spearman correlation, Kruskal-Wallis tests, and Mann-Whitney tests to identify associations.

Main Results:

  • LINE-1 methylation strongly correlated with LUMA and Infinium loci methylation, but AluYb8 methylation did not show significant association.
  • Methylation levels of LINE-1, AluYb8, and Infinium loci varied significantly by tumor site.
  • LINE-1 and LUMA methylation were associated with HPV16 E6 serology.
  • A subset of CpG loci exhibited significant hypermethylation associated with LINE-1 hypomethylation, with these loci being less repetitive, enriched in CpG islands, and proximal to transcription factor-binding sites.
  • Validation by pyrosequencing confirmed hypermethylation at specific loci (EVI2A, IFRD1, KLHL6, PTPRCAP) linked to LINE-1 hypomethylation.

Conclusions:

  • Global hypomethylation and gene-specific methylation are associated in a sequence-dependent manner in HNSCC.
  • Clinical characteristics and environmental exposures contributing to HNSCC may influence these coordinated epigenetic processes.

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