title: Epigenetic modulation of signal transduction pathways in HPV-associated HNSCC.
abstract: OBJECTIVE
  Human papilloma virus (HPV) positive and HPV negative head and neck squamous cell cancer (HNSCC) are biologically distinct with a prognostic advantage for HPV positive patients compared to HPV negative cases. DNA promoter methylation is central to human diseases such as cancer, including HNSCC, with reported genome-wide hypomethylaton and promoter hypermethylation in HPV positive HNSCC tumors. The goal of this study was to identify differentially methylated genes in HPV positive versus HPV negative primary HNSCC genomes with clues to signaling networks.
  
  
  METHODS
  Laboratory-based study.
  
  
  METHODS
  Primary care academic health care system.
  
  
  METHODS
  DNA from 4 HPV positive and 4 HPV negative freshly frozen primary HNSCC were subject to comprehensive genome-wide methylation profiling. Differentially methylated gene lists were examined using the Signal Transduction Pathways (canonical) filter in the Genomatix Pathway System (GePS).
  
  
  RESULTS
  Twofold methylation differences were observed between HPV positive and HPV negative cases for 1168 genes. Pathway analysis applied to investigate the biological role of the 1168 differentially methylated genes revealed 8 signal transduction pathways forming a network of 66 genes, of which 62% are hypermethylated.
  
  
  CONCLUSIONS
  Our study reveals a predominant hypermethylation profile for genes in signal transduction pathways of HPV positive HNSCC tumor genomes. Because signaling events in the cell play a critical role in the execution of key biological functions, insights into how complex cellular signaling cascades and networks may be programmed in HNSCC are likely to be critical in the development of new biological agents designed to hit multiple targets.
authors.affiliation: Department of Otolaryngology/Head and Neck Research, Henry Ford Hospital, Detroit, Michigan 48202, USA. mworsha1@hfhs.org
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Worsham
authors.forename: Kang Mei
authors.initials: KM
authors.lastname: Chen
authors.forename: Tamer
authors.initials: T
authors.lastname: Ghanem
authors.forename: Josena K
authors.initials: JK
authors.lastname: Stephen
authors.forename: George
authors.initials: G
authors.lastname: Divine
mesh_terms: D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000821:virology*; D051242:Caveolin 1 / Q000235:genetics; D019175:DNA Methylation; D057890:Epigenomics; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006258:Head and Neck Neoplasms / Q000821:virology*; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics; D008297:Male; D008875:Middle Aged; D047493:PPAR alpha / Q000235:genetics; D047495:PPAR gamma / Q000235:genetics; D027383:Papillomaviridae / Q000235:genetics*; D010865:Pilot Projects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D053669:Syndecan-2 / Q000235:genetics
chemical_list: D051242:Caveolin 1; D066246:ErbB Receptors; D019812:Heparan Sulfate Proteoglycans; D018960:Hyaluronan Receptors; D047493:PPAR alpha; D047495:PPAR gamma; D018719:Erb-b2 Receptor Tyrosine Kinases; D053669:Syndecan-2; C495540:CAV1 protein, human; C497483:CD44 protein, human; C508245:SDC2 protein, human; C512478:EGFR protein, human
keywords: gene networks; hypermethylation; pathways; signal transduction