Fragile genes as biomarkers: epigenetic control of WWOX and FHIT in lung, breast and bladder cancer

Oncogene. 2005 Feb 24;24(9):1625-33. doi: 10.1038/sj.onc.1208398.


This study aimed to (a) determine if DNA methylation is a mechanism of WWOX (WW domain containing oxidoreductase) and FHIT (fragile histidine triad) inactivation in lung, breast and bladder cancers; (b) examine distinct methylation patterns in neoplastic and adjacent tissues and (c) seek correlation of methylation patterns with disease status. Protein expression was detected by immunohistochemistry, and methylation status by methylation-specific PCR (MSP) and sequencing, in lung squamous cell carcinomas and adjacent tissues, invasive breast carcinomas, adjacent tissues and normal mammary tissues and bladder transitional cell carcinomas. Wwox and Fhit expression was reduced in cancers in association with hypermethylation. Differential patterns of WWOX and FHIT methylation were observed in neoplastic vs adjacent non-neoplastic tissues, suggesting that targeted MSP amplification could be useful in following treatment or prevention protocols. WWOX promoter MSP differentiates DNA of lung cancer from DNA of adjacent lung tissue. WWOX and FHIT promoter methylation is detected in tissue adjacent to breast cancer and WWOX exon 1 MSP distinguishes breast cancer DNA from DNA of adjacent and normal tissue. Differential methylation in cancerous vs adjacent tissues suggests that WWOX and FHIT hypermethylation analyses could enrich a panel of DNA methylation markers.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acid Anhydride Hydrolases / genetics*
  • Apoptosis / genetics
  • Base Sequence
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Chromosome Fragility / genetics*
  • DNA Methylation
  • DNA Primers
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Neoplasm Proteins / genetics*
  • Oxidoreductases / genetics*
  • Polymerase Chain Reaction
  • Promoter Regions, Genetic / genetics
  • Tumor Suppressor Proteins
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / pathology
  • WW Domain-Containing Oxidoreductase


  • DNA Primers
  • Neoplasm Proteins
  • Tumor Suppressor Proteins
  • fragile histidine triad protein
  • Oxidoreductases
  • WW Domain-Containing Oxidoreductase
  • WWOX protein, human
  • Acid Anhydride Hydrolases