Sensitive and specific detection of early gastric cancer with DNA methylation analysis of gastric washes

Gastroenterology. 2009 Jun;136(7):2149-58. doi: 10.1053/j.gastro.2009.02.085. Epub 2009 Apr 16.

Abstract

Background & aims: Aberrant DNA methylation is an early and frequent process in gastric carcinogenesis and could be useful for detection of gastric neoplasia. We hypothesized that methylation analysis of DNA recovered from gastric washes could be used to detect gastric cancer.

Methods: We studied 51 candidate genes in 7 gastric cancer cell lines and 24 samples (training set) and identified 6 for further studies. We examined the methylation status of these genes in a test set consisting of 131 gastric neoplasias at various stages. Finally, we validated the 6 candidate genes in a different population of 40 primary gastric cancer samples and 113 nonneoplastic gastric mucosa samples.

Results: Six genes (MINT25, RORA, GDNF, ADAM23, PRDM5, MLF1) showed frequent differential methylation between gastric cancer and normal mucosa in the training, test, and validation sets. GDNF and MINT25 were most sensitive molecular markers of early stage gastric cancer, whereas PRDM5 and MLF1 were markers of a field defect. There was a close correlation (r = 0.5-0.9, P = .03-.001) between methylation levels in tumor biopsy and gastric washes. MINT25 methylation had the best sensitivity (90%), specificity (96%), and area under the receiver operating characteristic curve (0.961) in terms of tumor detection in gastric washes.

Conclusions: These findings suggest MINT25 is a sensitive and specific marker for screening in gastric cancer. Additionally, we have developed a new method for gastric cancer detection by DNA methylation in gastric washes.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Analysis of Variance
  • Biomarkers, Tumor / analysis
  • Biomarkers, Tumor / genetics
  • Cell Line, Tumor
  • DNA Methylation*
  • DNA, Neoplasm / analysis
  • Early Detection of Cancer
  • Epigenesis, Genetic
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease*
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Precancerous Conditions / genetics*
  • Precancerous Conditions / pathology
  • Probability
  • ROC Curve
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sensitivity and Specificity
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / pathology*
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism

Substances

  • Biomarkers, Tumor
  • DNA, Neoplasm
  • Tumor Suppressor Proteins