Accumulation of promoter methylation suggests epigenetic progression in squamous cell carcinoma of the esophagus.
OBJECTIVE
Squamous esophageal cancer is common in non-Western countries and has a well-defined progression of preinvasive dysplasia leading to invasive squamous cell carcinoma. We examined the changes in promoter region methylation occurring during neoplastic progression.


METHODS
The frequency of epigenetic changes in the promoter region of 14 genes epigenetically silenced in other cancers was determined and examined the most frequent changes in dysplastic lesions using methylation-specific PCR. Invasive squamous carcinomas, low to high grade dysplasia, and normal esophagus were then examined for methylation changes in the promoter region of each of the eight most commonly methylated genes.


RESULTS
Methylation was most frequent for CDKN2A/p16INK4a (52%) but was also common for O(6)-methylguanine-DNA methyltransferase, E-cadherin (CDH1), and retinoic acid receptor beta2. Methylation at individual genes increased in frequency from normal to invasive cancer. Methylation of MLH1 was associated with microsatellite instability in most cases. The number of genes methylated in individual lesions increased as cellular atypia increased. In individual patients, cancers adjacent to dysplasia had the same epigenetic alterations as the less advanced lesions but often had additional methylation of other genes.


CONCLUSIONS
These findings suggest that epigenetic progression parallels the histologic changes observed in the progression of squamous carcinoma of the esophagus.
Guo
Mingzhou
M
Cancer Biology Program, Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA.
Ren
Jingli
J
House
Michael G
MG
Qi
Yu
Y
Brock
Malcolm V
MV
Herman
James G
JG
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D015820:Cadherins / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D044127:Epigenesis, Genetic; D004938:Esophageal Neoplasms / Q000235:genetics*; D006801:Humans; D053842:Microsatellite Instability; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics; D016133:Polymerase Chain Reaction / Q000379:methods; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000070957:MutL Protein Homolog 1