We quantified field cancerization of squamous cell carcinoma in the upper aerodigestive tract with epigenetic markers and evaluated their performance for risk assessment. Methylation levels were analyzed by quantitative methylation-specific PCR of biopsied specimens from a training set of 255 patients and a validation set of 224 patients. We also measured traditional risk factors based on demographics, lifestyle, serology, genetic polymorphisms, and endoscopy. The methylation levels of four markers increased stepwise, with the lowest levels in normal esophageal mucosae from healthy subjects without carcinogen exposure, then normal mucosae from healthy subjects with carcinogen exposure, then normal mucosae from cancer patients, and the highest levels were in cancerous mucosae (P < 0.05). Cumulative exposure to alcohol increased methylation of homeobox A9 in normal mucosae (P < 0.01). Drinkers had higher methylation of ubiquitin carboxyl-terminal esterase L1 and metallothionein 1M (P < 0.05), and users of betel quid had higher methylation of homeobox A9 (P = 0.01). Smokers had increased methylation of all four markers (P < 0.05). Traditional risk factors allowed us to discriminate between patients with and without cancers with 74% sensitivity (95% CI: 67%–81%), 74% specificity (66%–82%), and 80% area under the curve (67%–91%); epigenetic markers in normal esophageal mucosa had values of 74% (69%–79%), 75% (67%–83%), and 83% (79%–87%); and both together had values of 82% (76%–88%), 81% (74%–88%), and 91% (88%–94%). Epigenetic markers done well in the validation set with 80% area under the curve (73%–85%). We concluded that epigenetics could improve the accuracies of risk assessment. Cancer Prev Res; 4(12); 1982–92. ©2011 AACR.
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