title: Revisit of field cancerization in squamous cell carcinoma of upper aerodigestive tract: better risk assessment with epigenetic markers.
abstract: 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.
authors.affiliation: Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Yi-Chia
authors.initials: YC
authors.lastname: Lee
authors.forename: Hsiu-Po
authors.initials: HP
authors.lastname: Wang
authors.forename: Cheng-Ping
authors.initials: CP
authors.lastname: Wang
authors.forename: Jenq-Yuh
authors.initials: JY
authors.lastname: Ko
authors.forename: Jang-Ming
authors.initials: JM
authors.lastname: Lee
authors.forename: Han-Mo
authors.initials: HM
authors.lastname: Chiu
authors.forename: Jaw-Town
authors.initials: JT
authors.lastname: Lin
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamashita
authors.forename: Daiji
authors.initials: D
authors.lastname: Oka
authors.forename: Naoko
authors.initials: N
authors.lastname: Watanabe
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Matsuda
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Ushijima
authors.forename: Ming-Shiang
authors.initials: MS
authors.lastname: Wu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology*; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000235:genetics*; D004938:Esophageal Neoplasms / Q000235:genetics / Q000473:pathology*; D004947:Esophagus / Q000378:metabolism*; D005260:Female; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009092:Mucous Membrane / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics; D011446:Prospective Studies; D018570:Risk Assessment
chemical_list: D014408:Biomarkers, Tumor