{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T10:08:29Z","timestamp":1792058909779,"version":"4.4.0"},"reference-count":49,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2009,5,26]],"date-time":"2009-05-26T00:00:00Z","timestamp":1243296000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2009,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>BACKGROUND:<\/jats:title><jats:p>Esophageal squamous cell carcinomas (ESCCs) tend to have multiple primary lesions, and it is believed that they arise from background mucosae with accumulation of genetic\/epigenetic alterations. In this study, the objective was to elucidate the effects of smoking and drinking on the accumulation of epigenetic alterations in background mucosae.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS:<\/jats:title><jats:p>Genes that are silenced in human ESCCs were searched for by treating 3 ESCC cell lines with the demethylating agent, 5\u2010aza\u20102\u2032\u2010deoxycytidine and performing oligonucleotide microarrays. Methylation levels were analyzed by quantitative methylation\u2010specific polymerase chain reaction analysis of 60 ESCCs and their corresponding background mucosae.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS:<\/jats:title><jats:p>Forty\u2010seven genes were identified as methylation\u2010silenced in at least 1 of the 3 ESCC cell lines, and 14 of those genes (claudin 6 [<jats:italic>CLDN6<\/jats:italic>]; G protein\u2010coupled receptor 158 [<jats:italic>GPR158<\/jats:italic>]; homeobox A9 [<jats:italic>HOXA9<\/jats:italic>]; metallothionein 1M [<jats:italic>MT1M<\/jats:italic>]; neurofilament, heavy polypeptide 200 kDa [<jats:italic>NEFH<\/jats:italic>]; plakophilin 1 [<jats:italic>PKP1<\/jats:italic>]; protein phosphatase 1, regulatory [inhibitor] subunit 14A [<jats:italic>PPP1R14A<\/jats:italic>]; pyrin domain and caspase recruitment domain containing [<jats:italic>PYCARD<\/jats:italic>]; R\u2010spondin family, member 4 [<jats:italic>RSPO4<\/jats:italic>]; testis\u2010specific protein, Y\u2010encoded\u2013like 5 [<jats:italic>TSPYL5<\/jats:italic>]; ubiquitin carboxyl\u2010terminal esterase L1 [<jats:italic>UCHL1<\/jats:italic>]; zinc\u2010finger protein 42 homolog [<jats:italic>ZFP42<\/jats:italic>]; zinc\u2010finger protein interacting with K protein 1 homolog [<jats:italic>ZIK1<\/jats:italic>]; and zinc\u2010finger and SCAN domain containing 18 [<jats:italic>ZSCAN18<\/jats:italic>]) were used as markers. In the background mucosae, methylation levels of 5 genes (<jats:italic>HOXA9<\/jats:italic>, <jats:italic>MT1M<\/jats:italic>, <jats:italic>NEFH<\/jats:italic>, <jats:italic>RSPO4<\/jats:italic>, and <jats:italic>UCHL1<\/jats:italic>) had significant correlations with smoking duration (\u03c1 = .268; <jats:italic>P<\/jats:italic> = .044; \u03c1 = .405; <jats:italic>P<\/jats:italic> = .002; \u03c1 = .285; <jats:italic>P<\/jats:italic> = .032; \u03c1 = .300; <jats:italic>P<\/jats:italic> = .024; and \u03c1 = .437; <jats:italic>P<\/jats:italic> = .001, respectively). In contrast, an inverse correlation between <jats:italic>PYCARD<\/jats:italic> methylation levels and alcohol intake was observed (\u03c1 = \u2212.334, <jats:italic>P<\/jats:italic> = .025) among individuals with the inactive aldehyde dehydrogenase 2 (<jats:italic>ALDH2<\/jats:italic>) genotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS:<\/jats:title><jats:p>The current results suggested that ESCCs developed from an epigenetic field for cancerization, which was induced by exposure to carcinogenic factors, such as tobacco smoking. The epigenetic field defect will be a novel target for risk diagnosis and prevention of ESCCs. Cancer 2009. \u00a9 2009 American Cancer Society.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.24394","type":"journal-article","created":{"date-parts":[[2009,5,26]],"date-time":"2009-05-26T22:54:53Z","timestamp":1243378493000},"page":"3412-3426","source":"Crossref","is-referenced-by-count":120,"title":["The presence of aberrant DNA methylation in noncancerous esophageal mucosae in association with smoking 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