{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T06:48:26Z","timestamp":1790923706120,"version":"4.1.0"},"reference-count":31,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2006,3,13]],"date-time":"2006-03-13T00:00:00Z","timestamp":1142208000000},"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":[[2006,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>BACKGROUND<\/jats:title><jats:p>The tumor suppressor gene <jats:italic>TSLC1\/IGSF4<\/jats:italic> on chromosomal region 11q23 is frequently inactivated by promoter methylation in various cancers, including nonsmall cell lung carcinoma (NSCLC). Several studies have demonstrated that the hypermethylation of the CpG islands of genes, including tumor suppressors, is associated with exposure to tobacco smoke. The purpose of this study was to investigate the possible association of <jats:italic>TSLC1\/IGSF4<\/jats:italic> methylation with tobacco smoking as well as with the clinical characteristics of tumors using a large number of primary NSCLC.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>The promoter methylation of <jats:italic>TSLC1\/IGSF4<\/jats:italic> was analyzed in 103 primary NSCLC. TSLC1\/IGSF4 expression was examined by reverse transcription\u2010polymerase chain reaction (RT\u2010PCR) and immunohistochemistry, whereas its methylation status was determined by bisulfite single\u2010strand conformation polymorphism (SSCP) coupled with bisulfite sequencing.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>The <jats:italic>TSLC1\/IGSF4<\/jats:italic> promoter was methylated in 45 (44%) of 103 primary NSCLC. Methylation was observed in all histologic subtypes of NSCLC, including adenocarcinoma (29 of 68, 43%), squamous cell carcinoma (14 of 26, 54%), adenosquamous carcinoma (1 of 2, 50%), and large cell carcinoma (1 of 7, 14%). The incidence of methylation in tumors was significantly higher in male patients than in female patients (<jats:italic>P<\/jats:italic> = .027). The <jats:italic>TSLC1\/IGSF4<\/jats:italic> methylation was preferentially observed in heavy smokers (smoking index \u2265 800) (<jats:italic>P<\/jats:italic> = .0054). Furthermore, in smokers the methylation was significantly associated with pack\u2010years smoked (<jats:italic>P<\/jats:italic> = .034) and cigarettes per day (<jats:italic>P<\/jats:italic> = .021). The <jats:italic>TSLC1\/IGSF4<\/jats:italic> methylation was also significantly associated with a shorter disease\u2010free survival (<jats:italic>P<\/jats:italic> = .049), providing an independent prognostic factor (<jats:italic>P<\/jats:italic> = .038) in adenocarcinoma patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p><jats:italic>TSLC1\/IGSF4<\/jats:italic> methylation is associated with tobacco smoking and could be an indicator of poor prognosis. Cancer 2006. \u00a9 2006 American Cancer Society.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.21800","type":"journal-article","created":{"date-parts":[[2006,3,13]],"date-time":"2006-03-13T14:49:07Z","timestamp":1142261347000},"page":"1751-1758","source":"Crossref","is-referenced-by-count":67,"title":["Hypermethylation of the <i>TSLC1\/IGSF4<\/i> promoter is associated with tobacco smoking and a poor prognosis in primary nonsmall cell lung carcinoma"],"prefix":"10.1002","volume":"106","author":[{"given":"Shinji","family":"Kikuchi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Yamada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Fukami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoko","family":"Maruyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiko","family":"Ito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisao","family":"Asamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Matsuno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masataka","family":"Onizuka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinori","family":"Murakami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2006,3,13]]},"reference":[{"key":"e_1_2_5_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra023075"},{"key":"e_1_2_5_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm0795-686"},{"key":"e_1_2_5_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.20.11891"},{"key":"e_1_2_5_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/77083"},{"key":"e_1_2_5_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/93.9.691"},{"key":"e_1_2_5_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/83.16.1142"},{"key":"e_1_2_5_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.17.3.1366"},{"key":"e_1_2_5_9_2","first-page":"3419","article-title":"p16(INK4a) and histology\u2010specific methylation of CpG islands by exposure to tobacco smoke in non\u2010small cell lung cancer","volume":"61","author":"Kim DH","year":"2001","journal-title":"Cancer Res."},{"key":"e_1_2_5_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.11322"},{"key":"e_1_2_5_11_2","first-page":"3743","article-title":"Hypermethylation of RASSF1A promoter is associated with the age at starting smoking and a poor prognosis in primary non\u2010small cell lung cancer","volume":"63","author":"Kim DH","year":"2003","journal-title":"Cancer Res."},{"key":"e_1_2_5_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.14.8153"},{"key":"e_1_2_5_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/86934"},{"key":"e_1_2_5_14_2","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1999.6001"},{"key":"e_1_2_5_15_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M203620200"},{"key":"e_1_2_5_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.11348"},{"key":"e_1_2_5_17_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.2002.tb01297.x"},{"key":"e_1_2_5_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.10079"},{"key":"e_1_2_5_19_2","doi-asserted-by":"publisher","DOI":"10.4161\/cbt.84"},{"key":"e_1_2_5_20_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.2002.tb01329.x"},{"key":"e_1_2_5_21_2","first-page":"6320","article-title":"Involvement of TSLC1 in progression of esophageal squamous cell carcinoma","volume":"63","author":"Ito T","year":"2003","journal-title":"Cancer Res."},{"key":"e_1_2_5_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/mc.10156"},{"key":"e_1_2_5_23_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djh031"},{"key":"e_1_2_5_24_2","first-page":"5129","article-title":"Direct association of TSLC1 and DAL\u20101, two distinct tumor suppressor proteins in lung cancer","volume":"62","author":"Yageta M","year":"2002","journal-title":"Cancer Res."},{"key":"e_1_2_5_25_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-04-2206"},{"key":"e_1_2_5_26_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.5.1827"},{"key":"e_1_2_5_27_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.LAB.0000081391.28136.80"},{"key":"e_1_2_5_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2004.06.013"},{"key":"e_1_2_5_29_2","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.161.4.9908012"},{"key":"e_1_2_5_30_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.9.4045"},{"key":"e_1_2_5_31_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.16.8.4555"},{"key":"e_1_2_5_32_2","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.11599"}],"container-title":["Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fcncr.21800","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acsjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cncr.21800","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T12:45:09Z","timestamp":1760273109000},"score":1,"resource":{"primary":{"URL":"https:\/\/acsjournals.onlinelibrary.wiley.com\/doi\/10.1002\/cncr.21800"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,3,13]]},"references-count":31,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2006,4,15]]}},"alternative-id":["10.1002\/cncr.21800"],"URL":"https:\/\/doi.org\/10.1002\/cncr.21800","archive":["Portico"],"relation":{},"ISSN":["0008-543X","1097-0142"],"issn-type":[{"value":"0008-543X","type":"print"},{"value":"1097-0142","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,3,13]]}}}