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Hypermethylation of the TSLC1/IGSF4 promoter is associated with tobacco smoking and a poor prognosis in primary nonsmall cell lung carcinoma
Author(s) -
Kikuchi Shinji,
Yamada Daisuke,
Fukami Takeshi,
Maruyama Tomoko,
Ito Akihiko,
Asamura Hisao,
Matsuno Yoshihiro,
Onizuka Masataka,
Murakami Yoshinori
Publication year - 2006
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.21800
Subject(s) - methylation , dna methylation , medicine , bisulfite sequencing , adenocarcinoma , lung cancer , adenosquamous carcinoma , cpg site , carcinoma , cancer research , tumor suppressor gene , oncology , pathology , cancer , biology , carcinogenesis , gene , gene expression , genetics
BACKGROUND The tumor suppressor gene TSLC1/IGSF4 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 TSLC1/IGSF4 methylation with tobacco smoking as well as with the clinical characteristics of tumors using a large number of primary NSCLC. METHODS The promoter methylation of TSLC1/IGSF4 was analyzed in 103 primary NSCLC. TSLC1/IGSF4 expression was examined by reverse transcription‐polymerase chain reaction (RT‐PCR) and immunohistochemistry, whereas its methylation status was determined by bisulfite single‐strand conformation polymorphism (SSCP) coupled with bisulfite sequencing. RESULTS The TSLC1/IGSF4 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 ( P = .027). The TSLC1/IGSF4 methylation was preferentially observed in heavy smokers (smoking index ≥ 800) ( P = .0054). Furthermore, in smokers the methylation was significantly associated with pack‐years smoked ( P = .034) and cigarettes per day ( P = .021). The TSLC1/IGSF4 methylation was also significantly associated with a shorter disease‐free survival ( P = .049), providing an independent prognostic factor ( P = .038) in adenocarcinoma patients. CONCLUSIONS TSLC1/IGSF4 methylation is associated with tobacco smoking and could be an indicator of poor prognosis. Cancer 2006. © 2006 American Cancer Society.