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Promoter Methylation of DAL-1/4.1B Predicts Poor Prognosis in Non–Small Cell Lung Cancer

Authors' Affiliations: ¹ Tumor Suppression and Functional Genomics Project, National Cancer Center Research Institute; ² Thoracic Surgery and ³ Diagnostic Pathology Divisions, National Cancer Center Hospital, Tokyo, Japan; and ⁴ Department of Surgery, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan

Requests for reprints: Yoshinori Murakami, Tumor Suppression and Functional Genomics Project, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, 104-0045 Tokyo, Japan. Phone: 81-3-3547-5295; Fax: 81-3-5565-9535; E-mail: ymurakam{at}gan2.ncc.go.jp.

Purpose: DAL-1/4.1B is an actin-binding protein originally identified as a molecule whose expression is down-regulated in lung adenocarcinoma. We have previously shown that a lung tumor suppressor, TSLC1, associates with DAL-1, suggesting that both proteins act in the same cascade. The purpose of this study is to understand the molecular mechanisms and clinical significance of DAL-1 inactivation in lung cancer.

Experimental Design: We studied aberration of the DAL-1 in 103 primary non–small cell lung cancers (NSCLC) and 18 lung cancer cells. Expression and allelic and methylation status of DAL-1 was examined by reverse transcription-PCR, microsatellite analysis, and bisulfite sequencing or bisulfite single-strand conformational polymorphism, respectively.

Results: Loss of DAL-1 expression was strongly correlated with promoter methylation in lung cancer cells, whereas DAL-1 expression was restored by a demethylating agent, 5-aza-2'-deoxycytidine. The DAL-1 promoter was methylated in 59 (57%) primary NSCLC tumors, 37% of which were associated with loss of heterozygosity around the DAL-1 on chromosomal region 18p11.3. In squamous cell carcinomas, DAL-1 methylation was observed in 9 of 10 tumors at stage I, whereas the incidence of methylation gradually increased in adenocarcinomas as they progressed [13 of 36 (36%), 4 of 12 (33%), 14 of 17 (82%), and 3 of 3 (100%) tumors at stages I, II, III, and IV, respectively; P = 0.0026]. Furthermore, in adenocarcinomas, disease-free survival and overall survival were significantly shorter in patients with tumors harboring the methylated DAL-1 (P = 0.0011 and P = 0.045, respectively).

Conclusions: DAL-1 methylation is involved in the development and progression of NSCLC and provides an indicator for poor prognosis.

Key Words: tumor suppressor gene • bisulfite SSCP • disease-free survival

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