Promoter methylation of DAL-1/4.1B predicts poor prognosis in non-small cell lung cancer

Shinji Kikuchi, Daisuke Yamada, Takeshi Fukami, Mari Masuda, Mika Sakurai-Yageta, Yuko N. Williams, Tomoko Maruyama, Hisao Asamura, Yoshihiro Matsuno, Masataka Onizuka, Yoshinori Murakami

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Abstract

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.

Original languageEnglish
Pages (from-to)2954-2961
Number of pages8
JournalClinical Cancer Research
Volume11
Issue number8
DOIs
Publication statusPublished - 2005 Apr 15

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Kikuchi, S., Yamada, D., Fukami, T., Masuda, M., Sakurai-Yageta, M., Williams, Y. N., Maruyama, T., Asamura, H., Matsuno, Y., Onizuka, M., & Murakami, Y. (2005). Promoter methylation of DAL-1/4.1B predicts poor prognosis in non-small cell lung cancer. Clinical Cancer Research, 11(8), 2954-2961. https://doi.org/10.1158/1078-0432.CCR-04-2206