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

Research output: Contribution to journalArticle

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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
Externally publishedYes

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Non-Small Cell Lung Carcinoma
Methylation
Lung Neoplasms
decitabine
Neoplasms
Adenocarcinoma
Microfilament Proteins
Loss of Heterozygosity
Microsatellite Repeats
Reverse Transcription
Disease-Free Survival
Squamous Cell Carcinoma
Research Design
Polymerase Chain Reaction
Lung
Survival
Incidence
Proteins
hydrogen sulfite

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Kikuchi, S., Yamada, D., Fukami, T., Masuda, M., Sakurai-Yageta, M., Williams, Y. N., ... 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

Promoter methylation of DAL-1/4.1B predicts poor prognosis in non-small cell lung cancer. / Kikuchi, Shinji; Yamada, Daisuke; Fukami, Takeshi; Masuda, Mari; Sakurai-Yageta, Mika; Williams, Yuko N.; Maruyama, Tomoko; Asamura, Hisao; Matsuno, Yoshihiro; Onizuka, Masataka; Murakami, Yoshinori.

In: Clinical Cancer Research, Vol. 11, No. 8, 15.04.2005, p. 2954-2961.

Research output: Contribution to journalArticle

Kikuchi, S, Yamada, D, Fukami, T, Masuda, M, Sakurai-Yageta, M, Williams, YN, 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, vol. 11, no. 8, pp. 2954-2961. https://doi.org/10.1158/1078-0432.CCR-04-2206
Kikuchi S, Yamada D, Fukami T, Masuda M, Sakurai-Yageta M, Williams YN et al. Promoter methylation of DAL-1/4.1B predicts poor prognosis in non-small cell lung cancer. Clinical Cancer Research. 2005 Apr 15;11(8):2954-2961. https://doi.org/10.1158/1078-0432.CCR-04-2206
Kikuchi, Shinji ; Yamada, Daisuke ; Fukami, Takeshi ; Masuda, Mari ; Sakurai-Yageta, Mika ; Williams, Yuko N. ; Maruyama, Tomoko ; Asamura, Hisao ; Matsuno, Yoshihiro ; Onizuka, Masataka ; Murakami, Yoshinori. / Promoter methylation of DAL-1/4.1B predicts poor prognosis in non-small cell lung cancer. In: Clinical Cancer Research. 2005 ; Vol. 11, No. 8. pp. 2954-2961.
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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.",
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T1 - Promoter methylation of DAL-1/4.1B predicts poor prognosis in non-small cell lung cancer

AU - Kikuchi, Shinji

AU - Yamada, Daisuke

AU - Fukami, Takeshi

AU - Masuda, Mari

AU - Sakurai-Yageta, Mika

AU - Williams, Yuko N.

AU - Maruyama, Tomoko

AU - Asamura, Hisao

AU - Matsuno, Yoshihiro

AU - Onizuka, Masataka

AU - Murakami, Yoshinori

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N2 - 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.

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