Different histological types of non-small cell lung cancer have distinct folate and DNA methylation levels

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概要

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• Aberrant DNA methylation is a commonly observed epigenetic change in lung cancer. Folate has been suggested to play a role in the homeostasis of DNA methylation and has also been implicated in cancer chemotherapy. We investigated a possible role for folate in DNA methylation by measuring folate concentrations in tumors and adjacent normal tissues from 72 non-small cell lung cancer (NSCLC) patients. These were compared to DNA methylation levels and to clinicopathological features. Folate concentrations were determined as the sum of 5,10-methylenetetrahydrofolate and tetrahydrofolate. The MethyLight assay was used to quantitate methylation in promoter regions of P16(CDKN2A), APC, CDH13, RARB, RASSF1, RUNX3, and MYOD1. Methylation of LINE-1 repeats was used as a surrogate for global methylation. Folate levels in tumors correlated positively with LINE-1, CDH13, and RUNX3 methylation. Folate concentrations and methylation of LINE-1, RASSF1, and RUNX3 were significantly higher in adenocarcinoma compared to squamous cell carcinoma (SCC). Two sets of array-based data retrieved from the Gene Expression Omnibus consistently showed that expression of FOLR1, a folate transport enzyme, and GGH, an enzyme that prevents folate retention, were higher and lower, respectively, in adenocarcinomas compared to SCC. This was independently validated by quantitative RT-PCR in 26 adenocarcinomas and 13 SCC. Our results suggest that folate metabolism plays a role in aberrant DNA methylation in NSCLC. The histological subtype differences in folate concentration and DNA methylation observed here were associated with distinct expression patterns for folate metabolizing enzymes. These findings may have clinical applications for histology-directed chemotherapy with fluoropyrimidine and anti-folates in NSCLC. © 2009 Japanese Cancer Association.

• Japanese Cancer Association = 日本癌学会の論文
• 2009-12-10

著者

• ODA MAKOTO

  Department of General and Cardiothoracic Surgery, Kanazawa University School of Medicine

• WATANABE GO

  Department of General and Cardiothoracic Surgery, Kanazawa University School of Medicine

• Oda Makoto

  金沢大学 医学部心肺病態制御学

• Oda Makoto

  Department Of General And Cardiothoracic Surgery Kanazawa University School Of Medicine

• Watanabe G

  Department Of General And Cardiothoracic Surgery Kanazawa University School Of Medicine

• Oka Toshinori

  Tokushima Research Center Taiho Pharmaceutical

• Watanabe Go

  Department Of General And Cardiothoracic Surgery Kanazawa University

• Watanabe Go

  Department Of Applied Physics Graduate School Of Science And Engineering Waseda University

• Kawakami Kazuyuki

  Department Of General And Cardiothoracic Surgery Kanazawa University School Of Medicine

• Kawakami Kazuyuki

  Division Of Translational And Clinical Oncology Cancer Research Institute Kanazawa University

• Minamoto Toshinari

  Division Of Translational And Clinical Oncology Graduate School Of Medical Science Kanazawa Universi

• Minamoto Toshinari

  Division Of Molecular Diagnostic Pathology Cancer Research Institute Kanazawa University

• Oda Makoto

  Department Of Applied Biology Faculty Of Textile Science And Technology Shinshu University

• Takechi Teiji

  Product Planning And Lifecycle Management Department Taiho Pharmaceutical Co.

• JIN MingJi

  Division of Translational and Clinical Oncology, Molecular and Cellular Targeting Translational Onco

• FUKUI Yousuke

  Tokushima Research Center, Taiho Pharmaceutical Co.

• TSUKIOKA Sayaka

  Tokushima Research Center, Taiho Pharmaceutical Co.

• Oda Makoto

  Department Of General And Cardiothoracic Surgery Kanazawa University Graduate School Of Medical Scie

• Oka Toshinori

  Tokushima Research Center Taiho Pharmaceutical Co.

• Jin Mingji

  Division Of Translational And Clinical Oncology Molecular And Cellular Targeting Translational Oncol

• Fukui Yousuke

  Tokushima Research Center Taiho Pharmaceutical Co.

• Tsukioka Sayaka

  Tokushima Research Center Taiho Pharmaceutical Co.

• Minamoto Toshinari

  Division Of Translational And Clinical Oncology Molecular And Cellular Targeting Translational Oncol

• Oda Makoto

  Department Of General And Cardiothoracic Surgery Kanazawa University

• Jin Ming

  Division of Translational and Clinical Oncology, Molecular and Cellular Targeting Translational Oncology Center, Cancer Research Institute, Kanazawa University

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