DNA Methylation Profiles at Precancerous Stages Associated with Recurrence of Lung Adenocarcinoma

Takashi Sato, Eri Arai, Takashi Kohno, Koji Tsuta, Shun ichi Watanabe, Kenzo Soejima, Tomoko Betsuyaku, Yae Kanai

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

The aim of this study was to clarify the significance of DNA methylation alterations at precancerous stages of lung adenocarcinoma. Using single-CpG resolution Infinium array, genome-wide DNA methylation analysis was performed in 36 samples of normal lung tissue obtained from patients without any primary lung tumor, 145 samples of non-cancerous lung tissue (N) obtained from patients with lung adenocarcinomas, and 145 samples of tumorous tissue (T). Stepwise progression of DNA methylation alterations from normal lung tissue to non-cancerous lung tissue obtained from patients with lung adenocarcinomas, and then tumorous tissue samples, was observed at 3,270 CpG sites, suggesting that non-cancerous lung tissue obtained from patients with lung adenocarcinomas was at precancerous stages with DNA methylation alterations. At CpG sites of 2,083 genes, DNA methylation status in samples of non-cancerous lung tissue obtained from patients with lung adenocarcinomas was significantly correlated with recurrence after establishment of lung adenocarcinomas. Among such recurrence-related genes, 28 genes are normally unmethylated (average β-values based on Infinium assay in normal lung tissue samples was less than 0.2) and their DNA hypermethylation at precancerous stages was strengthened during progression to lung adenocarcinomas (ΔβT-N>0.1). Among these 28 genes, we focused on 6 for which implications in transcription regulation, apoptosis or cell adhesion had been reported. DNA hypermethylation of the ADCY5, EVX1, GFRA1, PDE9A, and TBX20 genes resulted in reduced mRNA expression in tumorous tissue samples. 5-Aza-2′-deoxycytidine treatment of lung cancer cell lines restored the mRNA expression levels of these 5 genes. Reduced mRNA expression in tumorous tissue samples was significantly correlated with tumor aggressiveness. These data suggest that DNA methylation alterations at precancerous stages determine tumor aggressiveness and outcome through silencing of specific genes.

Original languageEnglish
Article numbere59444
JournalPLoS One
Volume8
Issue number3
DOIs
Publication statusPublished - 2013 Mar 27

Fingerprint

DNA methylation
DNA Methylation
adenocarcinoma
lungs
Tissue
Recurrence
Genes
Lung
Tumors
decitabine
genes
sampling
Messenger RNA
lung neoplasms
Adenocarcinoma of lung
aggression
Neoplasms
tissues
DNA
Cell adhesion

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

DNA Methylation Profiles at Precancerous Stages Associated with Recurrence of Lung Adenocarcinoma. / Sato, Takashi; Arai, Eri; Kohno, Takashi; Tsuta, Koji; Watanabe, Shun ichi; Soejima, Kenzo; Betsuyaku, Tomoko; Kanai, Yae.

In: PLoS One, Vol. 8, No. 3, e59444, 27.03.2013.

Research output: Contribution to journalArticle

Sato, Takashi ; Arai, Eri ; Kohno, Takashi ; Tsuta, Koji ; Watanabe, Shun ichi ; Soejima, Kenzo ; Betsuyaku, Tomoko ; Kanai, Yae. / DNA Methylation Profiles at Precancerous Stages Associated with Recurrence of Lung Adenocarcinoma. In: PLoS One. 2013 ; Vol. 8, No. 3.
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