title: Integrated analysis of genetic and epigenetic alterations reveals CpG island methylator phenotype associated with distinct clinical characters of lung adenocarcinoma.
abstract: DNA methylation affects the aggressiveness of human malignancies. Cancers with CpG island methylator phenotype (CIMP), a distinct group with extensive DNA methylation, show characteristic features in several types of tumors. In this study, we initially defined the existence of CIMP in 41 lung adenocarcinomas (AdCas) through genome-wide DNA methylation microarray analysis. DNA methylation status of six CIMP markers newly identified by microarray analysis was further estimated in a total of 128 AdCas by bisulfite pyrosequencing analysis, which revealed that 10 (7.8%), 40 (31.3%) and 78 (60.9%) cases were classified as CIMP-high (CIMP-H), CIMP-low and CIMP-negative (CIMP-N), respectively. Notably, CIMP-H AdCas were strongly associated with wild-type epidermal growth factor receptor (EGFR), males and heavy smokers (P = 0.0089, P = 0.0047 and P = 0.0036, respectively). In addition, CIMP-H was significantly associated with worse prognosis; especially among male smokers, CIMP-H was an independent prognostic factor (hazard ratio 1.7617, 95% confidence interval 1.0030-2.9550, P = 0.0489). Compellingly, the existence of CIMP in AdCas was supported by the available public datasets, such as data from the Cancer Genome Atlas. Intriguingly, analysis of AdCa cell lines revealed that CIMP-positive AdCa cell lines were more sensitive to a DNA methylation inhibitor than CIMP-N ones regardless of EGFR mutation status. Our data demonstrate that CIMP in AdCas appears to be a unique subgroup that has distinct clinical traits from other AdCas. CIMP classification using our six-marker panel has implications for personalized medical strategies for lung cancer patients; in particular, DNA methylation inhibitor might be of therapeutic benefit to patients with CIMP-positive tumors.
authors.affiliation: Division of Molecular Oncology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Shinjo
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Byonggu
authors.initials: B
authors.lastname: An
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yokoyama
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takeuchi
authors.forename: Makiko
authors.initials: M
authors.lastname: Fujii
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Osada
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Usami
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Hidemi
authors.initials: H
authors.lastname: Ito
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Hida
authors.forename: Nobukazu
authors.initials: N
authors.lastname: Fujimoto
authors.forename: Takumi
authors.initials: T
authors.lastname: Kishimoto
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sekido
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kondo
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000368:Aged; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010641:Phenotype