Tumor Biology

, Volume 37, Issue 8, pp 10675–10684 | Cite as

Association between the CpG island methylator phenotype and its prognostic significance in primary pulmonary adenocarcinoma

  • Young Wha Koh
  • Sung-Min Chun
  • Young-Soo Park
  • Joon Seon Song
  • Geon Kook Lee
  • Shin Kwang Khang
  • Se Jin Jang
Original Article


Aberrant methylation of promoter CpG islands is one of the most important inactivation mechanisms for tumor suppressor and tumor-related genes. Previous studies using genome-wide DNA methylation microarray analysis have suggested the existence of a CpG island methylator phenotype (CIMP) in lung adenocarcinomas. Although the biological behavior of these tumors varies according to tumor stage, no large-scale study has examined the CIMP in lung adenocarcinoma patients according to tumor stage. Furthermore, there have been no reported results regarding the clinical significance of each of the six CIMP markers. To examine the CIMP in patients with pulmonary adenocarcinoma after a surgical resection, we performed methylation analysis of six genes (CCNA1, ACAN, GFRA1, EDARADD, MGC45800, and p16 INK4A) in 230 pulmonary adenocarcinoma cases using the SEQUENOM MassARRAY platform. Fifty-four patients (28 %, 54/191) were in the CIMP-high (CIMP-H) group associated with high nodal stage (P = 0.007), the presence of micropapillary or solid histology (P = 0.003), and the absence of an epidermal growth factor receptor (EGFR) mutation (P = 0.002). By multivariate analysis, CIMP was an independent prognostic marker for overall survival (OS) and disease-specific survival (P = 0.03 and P = 0.43, respectively). In the stage I subgroups alone, CIMP-H patients had lower OS rates than the CIMP-low (CIMP-L) group (P = 0.041). Of the six CIMP markers, ACAN alone was significantly associated with patient survival. CIMP predicted the risk of progression independently of clinicopathological variables and enables the stratification of pulmonary adenocarcinoma patients, particularly among stage I cases.


Pulmonary adenocarcinoma Methylation CpG island methylator phenotype Prognosis 



This study was supported by the Leading Foreign Research Institute Recruitment Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (MEST) (2011–0030105). The specimens and data used in this study were provided by the Asan Bio-Resource Center of the Korea Biobank Network (Seoul, South Korea).

Compliance with Ethical Standards

Conflicts of interests


Supplementary material

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Young Wha Koh
    • 1
  • Sung-Min Chun
    • 2
  • Young-Soo Park
    • 2
  • Joon Seon Song
    • 2
  • Geon Kook Lee
    • 3
  • Shin Kwang Khang
    • 2
  • Se Jin Jang
    • 2
  1. 1.Department of PathologyAjou University School of MedicineSuwonSouth Korea
  2. 2.Department of Pathology, Asan Medical Center, College of MedicineUniversity of UlsanSeoulSouth Korea
  3. 3.Center for Lung CancerNational Cancer CenterGoyangSouth Korea

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