title: Association between the CpG island methylator phenotype and its prognostic significance in primary pulmonary adenocarcinoma.
abstract: 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.
authors: Department of Pathology, Ajou University School of Medicine, Suwon, South Korea.
authors: Young Wha
authors: YW
authors: Koh
authors: Department of Pathology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea.
authors: Sung-Min
authors: SM
authors: Chun
authors: Department of Pathology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea.
authors: Young-Soo
authors: YS
authors: Park
authors: Department of Pathology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea.
authors: Joon Seon
authors: JS
authors: Song
authors: Center for Lung Cancer, National Cancer Center, Goyang, Republic of Korea.
authors: Geon Kook
authors: GK
authors: Lee
authors: Department of Pathology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea.
authors: Shin Kwang
authors: SK
authors: Khang
authors: Department of Pathology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea. jangsejin@amc.seoul.kr.
authors: Se Jin
authors: SJ
authors: Jang
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D010641:Phenotype; D011379:Prognosis; D012189:Retrospective Studies
chemical_list: D004273:DNA, Neoplasm; D009363:Neoplasm Proteins
keywords: CpG island methylator phenotype; Methylation; Prognosis; Pulmonary adenocarcinoma