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Published in: Virchows Archiv 6/2015

01-06-2015 | Original Article

Prognostic significance of promoter CpG island hypermethylation and repetitive DNA hypomethylation in stage I lung adenocarcinoma

Authors: Ye-Young Rhee, Tae-Hun Lee, Young Seok Song, Xianyu Wen, Hyojin Kim, Sanghoon Jheon, Choon-Taek Lee, Jei Kim, Nam-Yun Cho, Jin Haeng Chung, Gyeong Hoon Kang

Published in: Virchows Archiv | Issue 6/2015

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Abstract

In carcinogenesis of peripheral pulmonary carcinomas, multiple genetic and epigenetic alterations are involved. In this study, we quantified methylation levels of repetitive DNA elements (L1 and Alu) and six CpG island methylator phenotype (CIMP)-panel markers in various lesions representing steps in the development of lung adenocarcinoma (ADC), including atypical adenomatous hyperplasia, adenocarcinoma in situ, and invasive ADC. We then assessed methylation levels in an independent set of stage I ADCs (n = 100) and correlated methylation status with clinicopathological findings and clinical outcome. The pattern of changes in the methylation levels of L1 and Alu was different during progression of the lesion along the process of multistep carcinogenesis. A methylation level of >52.4 % of L1 and of >19.7 % of Alu in stage I ADC was associated with shorter cancer-specific survival in univariate but not in multivariate analysis. A tumor to normal lung tissue methylation ratio of >0.693 of L1 was an independent parameter heralding poor prognosis for stage I ADC patients. Methylation of CIMP-related genes was found in ADC. Stage I ADC cases without methylation of any of the six markers had a significantly shorter cancer-specific survival than ADC with methylation of one or more markers. The combination of tumor to normal L1 methylation ratio > 0.693 and absence of methylation of CIMP markers correlated independently with shorter cancer-specific survival. In conclusion, our findings suggest that Alu hypomethylation is an early and L1 hypomethylation a later event during multistep pulmonary carcinogenesis. The prognostic significance of the combination of methylation status of L1 and CIMP markers must be validated in large-scale studies of pulmonary ADC.
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Metadata
Title
Prognostic significance of promoter CpG island hypermethylation and repetitive DNA hypomethylation in stage I lung adenocarcinoma
Authors
Ye-Young Rhee
Tae-Hun Lee
Young Seok Song
Xianyu Wen
Hyojin Kim
Sanghoon Jheon
Choon-Taek Lee
Jei Kim
Nam-Yun Cho
Jin Haeng Chung
Gyeong Hoon Kang
Publication date
01-06-2015
Publisher
Springer Berlin Heidelberg
Published in
Virchows Archiv / Issue 6/2015
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI
https://doi.org/10.1007/s00428-015-1749-0

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