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DNA methylation profile during multistage progression of pulmonary adenocarcinomas

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Abstract

Multiple genetic and epigenetic alterations are known to be involved in the carcinogenesis of peripheral pulmonary adenocarcinoma (ADC). However, epigenetic abnormalities have not been extensively investigated in the following multistage progression sequence: atypical adenomatous hyperplasia (AAH) to adenocarcinoma in situ (AIS), to invasive ADC. To determine the potential role of promoter methylation during ADC development of the lung, we examined methylation status in 20 normal, 20 AAH, 30 AIS, and 60 ADC lung tissues and compared methylation status among the lesions. The MethyLight assay was used to determine the methylation status of 18 CpG island loci, which were hypermethylated in ADC compared to noncancerous lung tissues. The mean number of methylated CpG island loci was significantly higher in ADC than in AAH and AIS, (p < 0.003 between ADC and AAH, p < 0.005 between ADC and AIS). Aberrant methylation of HOXA1, TMEFF2, and RARB was frequently observed in preinvasive lesions, including AAH and AIS. Furthermore, methylation of PENK, BCL2, RUNX3, DLEC1, MT1G, GRIN2B, CDH13, CCND2, and HOXA10 was significantly more frequent in invasive ADC than AAH or AIS. Our results indicate that epigenetic alterations are involved in the multistep progression of pulmonary ADC development, and aberrant CpG island methylation accumulates during multistep carcinogenesis. In addition, aberrant methylation of HOXA1, TMEFF2, and RARB occurred in preinvasive lesions, which indicates that epigenetic alterations of these genes are involved in the early stages of pulmonary ADC development. In contrast, hypermethylation of PENK, BCL2, RUNX3, DLEC1, MT1G, GRIN2B, CDH13, CCND2, and HOXA10 was more frequent in invasive ADC than in preinvasive lesions, which indicates that methylation of these genes occurs later during tumor invasion in the AAH–AIS–ADC sequence.

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Acknowledgments

This study was supported by the 21C Frontier Functional Human Genome Project, Ministry of Science & Technology in Korea (FG09-11-02; to GHK), by a grant from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (0720540; to GHK), by a grant no 03-2009-002 from the SNUBH Research Fund (to JHC) and by a grant from Korea Healthcare technology R&D project, Ministry of Health and Welfare, Republic of Korea (A084578; to JHC)

Conflict of interest statement

We declare that we have no conflicts of interest.

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Authors and Affiliations

  1. Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea

    Jin-Haeng Chung & Hyun Ju Lee

  2. Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea

    Jin-Haeng Chung, Hyun Ju Lee, Nam-Yun Cho & Gyeong Hoon Kang

  3. Department of Pathology, Korea University Guro Hospital, Seoul, South Korea

    Baek-hui Kim

  4. Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea

    Nam-Yun Cho & Gyeong Hoon Kang

  5. Department of Pathology, Seoul National University College of Medicine and Cancer Research Institute, Seoul National University Hospital, 28 Yongon-dong, Chongno-gu, Seoul, 110–744, South Korea

    Gyeong Hoon Kang

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  1. Jin-Haeng Chung
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Correspondence to Gyeong Hoon Kang.

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Chung, JH., Lee, H.J., Kim, Bh. et al. DNA methylation profile during multistage progression of pulmonary adenocarcinomas. Virchows Arch 459, 201–211 (2011). https://doi.org/10.1007/s00428-011-1079-9

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  • DOI: https://doi.org/10.1007/s00428-011-1079-9

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