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

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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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Acknowledgments

This work was partly supported by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A111405 to JH Chung); a grant from grant no. 0420140250 from the SNUH Research Fund (to GH Kang); a grant from the Priority Research Centers Program through the National Research Foundation of Korea (NRF) funded by MEST (2009–0093820 to GH Kang); the NRF grant funded by the Korea government (MSIP) (2011–0030049 to GH Kang); and a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI14C1277 to GH Kang).

Conflict of interest

We declare that we have no conflict of interest.

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Authors and Affiliations

  1. Department of Pathology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul, 110-744, South Korea

    Ye-Young Rhee, Xianyu Wen, Hyojin Kim & Gyeong Hoon Kang

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

    Tae-Hun Lee, Young Seok Song, Nam-Yun Cho & Gyeong Hoon Kang

  3. Departments of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Bundang, South Korea

    Sanghoon Jheon

  4. Departments of Internal Medicine, Seoul National University Bundang Hospital, Bundang, South Korea

    Choon-Taek Lee

  5. Department of Neurology, Chungnam National University School of Medicine, Daejeon, South Korea

    Jei Kim

  6. Departments of Pathology, Seoul National University Bundang Hospital, Bundang, South Korea

    Jin Haeng Chung

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  1. Ye-Young Rhee
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  2. Tae-Hun Lee
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Supplementary Figure 1

Methylation frequencies of each CpG island methylator phenotype marker in precursor lesions of ADC. NL-ADC, non-neoplastic lung tissue from patients with lung adenocarcinoma; NL, normal lung tissue from patients with non-neoplastic lung disease; AAH, atypical adenomatous hyperplasia; AIS, adenocarcinoma in situ; ADC-T1a, adenocarcinoma of the T1a stage; ADC > T1a, adenocarcinoma of the T1b stage or higher (JPEG 184 kb)

Supplementary Figure 2

Kaplan–Meier log-rank test of cancer-specific survival in patients with stage I adenocarcinoma according to methylation status of each CIMP marker. Green line, presence of methylation; blue line, absence of methylation (JPEG 301 kb)

Supplementary Figure 3

In our previous study, we analyzed methylation statuses of 18 cancer-specific methylation markers in precursor lesions of ADC. A progressive increase in the number of methylated markers was noted along with progression of the lesion (GIF 14 kb)

High-Resolution Image (TIFF 89 kb)

Supplementary Figure 4

A significant difference in L1 methylation level was noted between adenocarcinomas and squamous cell carcinomas (JPEG 103 kb)

Supplementary Figure 5

Kaplan–Meier survival curves for stage I adenocarcinoma patients with postoperative chemotherapy (n = 62, a) or without postoperative chemotherapy (n = 38, b) according to methylation status of CIMP markers. (JPEG 297 kb)

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Rhee, YY., Lee, TH., Song, Y.S. et al. Prognostic significance of promoter CpG island hypermethylation and repetitive DNA hypomethylation in stage I lung adenocarcinoma. Virchows Arch 466, 675–683 (2015). https://doi.org/10.1007/s00428-015-1749-0

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