Genome-Wide DNA Methylation Profiling in Early Stage I Lung Adenocarcinoma Reveals Predictive Aberrant Methylation in the Promoter Region of the Long Noncoding RNA PLUT: An Exploratory Study.

Abstract

INTRODUCTION:

Surgical procedure is the treatment of choice in early stage I lung adenocarcinoma. However, a considerable number of patients experience recurrence within the first 2 years after complete resection. Suitable prognostic biomarkers that identify patients at high risk of recurrence (who may probably benefit from adjuvant treatment) are still not available. This study aimed at identifying methylation markers for early recurrence that may become important tools for the development of new treatment modalities.

METHODS:

Genome-wide DNA methylation profiling was performed on 30 stage I lung adenocarcinomas, comparing 14 patients with early metastatic recurrence with 16 patients with a long-term relapse-free survival period using methylated-CpG-immunoprecipitation followed by high-throughput next-generation sequencing. The differentially methylated regions between the two subgroups were validated for their prognostic value in two independent cohorts using the MassCLEAVE assay, a high-resolution quantitative methylation analysis.

RESULTS:

Unsupervised clustering of patients in the discovery cohort on the basis of differentially methylated regions identified patients with shorter relapse-free survival (hazard ratio: 2.23; 95% confidence interval: 0.66-7.53; p = 0.03). In two validation cohorts, promoter hypermethylation of the long noncoding RNA PLUT was significantly associated with shorter relapse-free survival (hazard ratio: 0.54; 95% confidence interval: 0.31-0.93; p < 0.026) and could be reported as an independent prognostic factor in the multivariate Cox regression analysis.

CONCLUSIONS:

Promoter hypermethylation of the long noncoding RNA PLUT is predictive in patients with early stage I adenocarcinoma at high risk for early recurrence. Further studies are needed to validate its role in carcinogenesis and its use as a biomarker to facilitate patient selection and risk stratification.

• Authors: Soo-Zin Kim-Wanner, Yassen Assenov, Mridul B Nair, Dieter Weichenhan, Axel Benner, Natalia Becker, Katharina Landwehr, Ruprecht Kuner, Holger Sültmann, Manel Esteller, Ina Koch, Michael Lindner, Michael Meister, Michael Thomas, Matthias Bieg, Ursula Klingmüller, Matthias Schlesner, Arne Warth, Benedikt Brors, Erhard Seifried, Halvard Bönig, Christoph Plass, Angela Risch, Thomas Muley
• Journal: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer (J Thorac Oncol) Vol. 15 Issue 8 Pg. 1338-1350 (08 2020) ISSN: 1556-1380 [Electronic] United States
• PMID: 32272161 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers, Tumor
• RNA, Long Noncoding

Topics

• Adenocarcinoma of Lung (genetics)
• Biomarkers, Tumor (genetics, metabolism)
• DNA Methylation
• Humans
• Lung Neoplasms (genetics)
• Neoplasm Recurrence, Local (genetics)
• Prognosis
• Promoter Regions, Genetic
• RNA, Long Noncoding