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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Oncol. | doi: 10.3389/fonc.2019.01281

A Diagnostic Panel of DNA Methylation Biomarkers for Lung Adenocarcinoma

 Nan Shen1, 2, Jun Du3, Hui Zhou4, Yi Pan5,  Jörg D. Hoheisel5, Zonghui Jiang6, Ling Xiao7*, Yue Tao1* and  Xi Mo1*
  • 1Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China
  • 2Department of Infectious Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, China
  • 3School of Medicine, Shanghai Jiao Tong University, China
  • 4Department of Lymphoma and Hematology, Hunan Cancer Hospital, China
  • 5Functional Genome Analysis, German Cancer Research Center (DKFZ), Germany
  • 6The First People’s Hospital of Yunnan Province, China
  • 7Department of Histology and Embryology, School of Basic Medical Sciences, Central South University, China

Lung adenocarcinoma (LUAD) is one of the most common cancers and lethal diseases in the world. Recognition of the undetermined lung nodules at an early stage is useful for a favorable prognosis. However, there is still no good method to identify the undetermined lung nodules and predict their clinical outcome. DNA methylation alteration is frequently observed in LUAD and may play important roles in carcinogenesis, diagnosis and prediction. This study took advantage of publicly available methylation profiling resources and a machine learning method to investigate methylation differences between LUAD and adjacent non-malignant tissue. The prediction panel was first constructed using 338 tissue samples from LUAD patients including 149 non-malignant ones. This model was then validated with data from The Cancer Genome Atlas (TCGA) database and clinic samples. As a result, the methylation status of four CpG loci in HOXA9, KRTAP8-1, CCND1 and TULP2 were highlighted as informative markers. A random forest classification model with an accuracy of 94.57% and kappa of 88.96% was obtained. To evaluate this potential panel for LUAD, the methylation levels of four CpG loci in HOXA9, KRTAP8-1, CCND1 and TULP2 of tumor samples and matched adjacent lung samples from 25 patients with LUAD were tested. In these LUAD patients, the methylation of HOXA9 was significantly up-regulated, whereas the methylation of KRTAP8-1, CCND1 and TULP2 were down-regulated obviously in tumor samples compared with adjacent tissues. Our study demonstrates that the methylation of HOXA9, KRTAP8-1, CCND1 and TULP2 has great potential for the early recognition of LUAD in the undetermined lung nodules. The findings also exhibit that the application of improved mathematic algorithms can yield accurate and particularly robust and widely applicable marker panels. This approach could greatly facilitate the discovery process of biomarkers in various fields.

Keywords: Lung Adenocarcinoma, DNA Methylation, random forest, HOXA9, KRTAP8-1, CCND1, TULP2, biomarker

Received: 26 Apr 2019; Accepted: 05 Nov 2019.

Copyright: © 2019 Shen, Du, Zhou, Pan, Hoheisel, Jiang, Xiao, Tao and Mo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
PhD. Ling Xiao, Department of Histology and Embryology, School of Basic Medical Sciences, Central South University, Changsha, China, xiaolingcsu@csu.edu.cn
PhD. Yue Tao, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, taoyue@scmc.com.cn
PhD. Xi Mo, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, Xi.Mo@shsmu.edu.cn