Research Paper Volume 12, Issue 8 pp 7183—7206

Integrated data analysis reveals significant associations of KEAP1 mutations with DNA methylation alterations in lung adenocarcinomas

Mohamed Elshaer 1, 4, , Ahmed Islam ElManawy 2, 5, , Ahmed Hammad 1, 6, , Akhileshwar Namani 1, , Xiu Jun Wang 3, , Xiuwen Tang 1, ,

  • 1 Department of Biochemistry and Department of Thoracic Surgery of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, PR China
  • 2 College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou 310058, PR China
  • 3 Department of Pharmacology and Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, PR China
  • 4 Labeled Compounds Department, Hot Labs Center, Egyptian Atomic Energy Authority, Cairo 13759, Egypt
  • 5 Agricultural Engineering Department, Faculty of Agriculture, Suez Canal University, Ismailia 41522, Egypt
  • 6 Radiation Biology Department, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Cairo 13759, Egypt

received: November 11, 2019 ; accepted: March 29, 2020 ; published: April 23, 2020 ;

https://doi.org/10.18632/aging.103068
How to Cite

Copyright © 2020 Elshaer et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

KEAP1 regulates the cytoprotection induced by NRF2 and has been reported to be a candidate tumor suppressor. Recent evidence has shown that mutations in several driver genes cause aberrant DNA methylation patterns, a hallmark of cancer. However, the correlation between KEAP1 mutations and DNA methylation in lung cancer has still not been investigated. In this study, we systematically carried out an integrated multi-omics analysis to explore the correlation between KEAP1 mutations and DNA methylation and its effect on gene expression in lung adenocarcinoma (LUAD). We found that most of the DNA aberrations associated with KEAP1 mutations in LAUD were hypomethylation. Surprisingly, we found several NRF2-regulated genes among the genes that showed differential DNA methylation. Moreover, we identified an 8-gene signature with altered DNA methylation pattern and elevated gene expression levels in LUAD patients with mutated KEAP1, and evaluated the prognostic value of this signature in various clinical datasets. These results establish that KEAP1 mutations are associated with DNA methylation changes capable of shaping regulatory network functions. Combining both epigenomic and transcriptomic changes along with KEAP1 mutations may provide a better understanding of the molecular mechanisms associated with the progression of lung cancer and may help to provide better therapeutic approaches.

Abbreviations

KEAP1: Kelch-like ECH-associated protein 1; NRF2: nuclear factor erythroid 2-related 2; LUAD: lung adenocarcinoma; NSCLC: non-small-cell lung cancer; CpG: cytosine-guanine; TCGA: The Cancer Genome Atlas; GO: gene ontology; KEGG: kyoto encyclopedia of genes and genomes; DAVID: Database for Annotation, Visualization, and Integrated Discovery; PPI: protein-protein interaction; ARE: antioxidant response element; DNMT: DNA methyl transferases; TET enzymes: ten-eleven translocation methyl cytosine dioxygenase; DNMT1: DNA methyltransferase 1.