Genome Wide Methylome Alterations in Lung Cancer

Abstract

Aberrant cytosine 5-methylation underlies many deregulated elements of cancer. Among paired non-small cell lung cancers (NSCLC), we sought to profile DNA 5-methyl-cytosine features which may underlie genome-wide deregulation. In one of the more dense interrogations of the methylome, we sampled 1.2 million CpG sites from twenty-four NSCLC tumor (T)–non-tumor (NT) pairs using a methylation-sensitive restriction enzyme- based HELP-microarray assay. We found 225,350 differentially methylated (DM) sites in adenocarcinomas versus adjacent non-tumor tissue that vary in frequency across genomic compartment, particularly notable in gene bodies (GB; p<2.2E-16). Further, when DM was coupled to differential transcriptome (DE) in the same samples, 37,056 differential loci in adenocarcinoma emerged. Approximately 90% of the DM-DE relationships were non-canonical; for example, promoter DM associated with DE in the same direction. Of the canonical changes noted, promoter (PR) DM loci with reciprocal changes in expression in adenocarcinomas included HBEGF, AGER, PTPRM, DPT, CST1, MELK; DM GB loci with concordant changes in expression included FOXM1, FERMT1, SLC7A5, and FAP genes. IPA analyses showed adenocarcinoma-specific promoter DMxDE overlay identified familiar lung cancer nodes [tP53, Akt] as well as less familiar nodes [HBEGF, NQO1, GRK5, VWF, HPGD, CDH5, CTNNAL1, PTPN13, DACH1, SMAD6, LAMA3, AR]. The unique findings from this study include the discovery of numerous candidate The unique findings from this study include the discovery of numerous candidate methylation sites in both PR and GB regions not previously identified in NSCLC, and many non-canonical relationships to gene expression. These DNA methylation features could potentially be developed as risk or diagnostic biomarkers, or as candidate targets for newer methylation locus-targeted preventive or therapeutic agents.

Integrative CAGE and DNA Methylation Profiling Identify Epigenetically Regulated Genes in NSCLC

“…Only one of our candidates (AIM2) was among 57 upregulated and hypomethylated genes in LUADs reported by Selamat and colleagues (43). In addition, we observed no overlap between our candidates and genes reported by Mullapudi and colleagues, where 24 NSCLC tumors were compared with nontumor tissues, using a methylation-sensitive restriction enzyme-based HELPmicroarray assay (44). The relatively small overlap indicates that despite previous reports, there is no consensus on epigenetically regulated genes in NSCLC.…”

Peer Review #1 of "Identification of key genes in non-small cell lung cancer by bioinformatics analysis (v0.1)"

“…MELK involved in the process of cell cycle, cell proliferation, tumor formation and apoptosis . Moreover, MELK expression was elevated and closely related to the prognosis of NSCLC patients (Mullapudi et al 2015;Christopher J Giuliano et al 2018). Combined these together, It suggests that these seven genes have a close relation with the prognosis of NSCLC patients, and they may act as the prognostic indicators in NSCLC.…”

Identification of nine microRNAs as potential biomarkers for lung adenocarcinoma

“…Overexpressed ERG variant 2 was found in lung tumors compared to adjacent tissues, which suggested that ERG might exert an oncogenic effect in lung tumors through functions encoded by variant 2 . Aberrantly methylated NTRK3 has been demonstrated to be involved in various cancers including colorectal cancer and lung cancer . Poor survival in lung cancer was closely associated with NTRK3 .…”

“…As a member of the SIX family, Six1 was found to be up‐regulated in LUAD and contributes to preinvasive‐to‐invasive adenocarcinoma progression by inducing epithelial–mesenchymal transition and nuclear atypia . The protein SLC7A5 is part of a two‐protein complex with SLC3A2 and the gene was hypermethylated and its expression increased in lung cancer . Moreover, SLC7A5 was also reported to be differentially expressed between adenocarcinoma and squamous cell lung cancers .…”