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.