Integrative multi-omics analysis identifies methylation-associated lncRNAs FAM83A-AS2 and AC012213.1 as candidate...

The Motivation: Long non-coding RNAs (lncRNAs) are important regulators of gene expression and are increasingly implicated in cancer. However, the extent to which aberrant DNA methylation is associated with lncRNA dysregulation in lung adenocarcinoma (LUAD) remains underexplored.

By integrating RNA-seq and Illumina 450K methylation data from 473 LUAD and 32 normal lung samples in TCGA, we identified 2,668 differentially expressed lncRNAs and 20,843 differentially methylated CpG sites. Mapping CpGs to lncRNA promoters (-1.5 kb from the annotated TSS) and Spearman correlation analysis highlighted seven lncRNAs with inverse promoter methylation-expression patterns; FAM83A-AS2 and AC012213.1 showed the most consistent associations and were linked to poorer overall survival in Kaplan-Meier and Cox models (adjusted for age, sex, and tumor stage). A two-lncRNA prognostic score derived using LASSO Cox regression showed moderate time-dependent discrimination at 590 days (AUC = 0.72) within the TCGA cohort. An exploratory lncRNA-miRNA-mRNA network suggested miRNA-mediated regulation of LUAD genes, with enrichment analyses linking targets to chromatin modification and epigenetic regulation. These findings nominate FAM83A-AS2 and AC012213.1 as candidate epigenetically associated prognostic lncRNAs in LUAD, warranting validation in independent cohorts and functional studies.