Epigenetic and transcriptional consequences of MTAP-loss in lung adenocarcinoma.

Abstract

8624 Background: Lung adenocarcinoma (LUAD), the most common lung cancer subtype, has poor survival rates and limited treatment options. Among its molecular drivers, loss of methylthioadenosine phosphorylase (MTAP) is linked to aggressive development and poor outcomes, yet its downstream effects remain unclear. MTAP is essential for purine biosynthesis and S-adenosyl methionine (SAM) production, a key methyl donor for epigenetic regulation. MTAP-loss leads to methylthioadenosine (MTA) accumulation, which inhibits methyltransferase activity and disrupts epigenetic control. However, the impact of MTAP deficiency on transcriptional and metabolic programming in LUAD is still largely unknown, highlighting a critical gap for targeted therapy. This study examines these molecular consequences to identify potential therapeutic vulnerabilities in MTAP-deficient LUAD. Methods: RNA-sequencing data for 510 LUAD samples were obtained from The Cancer Genome Atlas (TCGA) via cBioPortal. Samples were classified as MTAP-loss (n=64) or MTAP-normal (n=446) based on mutational data. Differential gene expression was performed using the DESeq2 package for R and the Benjamini-Hochberg procedure was used to control for false discovery rate. DNA methylation (Illumina Human Methylation 450k) was compared between MTAP-loss (n=46) and MTAP-normal (n=404) cohorts. Significantly altered probes were mapped to differentially expressed genes (DEGs). Pathway and gene ontology (GO) analyses were conducted using KEGG, GO, and EnrichR to identify dysregulated pathways. Results: DNA methylation analysis revealed 581 hypomethylated and only 51 hypermethylated probes in MTAP-loss samples, underscoring a global hypomethylation phenotype likely driven by MTA accumulation. We identified 343 differentially expressed, hypomethylated genes in MTAP-loss LUAD samples. Of these, upregulated genes were highly enriched in mitochondrial function and stress response pathways, whereas downregulated genes were linked to cell differentiation and developmental processes, suggesting an epigenetically driven metabolic reprogramming. Notably, these alterations may confer heightened cellular survival and adaptability under stress, while curtailing normal differentiation programs. Conclusions: Our findings indicate that MTAP loss in LUAD leads to a coordinated shift in DNA methylation and gene expression, promoting survival-focused metabolic and stress responses at the expense of normal regulatory pathways. These results highlight novel vulnerabilities in MTAP-deficient tumors and suggest potential targets for precision therapies.