WCLC 2025 - Posters & ePosters-P2.02.40 Multiomics Assessment of Lung Adenocarcinoma Subtypes Defined Through Tumor Purity-Adjusted DNA Methylation

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This study presents a multiomics analysis of lung adenocarcinoma (LUAD) subtypes defined by tumor purity-adjusted DNA methylation profiling. Using a discovery cohort of 95 tumors from Skåne’s University Hospital and validation cohorts from TCGA (418 samples) and Sandoval (322 samples), the researchers applied DNA methylation clustering adjusted for tumor cell content to identify four robust epigenetic subtypes (M1-M4) present consistently across cohorts. These subtypes reflect distinct tumor cell methylation states and demonstrate unique molecular and clinical characteristics.<br /><br />M1 tumors were characterized by older patients, a high proportion of never-smokers, lower proliferation rates, and a predominance of genomic variants. This subtype correlated with the "Terminal Respiratory Unit" transcriptional subtype and better prognosis. M4 tumors, enriched for the "Proximal Proliferative" transcriptional subtype, showed higher tumor mutational burden, most of the cohort's variants, lower immune response, hypomethylation, and worse survival outcomes. M2 and M3 subtypes shared genomic variants in STK11 but differed in DNA methylation and gene expression of a NAPSA/surfactant metabolism metagene: M3 had higher surfactant gene expression and promoter hypermethylation, while M2 exhibited higher immune response signatures and lower tumor purity.<br /><br />Proteogenomic and transcriptomic data aligned with the DNA methylation-based subtypes, with M1 and M4 showing concordant biological features in mRNA and protein profiles. Cell lines classified according to these epigenetic patterns recapitulated the tumor sample molecular signatures, supporting their biological relevance.<br /><br />Survival analyses demonstrated that M2 and M3 subtypes had significantly poorer overall and disease-specific survival compared to M1. Tumor purity and immune cell infiltration estimates varied among subtypes, further defining their distinct tumor microenvironments.<br /><br />Overall, this comprehensive multi-layered omics study establishes four lung adenocarcinoma epigenetic subtypes with clinical and biological relevance. Adjusting DNA methylation analysis for tumor purity enabled the identification of subtypes that integrate genomic, transcriptomic, proteomic, and metabolomic data, thereby providing potential avenues for improved molecular classification and personalized therapeutic strategies in lung adenocarcinoma.

Asset Subtitle

Deborah F. Nacer de Oliveira

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Speaker Deborah F. Nacer de Oliveira

Topic Tumor Biology – Preclinical Biology

Keywords

lung adenocarcinoma

DNA methylation

tumor purity adjustment

epigenetic subtypes

multiomics analysis

tumor microenvironment

molecular classification

prognostic biomarkers

proteogenomics

personalized therapy