Abstract 5672: Transcriptomic profiling of lung adenocarcinoma from never-smokers reveals molecular subtypes with clinical implications

Abstract

Abstract Lung cancer is the leading cause of cancer mortality worldwide and about 10-25% of lung cancers are from never-smokers (LCINS). Previous genomic studies of LCINS identified multiple genomic subtypes with different genetic drivers and evolutionary processes. To dissect the profile of LCINS cell states and tumor microenvironment, and their relationship with genomic lesions, we sequenced and assembled a large RNA-seq data set of 685 samples of lung adenocarcinoma from never-smokers and integrated them with whole genome sequencing data, pathological features and clinical outcomes from the same subjects. We identified three transcriptomic subtypes defined by distinct gene expression patterns. The three subtypes were associated with different pathway activities and showed remarkable heterogeneity in cell composition, lineage fidelity and pathological features. The genomic driver events and mutational signatures were significantly enriched in specific subtypes. Clinical outcomes also differed across the subtypes. For example, one subtype had prolonged overall survival and was associated with predicted response to immune checkpoint blockade. This study emphasizes the importance of transcriptome-based classification of LCINS, which has profound clinical implications beyond those provided by genomic and pathological assessment. Citation Format: Wei Zhao, Tongwu Zhang, Phuc H. Hoang, Jian Sang, Maria Teresa Landi. Transcriptomic profiling of lung adenocarcinoma from never-smokers reveals molecular subtypes with clinical implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5672.