Proteogenomic characterization identifies clinical subgroups in EGFR and ALK wild-type never-smoker lung adenocarcinoma

• Published in: Experimental & molecular medicine 2024, 56(0), , pp.2082-2095
• Main Authors: Kim, Hyondeog, Lee, Wonyeop, Kim, Youngwook, Lee, Sang-Jin, Choi, Wonyoung, Lee, Geon Kook, Park, Seung-Jin, Ju, Shinyeong, Kim, Seon-Young, Lee, Cheolju, Han, Ji-Youn
• Format: Article
• Language: English
• Subjects: 38; 38/39; 45/43; 45/47; 631/114/2404; 631/114/2784; 631/337/2019; 631/67/69; 82/80; Adenocarcinoma; Angiogenesis; Artificial intelligence; Biomedical and Life Sciences; Biomedicine; Copy number; CXCL13 protein; Epidermal growth factor receptors; ErbB protein; Immune checkpoint inhibitors; Immunotherapy; Lung cancer; Lung diseases; MAP kinase; Medical Biochemistry; Medical prognosis; Molecular Medicine; Mutation; Proteomes; Quality of life; Stem Cells; Therapeutic targets; Transcriptomes; Tumors; 생화학
• ISSN: 2092-6413; 1226-3613; 2092-6413
• DOI: 10.1038/s12276-024-01320-0

Patients with lung adenocarcinoma who have never smoked (NSLA) and lack key driver mutations, such as those in the EGFR and ALK genes, face limited options for targeted therapies. They also tend to have poorer outcomes with immune checkpoint inhibitors than lung cancer patients who have a history of smoking. The proteogenomic profile of nonsmoking lung adenocarcinoma patients without these oncogenic driver mutations is poorly understood, which complicates the precise molecular classification of these cancers and highlights a significant area of unmet clinical need. This study analyzed the genome, transcriptome, and LC‒MS/MS-TMT-driven proteome data of tumors obtained from 99 Korean never-smoker lung adenocarcinoma patients. NSLA tumors without EGFR or ALK driver oncogenes were classified into four proteogenomic subgroups: proliferation, angiogenesis, immune, and metabolism subgroups. These 4 molecular subgroups were strongly associated with distinct clinical outcomes. The proliferation and angiogenesis subtypes were associated with a poorer prognosis, while the immune subtype was associated with the most favorable outcome, which was validated in an external lung cancer dataset. Genomic-wide impacts were analyzed, and significant correlations were found between copy number alterations and both the transcriptome and proteome for several genes, with enrichment in the ERBB, neurotrophin, insulin, and MAPK signaling pathways. Proteogenomic analyses suggested several targetable genes and proteins, including CDK s and ATR , as potential therapeutic targets in the proliferation subgroup. Upregulated cytokines, such as CCL5 and CXCL13 , in the immune subgroup may serve as potential targets for combination immunotherapy. Our comprehensive proteogenomic analysis revealed the molecular subtypes of EGFR- and ALK -wild-type NSLA with significant unmet clinical needs. Molecular subtypes in non-smoker lung cancer: proteogenomic insights Lung cancer is the leading cause of cancer deaths worldwide, with increasing cases in non-smokers, particularly Asian women. This research investigates lung adenocarcinoma in non-smokers who don’t have common genetic changes, using a multi-omics approach. The study involved 99 patients, specifically those without typical EGFR or ALK mutations, to better understand the disease at a molecular level and find new treatments. The study shows the variety within non-smoker lung cancers and suggests that different groups may need specific treatmen