RAS signaling in lung adenocarcinoma is defined by lineage context and DUSP4 loss

Authors

• Minjeong Kim, College of Medicine
• Wisut Lamlertthon, Chulabhorn Royal Academy
• Heejoon Jo, College of Medicine
• Yan Cui, Genomics
• Miyeon Yeon, University of Tennessee Health Science Center
• Hyo Young Choi, University of Tennessee Health Science Center
• Katherine A. Hoadley, UNC Lineberger Comprehensive Cancer Center
• Matthew P. Smeltzer, School of Public Health
• Michele C. Hayward, UNC Lineberger Comprehensive Cancer Center
• Matthew D. Wilkerson, Uniformed Services University of the Health Sciences
• Liza Makowski, College of Medicine
• D. Neil Hayes, College of Medicine

Abstract

BACKGROUND. The molecular landscape of lung adenocarcinoma (LUAD) is often illustrated as a driver-oncogene pie chart, but identical mutations exhibit heterogeneous signaling shaped by comutations, transcriptional programs, and lineage context. We propose a lineage-integrated signaling framework using an EGFR mutation signature (mSig). METHODS. We defined EGFR mSig using differentially expressed genes in EGFR-mutant (EGFR-mt) LUADs. Semisupervised clustering and machine learning models were used to test reproducibility in different combinations of datasets. We analyzed molecular subtypes, lineage markers, co-occurring mutations, and EGFR copy number alterations in EGFR mSig-defined subtypes of LUAD. RESULTS. EGFR mSig showed robust classification performance (area under receiver operating characteristic curve = 0.83–0.95; mean negative predictive value = 96.3%). Validated gene expression subtypes and lung lineage markers were closely aligned with EGFR mSig status. Most EGFR mSig⁺ tumors, including many without EGFR mutations, belonged to the bronchioid subtype. A subset of canonical RAS mutations were mSig⁺ and mirrored the EGFR mutation pattern. EGFR WT/mSig^– tumors were enriched for nonbronchioid subtypes and had comutations in TP53 or RAS/RAF/RTKs. We highlight a parsimonious collection of coordinated mutations, including RAS, KEAP1, STK11, TP53, and CDKN2A, that taken together suggest coordination of tumor signaling previously suggested but now reproduced and expanded. CONCLUSION. A potentially novel EGFR mSig that captures the transcriptional footprint of EGFR activation revealed a subset of EGFR WT LUADs with mt-like features. mSig refines LUAD taxonomy beyond mutation-only pie-chart models by incorporating lineage and comutation context. Lineage-directed stratification with coalteration identifies clinically relevant groups across EGFR and RAS states and highlights treatment opportunities for patients currently considered oncogene-negative.

Publication Title

Jci Insight

Recommended Citation

Kim, M., Lamlertthon, W., Jo, H., Cui, Y., Yeon, M., Choi, H., Hoadley, K., Smeltzer, M., Hayward, M., Wilkerson, M., Makowski, L., & Neil Hayes, D. (2026). RAS signaling in lung adenocarcinoma is defined by lineage context and DUSP4 loss. Jci Insight, 11 (8), 1-15. https://doi.org/10.1172/JCI.INSIGHT.200912