RAS signaling in lung adenocarcinoma is defined by lineage context and DUSP4 loss
Minjeong Kim, Wisut Lamlertthon, Heejoon Jo, Yan Cui, Miyeon Yeon, Hyo Young Choi, Katherine A. Hoadley, Matthew P. Smeltzer, Michele C. Hayward, Matthew D. Wilkerson, Liza Makowski, D. Neil Hayes
Minjeong Kim, Wisut Lamlertthon, Heejoon Jo, Yan Cui, Miyeon Yeon, Hyo Young Choi, Katherine A. Hoadley, Matthew P. Smeltzer, Michele C. Hayward, Matthew D. Wilkerson, Liza Makowski, D. Neil Hayes
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Clinical Research and Public Health Cell biology Clinical Research Oncology

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

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.FUNDING National Cancer Institute (NCI) U01CA272541, R01CA262296, U24CA264021, UG1CA233333, R01CA211939.

Authors

Minjeong Kim, Wisut Lamlertthon, Heejoon Jo, Yan Cui, Miyeon Yeon, Hyo Young Choi, Katherine A. Hoadley, Matthew P. Smeltzer, Michele C. Hayward, Matthew D. Wilkerson, Liza Makowski, D. Neil Hayes

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Figure 1

Performance and reproducibility of the EGFR mutation signature in LUAD.

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Performance and reproducibility of the EGFR mutation signature in LUAD. ...
(A–C) Radar plots showing performance metrics of the EGFR mutation signature (mSig) across datasets. (D–F) Heatmaps of gene expression profiles of patients with LUAD semisupervised by EGFR mutation status and molecular subtype. Rows represent the 1,020 genes included in the EGFR mSig. Columns represent individual patients, clustered by LUAD molecular subtypes (bronchioid, magnoid, and squamoid), with EGFR mutation and mSig status using a semisupervised approach. Annotations indicate EGFR mutation status and EGFR mSig status. mt or mSig+ tumors are shown with dark gray bars, and WT tumors are shown with light gray bars. (A and D) Training cohort (MSKCC). (B and E) Validation cohort 1 (UNC + TSP). (C and F) Validation cohort 2 (TCGA). NPV, negative predictive value; PPV, positive predictive value; mt, mutant.