Abstract
Lung adenocarcinoma (LUAD) needs to be stratified for its heterogeneity. Oncogenic driver alterations such as EGFR mutation, ALK translocation, ROS1 translocation, and BRAF mutation predict response to treatment for LUAD. Since oncogenic driver alterations may modulate immune response in tumor microenvironment that may influence prognosis in LUAD, the effects of EGFR, ALK, ROS1, and BRAF alterations on tumor microenvironment remain unclear. Immune-related prognostic model associated with oncogenic driver alterations is needed. In this study, we performed the Cox-proportional Hazards Analysis based on the L1-penalized (LASSO) Analysis to establish an immune-related prognostic model (IPM) in stage I-II LUAD patients, which was based on 3 immune-related genes (PDE4B, RIPK2, and IFITM1) significantly enriched in patients without EGFR, ALK, ROS1, and BRAF alterations in The Cancer Genome Atlas (TCGA) database. Then, patients were categorized into high-risk and low-risk groups individually according to the IPM defined risk score. The predicting ability of the IPM was validated in GSE31210 and GSE26939 downloaded from the Gene Expression Omnibus (GEO) database. High-risk was significantly associated with lower overall survival (OS) rates in 3 independent stage I-II LUAD cohorts (all P < 0.05). Moreover, the IPM defined risk independently predicted OS for patients in TCGA stage I-II LUAD cohort (P = 0.011). High-risk group had significantly higher proportions of macrophages M1 and activated mast cells but lower proportions of memory B cells, resting CD4 memory T cells and resting mast cells than low-risk group (all P < 0.05). In addition, the high-risk group had a significantly lower expression of CTLA-4, PDCD1, HAVCR2, and TIGIT than the low-risk group (all P < 0.05). In summary, we established a novel IPM that could provide new biomarkers for risk stratification of stage I-II LUAD patients.
Highlights
Lung adenocarcinoma (LUAD) is the most common type of lung cancer that comprises around 40% of all lung cancer, and it is one of the most aggressive and rapidly fatal tumor types [1]
A total of 110 patients had no mutation in EGFR, ALK, ROS1, and BRAF mutation and were categorized as WT group (n=110), and the remaining 61 patients had at least one somatic mutation (EGFR, ALK, ROS1, or BRAF) and were categorized as MUT group (n=61)
Gene Set Enrichment Analysis (GSEA) analysis of WT group and MUT group showed the immune response of WT group was markedly stronger than MUT group, that 50 gene sets were upregulated in lung adenocarcinoma, and 30 gene sets were upregulated in WT group, among which 2 immune-related gene sets were greatly enriched, with normalized P < 0.05 (Figure 2)
Summary
Lung adenocarcinoma (LUAD) is the most common type of lung cancer that comprises around 40% of all lung cancer, and it is one of the most aggressive and rapidly fatal tumor types [1]. Molecular alterations including EGFR mutation, ALK translocation, ROS1 translocation, and BRAF mutation provide definite targets for drugs in precision medicine [6]. Similar to conventional chemotherapies, the development of resistance for these new-targeted drugs is still a major challenge for treatment effectiveness. Despite the success of targeted-based therapies, early diagnosis and surgical resection of early-stage disease remain the best opportunity for a cure, for that outcome varies differently between LUAD patients at early stage and advanced stage [7, 8]. In spite of its early stage of development, LUAD patients at stage I-II are at substantial risk for recurrence and death, even after complete surgical resection. More indicators are urged to be evaluated for further stratified LUAD patients at stage I-II to provide precision treatment
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
