Deep proteogenomic investigations elucidate the NRF2 antioxidant mechanism as a major driving mechanism of lung adenocarcinoma in Asia

Abstract

Background: Lung adenocarcinoma is a global leading cause of death. Despite modern therapeutic interventions, undesirable outcomes such as drug resistances and disease recurrence still occur. Therefore, continued investigations of disease driving mechanisms and counteracting strategies are urgently needed.

Methods: We re-visited two deep-proteogenomic resources of lung adenocarcinoma published recently. These resources were derived from patient cohorts with decent sizes in Taiwan and China. The gene set enrichment analysis (GSEA) was performed. A heatmap was produced by the generalized association plot (GAP).

Results: Among 189 common oncogenic pathways investigated, the nuclear factor erythroid 2-related factor 2 (NRF2) downstream antioxidant mechanism was uncovered for the first time the leading oncogenic mechanism of lung adenocarcinoma in Taiwan. The gene levels of NRF2 (also known as NFE2L2) is negatively correlated with those of KEAP1 (Pearson's correlation = -0.275, p = 0.009) in patients' tumor tissues. Furthermore, the protein levels of EIF2S2 and PGD are higher in patients with more advanced stages in the Taiwan cohort (p = 0.001 and 0.05, respectively), and are indicative of poorer progression-free survival (PFS) and overall survival (OS) in the China cohort (all Cox-regression p < 0.05). On the other hand, EPHX1 is higher in patients with earlier stages in Taiwan (p = 0.003), and are indicative of better PFS and OS in China (both Cox-regression p < 0.05). When the patients were stratified using the median protein abundances for Kaplan-Meier visualizations, patient strata with higher EIF2S2, PGD, and EPHX1 have significantly poorer PFS (log-rank p = 0.041); poorer OS (p = 0.006), and better PFS and OS (p = 0.001 and 0.030), respectively.

Conclusion: The NRF2 downstream antioxidant mechanism is one major driving mechanism of lung adenocarcinoma in Asia, and represents important directions for future therapeutic interventions. Major downstream proteins such as EIF2S2, PGD, and EPHX1 are indicative of cancer stages and prognosis.