The aim of this study was to examine the genomic characteristics and explore the molecular mechanisms underlying adrenal metastases in lung adenocarcinoma. 57 patients diagnosed with lung adenocarcinoma (LUAD) and adrenal metastases (AM) were enrolled, alongside 33 controls diagnosed with non-adrenal metastases (non-AM) at the time of diagnosis. The primary lung cancer tissue sample were analyzed using next-generation sequencing. The molecular and clinical features were correlated with clinical outcomes. TP53, EGFR and KRAS were the most frequently mutated gene in both groups. EGFR mutations, especially rare variants (G724A, L747P, Q701 L, G719C, V769 L and S768I), exhibited significant enrichment in the non-AM group (P<0.001). An elevated age-related signature in the group of patients with AM, whereas the non-AM group exhibited a higher BRCA signature. Potential prognostic biomarkers such as KEAP1, LRP1B, NOTCH1 and RET mutations were detected in the non-AM group, while ALK mutations in the AM group correlated with shorter overall survival (P<0.001). KRAS mutations in the early synchronous adrenal metastases group were also associated with shorter OS (P<0.001). The analysis of 425 tumor genes in 29 patients with adrenal metastases showed significant enrichment in pathways associated with invasion and metastasis, including TNF signaling pathway and TGF-β signaling pathway. Patients without EGFR mutations in LUAD need to be more concerned about adrenal metastases. Meanwhile, patients with adrenal metastases harboring ALK or KRAS mutations have a poor prognosis and require more aggressive treatment. The TNF and TGF-β pathways might be associated with adrenal metastasis.Copyright © 2024. Published by Elsevier Inc.