A comparative analysis of serum and tissue proteomic profiles in non-small cell lung cancer patients with or without brain metastasis

To identify specific, sensitive, and non-invasive circulating protein biomarkers that could facilitate the diagnosis of brain metastasis (BrM) and improve risk prediction for BrM among patients with non-small cell lung cancer (NSCLC). We performed data-independent acquisition mass spectrometry (DIA-MS)-based proteomic profiling of 14 tissue specimens obtained from 7 patients, together with 89 serum samples from NSCLC and NSCLC-BrM cohorts, to identify candidate biomarkers associated with BrM. A total of 12,808 proteins were identified in the tissue proteome and 6041 proteins in the serum proteome, representing an extensive proteomic analysis of lung cancer with BrM reported to date. Using integrated analyses, we identified a four-protein classifier that served as biomarkers for predicting the risk of NSCLC metastasis to the brain. Notably, PSMA4, LAP3, and LZIC were consistently downregulated in both the sera and tissues of patients with NSCLC-BrM compared with those with NSCLC without BrM. These biomarkers were subsequently validated by ELISA in an additional cohort, demonstrating high concordance with the PRM results. Immunohistochemical analyses further supported the utility of these proteins in distinguishing BrM from primary brain tumors. The integrated analysis of tissue and serum proteomics across the cohorts supports the potential value of proteomics-guided, biomarker-assisted diagnosis and risk prediction in BrM and may help enable more accurate stratification and more targeted treatment strategies.