Abstract / Summary
Objective: Antinuclear antibodies (ANA) have the potential to be a new diagnostic marker for prognosis assessment of lung adenocarcinoma (LUAD). However, the circulating proteins underlying this association remain incompletely characterized. This study aimed to identify ANA-associated circulating proteins using proteomic profiling and to explore their associations with progression-free survival (PFS) and coagulation measurements in patients with LUAD. Methods: Pilot proteomic profiling was performed in healthy controls and in patients with LUAD stratified by ANA status. Candidate proteins were subsequently evaluated in an independent ELISA validation cohort. A retrospective cohort of 158 patients was analyzed to assess the association between circulating tissue factor pathway inhibitor (TFPI) concentration and PFS using Cox proportional hazards regression. TFPI was modeled continuously per 100-pg/mL increase. Restricted cubic spline (RCS) analysis, proportional hazards testing, sensitivity analyses, subgroup analyses, exploratory analysis using a data-derived TFPI cutoff, and correlation analyses with coagulation parameters were also performed. Results: Proteomic profiling identified TFPI as an ANA-associated candidate, and ELISA validation showed higher circulating TFPI levels in ANA-positive than in ANA-negative patients. Higher TFPI was associated with a greater risk of progression after adjustment for age, sex, pathological stage, and treatment (adjusted HR, 1.083; 95% CI, 1.019-1.151; P = 0.010). After additional adjustment for ANA status, the linear association was attenuated (HR, 1.066; 95% CI, 0.992-1.145; P = 0.082). RCS analysis demonstrated a significant nonlinear association between TFPI and PFS after multivariable adjustment (P overall = 0.006; P nonlinearity = 0.048), which persisted after further adjustment for ANA status (P overall = 0.027). TFPI was positively correlated with fibrinogen (FIB), fibrin degradation products (FDP), and D-dimer, and the association with D-dimer remained significant after multivariable adjustment and FDR correction. Conclusion: Circulating TFPI was identified as an ANA-associated candidate biomarker and was associated with shorter PFS and coagulation activation in LUAD. These exploratory findings require prospective external validation.