High Intratumoral PROS1 Expression Is Associated with Improved Survival, Reduced Hypoxia Score Markers, and Alterations in Gene Expression Associated with Oncogene Signaling and Cell Cycle Signaling in Selected Solid Tumors

Protein S (PS), encoded by PROS1, is a vitamin K-dependent physiological anticoagulant with emerging, context-dependent roles in tumor biology. In pancreatic ductal adenocarcinoma (PDAC), exogenous PS suppresses tumor growth and intratumoral hypoxia in preclinical models. Notably, high intratumoral PROS1 expression is associated with improved survival and attenuation of oncogenic, hypoxia-responsive, and EMT-related transcriptional programs in PDAC. Here, we examined associations between intratumoral PROS1 expression and overall survival, hypoxia-associated signaling, and genomic instability across nine cancer types using publicly available cBioPortal datasets. Tumors were stratified by low versus high PROS1 expression. Genomic instability was assessed using tumor mutational burden, aneuploidy, and tumor break load, where available. High PROS1 expression was associated with improved survival in ovarian serous cystadenocarcinoma and lung adenocarcinoma in exploratory, unadjusted Mantel-Haenszel hazard ratio analyses. It was also inversely associated with genomic instability markers in ovarian, lung adenocarcinoma, and PDAC. Meta-analyses in select genes under low and high PROS1 expression conditions revealed shifts in pathways linked to oncogenic signaling, cell-cycle regulation, hypoxia, and EMT. Collectively, these findings position PROS1 as a candidate prognostic biomarker in selected cancers and support further investigation of PROS1’s roles in limiting tumor progression and preserving genomic stability.