Pan-cancer analysis of SPINT2 reveals context-dependent patterns and prognostic relevance across solid cancers

Abstract Serine Protease Inhibitor Kunitz type-2 (SPINT2) has been reported to play a role in the progression of various tumor types. This inhibitor is generally described as a tumor suppressor that affects migration and invasion. However, a few recent studies have reported the opposite, suggesting an oncogenic role for SPINT2 . Understanding how molecules influence cancer biology is crucial for their use as biomarkers, prognostic indicators, or therapeutic targets, thereby advancing personalized oncology. Hence, this study aims to characterize SPINT2 across solid tumors by evaluating its expression, regulatory mechanisms, and potential as a prognostic biomarker. An integrated approach using TCGA and CCLE datasets, patient samples and tumor cell lines was performed to assess SPINT2 expression, regulation, and clinical outcome associations across multiple solid tumor types. This study provides the first pan-cancer analysis of SPINT2 across 31 solid tumor types, including 13 not previously investigated. SPINT2 expression significantly decreased from normal to malignant tissue in 9 non-epithelial/atypical-epithelial tumors and increased in 17 typical epithelial carcinomas. Promoter methylation was higher in non-epithelial and lower in epithelial tumors, mirroring respective SPINT2 expression patterns. This lineage-associated pattern may help contextualize the discrepant tumor-suppressive and oncogenic roles reported for SPINT2 and is likely influenced by tumor origin and molecular context. SPINT2 expression was significantly associated with survival across three tumor types by univariate analysis, while multivariate analysis identified SPINT2 as an independent prognostic factor in six distinct tumor types. These findings support SPINT2 as a promising tumor-type-specific biomarker with associations that differ across neoplasms.