Abstract 2398: Pregnancy-specific glycoproteins in tumors are strong predictors of outcome in female lung adenocarcinoma patients

Abstract Pregnancy-specific glycoproteins (PSGs) are normally critical regulators of maternal immune tolerance during pregnancy, preventing fetal rejection by modulating innate and adaptive immune responses. Recent studies have identified that mRNA expression of PSG genes in tumors is associated with poor prognosis in lung, mesothelioma, breast, and ovarian cancers. Given their pregnancy-related function, we hypothesized that PSGs could exert sex-specific effects in some cancers. An analysis of sex-differential effects of PSGs as prognostic markers was conducted using two datasets from The Cancer Genome Atlas (TCGA) including 235 male and 271 female patients and Clinical Proteomic Tumor Analysis Consortium (CPTAC) including 70 male and 36 female patients. To assess the predictive power of PSGs, we evaluated whether incorporating PSG expression levels improved machine learning models for survival prediction. Lung adenocarcinoma (LUAD) was identified as showing a significant sex-specific prognostic difference. Female LUAD patients expressing PSG genes had notably worse survival outcomes compared to those without PSG expression. Male patients did not show similar effects. Combinatorial analysis showed that a combination of PSG3, PSG7, and PSG8 expression resulted in particularly poor prognosis in the female group (30% of the female patients) with p = 8.67E-06. This finding was independently validated in the smaller CPTAC dataset with p = 0.0382. Further analysis of correlated pathway changes revealed that female LUAD patients with PSG expression exhibited enrichment of the "KRAS Signaling Down" pathway, suggesting a potential mechanism underlying the observed sex-specific effects. Including the KRAS pathway activity into the PSG model demonstrated robust performance in predicting survival outcomes for female patients (validated C-index = 0.78 using the CPTAC dataset) but did not improve prediction for male patients. These findings highlight a unique role for PSGs in influencing LUAD progression and survival in a sex-dependent manner. Targeting PSG-related pathways may offer a tailored treatment strategy for female LUAD patients, potentially improving outcomes. Further research is needed to unravel the relationship between PSG expression and KRAS pathway activation. We also plan to examine the sex-specific prognostic difference, looking into pregnancy history and the influence of hormone-related genes. Since PSGs are not typically expressed in the absence of pregnancy, they could be a promising drug target. Citation Format: Jung Hun Oh, 1 Gabrielle Rizzuto, 1 Rena Elkin, 1 Corey Weistuch, 1 Larry Norton, 1 Gabriela Dveksler, 2 Joseph O. Deasy1. Pregnancy-specific glycoproteins in tumors are strong predictors of outcome in female lung adenocarcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2398.