8028 Background: Pregnancy-specific glycoproteins (PSGs) are essential for maintaining maternal immune tolerance by modulating innate and adaptive responses to prevent fetal rejection. Given our prior finding that increased PSG expression is associated with worse outcomes for female lung cancer patients, we aimed to investigate whether copy number alterations (CNAs) show the same sex-dependent effect on survival in early-stage disease. Methods: We evaluated the sex-specific impact of PSG CNAs across two lung adenocarcinoma (LUAD) cohorts: The Cancer Genome Atlas (TCGA) (n = 503; 269 females, 234 males) and MSK-IMPACT (n = 3,863; 2,450 females, 1,413 males). CNAs were retrieved from cBioPortal for the TCGA cohort and determined via the FACETS algorithm on BAM files for the MSK-IMPACT cohort. Overall survival (OS) differences between patients with and without PSG copy number amplification were analyzed using Kaplan-Meier curves along with log-rank tests. Additionally, we examined the association between tumor stage and the prognostic impact of PSG copy number amplification. Results: In the TCGA cohort, female patients with PSG copy number amplification exhibited significantly worse OS compared to those without (HR = 1.96, p = 0.0039), while no significant survival difference was observed in males (HR = 1.37, p = 0.1902). This sex-specific trend was further validated in the MSK-IMPACT cohort, where the association between PSG copy number amplification and poor OS was highly significant in females (HR = 1.46, p = 7.5×10 -6 ) but relatively weaker in males (HR = 1.29, p = 0.0089). Notably, the prognostic impact of PSG copy number amplification was stage-dependent; while no significant survival differences were found for either sex in Stage 4 disease across both cohorts, the effect was highly pronounced in early-stage female patients. In the TCGA cohort, female patients with early-stage disease showed increasingly significant survival disparities between patients with and without PSG copy number amplification as stage decreased (Stage ≤ 3: HR = 1.81, p = 0.0182; Stage ≤ 2: HR = 2.03, p = 0.0129; Stage 1: HR = 2.51, p = 0.0047), whereas no such associations were found in males. Similarly, in the MSK-IMPACT cohort where tumor stage was dichotomized (Stages 1–3 vs. Stage 4), female patients with Stage ≤ 3 disease showed a strong survival difference between patients with and without PSG copy number amplification (HR = 1.86, p = 1.79×10 -5 ), which remained significantly stronger than the association observed in the male patients (HR = 1.49, p = 0.0129). Conclusions: Our findings raise the question of the potential role of PSG-mediated immune modulation in promoting tumor progression in early-stage female lung cancer patients, and suggest that there may be value in sex-stratified approaches to clinical risk assessment and in therapeutic targeting.
Oh et al. (2026) studied this question.