Copy number amplification of PSG is associated with poor survival in female lung adenocarcinoma patients

Pregnancy-specific glycoproteins (PSGs) play a pivotal role in establishing and maintaining maternal immune tolerance during pregnancy, preventing fetal rejection through targeted modulation of innate and adaptive immune responses. In our previous work, we found that elevated tumor mRNA expression of PSG genes was associated with worse overall survival in lung cancer, with a significantly stronger effect observed in female patients. Based on this finding, we hypothesized that PSG copy number alterations (CNAs) show a similar sex-dependent effect on survival in lung cancer. We assessed the sex-specific impact of PSG CNAs using two lung adenocarcinoma (LUAD) cohorts: The Cancer Genome Atlas (TCGA) LUAD cohort (269 females, 234 males) and the Memorial Sloan Kettering Cancer Center (MSK)-IMPACT LUAD cohort (2,450 females, 1,413 males). CNAs in the TCGA LUAD dataset were retrieved from cBioPortal and CNAs in the MSK-IMPACT dataset were determined using the FACETS algorithm. Differences in overall survival between patients with PSG copy number gain and those without were assessed using Kaplan-Meier analysis with log-rank test. Tumor mutational burden (TMB) was also compared between the two groups using a two-sample t-test. In the TCGA cohort, female patients with PSG copy number gain (n=48) showed significantly worse overall survival compared to those without copy number gain (n=221; log-rank p=0.0039). In contrast, no significant survival difference was observed in males with PSG copy number gain (n=60) vs. those without (n=174; log-rank p=0.1902). In the MSK-IMPACT cohort, female patients with PSG copy number gain (n=426) showed significantly worse overall survival compared to those without copy number gain (n=2,024; log-rank p=7.5×10⁻⁶; hazard ratio [HR]=1.46, 95% CI: 1.24-1.73). In males, PSG copy number gain was associated with a significantly weaker trend toward poorer survival (n=276 with PSG copy number gain vs. n=1,137 without; log-rank p=0.0089; HR=1.29, 95% CI: 1.07-1.56). Notably, TMB was significantly higher in patients with PSG copy number gain compared to those without, in both females and males (p<0.0001 for both). Among patients receiving immunotherapy in the MSK-IMPACT cohort, no significant survival difference was observed between those with and without PSG copy number gain in both female (n=344) and male (n=248) groups. In this study, we demonstrated that copy number gains of PSG are associated with significantly worse overall survival in female LUAD patients compared to male LUAD patients, and this sex-dependent association is unlikely to be relevant to tumor immunity. These results highlight PSG copy number status as a novel sex-specific prognostic biomarker in lung cancer. These findings warrant further investigation into the underlying biological mechanisms and support future exploration of PSG-targeted therapeutic strategies tailored to female lung cancer patients.