Context-Dependent Associations of PROGINS Variants with Progesterone Receptor Signaling and Biological Features in...

Background: Progesterone signaling has been implicated in diffuse glioma biology, but the factors contributing to variability in progesterone receptor (PGR) activity remain incompletely understood. We investigated whether PROGINS-related PGR variants detected in tumor-derived DNA were associated with PGR expression and selected biological features of diffuse gliomas. Methods: This retrospective translational study included 66 patients with histopathologically confirmed diffuse gliomas. Three PROGINS-associated PGR variants-the Alu insertion, V660L (rs1042838), and H770H (rs1042839)-were analyzed using DNA extracted from fresh-frozen tumor tissue. Relative PGR gene expression, tissue PGR protein concentrations, Ki-67 labeling index, and p53 immunoreactivity were evaluated together with IDH status, ATRX expression, and 1p/19q co-deletion. Separate multivariable regression models assessed variant-specific associations and prespecified variant × sex and variant × tumor grade interactions. Multiple testing within the reported multivariable models was addressed using the Benjamini-Hochberg false discovery rate procedure. Results: Relative PGR gene expression was lower in high-grade than in low-grade gliomas (p = 0.039), whereas tissue PGR protein concentrations did not differ significantly according to grade. In multivariable analyses, V660L L-allele carriage was associated with higher PGR expression and lower Ki-67 labeling indices, H770H G-allele carriage was associated with lower PGR expression and higher p53 immunoreactivity, and Alu insertion carrier status was associated with lower PGR expression. Significant variant × sex interactions were identified for several outcomes, and an H770H × tumor grade interaction was observed for PGR expression. All nominally significant associations reported in the multivariable models remained significant after false discovery rate correction. Conclusions: PROGINS-related PGR variants detected in tumor-derived DNA are associated with selected biological features of diffuse gliomas, with several associations differing according to biological sex and, for selected outcomes, tumor grade. These findings support a context-dependent relationship between PGR variant status and glioma phenotype but do not establish functional causality or clinical biomarker utility. Independent functional and longitudinal studies are required to determine the biological and potential clinical relevance of these associations.