Higher levels of the estrogen-related receptor GPER1 in tumor samples were associated with longer overall survival among women younger than 55 with IDH-wildtype grade 3 or 4 glioma, according to a retrospective analysis. In that group, patients with high tumor GPER1 expression had reported overall survival of 754 days. The authors described that as at least a 50% to 104% increase compared with the other groups, although the supplied analysis does not give the comparator details, hazard ratios, confidence intervals or exact p-value.
The result is an association in tumor data, not evidence that GPER1 itself extended anyone’s life. The study combined patient data with gene-expression and methylation analyses, then used experiments in U251 glioblastoma cells to explore possible biological explanations.
A pattern by age and sex
Across the four sex-and-age groups, the younger female group had the longest reported median overall survival: 648 days. The corresponding figures were 380 days for women over 55, 466 days for men under 55 and 388 days for men over 55. The analysis reported a significant difference between the groups, but the supplied results do not include an exact p-value or a measure such as a hazard ratio.
The researchers did not find a significant difference in GPER1 expression itself across the four groups. Instead, the survival pattern appeared when expression was considered within the age-and-sex categories, with the high-expression younger-female group standing out in the reported analysis.
To build the comparison, the researchers first selected 335 IDH-wildtype samples and retained 308 unique primary tumors that had grade 3 or 4 disease, overall-survival data and sex information. They divided patients into groups younger or older than 55, then compared survival across four age-sex groups and eight groups after splitting tumors into high and low GPER1 expression. The expression threshold was selected statistically, with a minimum group proportion of 25%.
The molecular clues were unevenly distributed
The study also examined methylation at the GPER1 gene locus. This analysis covered 136 of the 308 patients and looked at 40 CpG sites. The four subgroup sizes were 21 younger women, 20 younger men, 41 older women and 54 older men.
Using genes with an absolute correlation above 0.5 and an adjusted p-value below 0.05, the researchers compared GPER1 with the activity of other genes within each group. The younger-female group showed the strongest reported negative-correlation pattern: 81 genes moved in the opposite direction to GPER1, compared with 15 in older women and two reported for the male groups. These are expression associations, so they do not show that GPER1 caused the pattern or that the genes drove the survival difference.
The younger-female gene list was enriched for terms involving the cell cycle, the process by which cells grow and divide, as well as mitotic recombination and chromosome organization. Gene-set enrichment can point to biological themes in a dataset, but it does not establish a direct mechanism or a clinical benefit.
A cell experiment offered a possible explanation
The researchers then increased GPER1 expression temporarily in U251 glioblastoma cells and compared the cells with controls. Under the study’s stated criteria, 34 genes were differentially expressed: 24 were more active and 10 were less active in the GPER-overexpressing cells. The analysis counted genes when the absolute fold change exceeded 1.7 and the reported p-value was below 0.05.
Taken together with the patient-data correlations, the cell experiment led the authors to propose that GPER1 may be linked to impaired cell-cycle control in the younger-female pattern. That interpretation remains provisional. The laboratory result came from transient overexpression in U251 cells, while the patient analysis measured tumor samples rather than testing what happens when GPER1 is altered in people.
A signal that still needs testing
Several features limit how far the findings can be taken. The patient analysis was retrospective and observational, so differences between groups could reflect other factors rather than GPER1. The methylation results came from 136 of the 308 patients, with subgroup sizes ranging from 20 to 54.
The laboratory result came from an in-vitro U251 model, not a patient intervention. The reported survival findings also lack hazard ratios, confidence intervals and exact p-values, making the size and precision of the association difficult to assess from the supplied analysis.
The findings nominate GPER1 expression and a GPER1-locus methylation pattern as possible markers for further study in selected younger women. They do not establish a validated prognostic test, show that methylation causes altered GPER1 expression or survival, or demonstrate that GPER1 is an effective human treatment target. The signal will need replication and further biological testing.
Paper data and sources
Original title: G-protein coupled estrogen receptor 1 (GPER1) expression improves survival of glioblastoma patients depending on sex and age: biological mechanisms and epigenetic regulation
Authors: Gantner A, Soudre-Bau L, Bailly Y et al.
Journal/Repository: Frontiers in endocrinology
Status: Peer-reviewed
First online: 2026-10-10
DOI: Not available
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