RPL22 mutation is a favourable prognostic subset within mismatch repair-deficient endometrial cancer: a retrospective cohort study

Background Although mismatch repair-deficient (dMMR) endometrial cancers are highly immunogenic and commonly responsive to immune checkpoint inhibitors, their heterogeneous outcomes indicate that dMMR status alone is insufficient to predict therapeutic benefit. The RPL22 gene – frequently mutated in microsatellite instability-high tumours – represents a candidate biomarker whose prognostic significance in dMMR endometrial cancer remains largely unexplored.Methods In this retrospective cohort study, we analysed 250 patients with immunohistochemically confirmed dMMR endometrial cancer diagnosed between 2008 and 2022. The RPL22 p.K15Rfs*5 mutation was detected by Sanger sequencing and analysed in relation to MMR protein expression pattern, histologic subtype, treatment modality, recurrence pattern, cancer-specific survival (CSS), and progression-free survival (PFS).Results RPL22 mutations were identified in 78.4% (196/250) of dMMR tumours, at a comparable frequency in MLH1-PMS2-deficient (79.2%) and MSH2-MSH6-deficient (76.1%) cases (p = 0.596), and were unrelated to FIGO stage, treatment, or recurrence pattern. RPL22-mutant tumours had significantly better CSS (p < 0.001) and PFS (p = 0.002) than wild-type tumours. MLH1-PMS2-deficient tumours showed worse CSS than MSH2-MSH6-deficient tumours (p = 0.008); within this subgroup, RPL22-mutant tumours had better CSS and PFS than wild-type tumours (p < 0.001 and p = 0.005, respectively). In aggressive histologic subtypes, RPL22 mutations were associated with better CSS (p = 0.003). In multivariable analysis including FIGO stage, RPL22 mutations remained independently associated with better CSS (HR = 0.14; 95% CI, 0.05–0.43; p = 0.001) and PFS (HR = 0.43; 95% CI, 0.23–0.81; p = 0.009).Conclusions In this hypothesis-generating retrospective cohort, the RPL22 p.K15Rfs*5 mutation identified a favourable prognostic subset within dMMR endometrial cancers, particularly among MLH1-PMS2-deficient tumours and aggressive histologic subtypes. Because treatment was not modelled and cancer-specific deaths were few, prospective validation in treatment-annotated cohorts is required before routine clinical implementation.