Clonal Progression of a DNA Polymerase Epsilon–Mutant Endometrial Cancer With Immune Evasion Characteristics and Metastasis
Renal transplant recipients are at significantly higher risk of developing malignancies because of chronic immunosuppression. Although DNA polymerase epsilon (POLE)-mutated endometrioid carcinoma (EC) typically presents as early-stage disease with an excellent prognosis and rare metastasis, we conducted a study on POLE-mutated EC in a transplant recipient that rapidly progressed and metastasized. We aimed to first elucidate the molecular and immunological mechanisms of rapid and malignant progression in the tumor. To understand the mechanisms underlying this atypical clinical course, we performed histological and immunohistochemical comparisons of the primary endometrial tumor and metastatic peritoneal lesions, alongside next-generation sequencing and RNA sequencing analyses. The primary and metastatic lesions shared 17 somatic mutations, indicating a common origin but demonstrated divergent evolution. Gene expression profiling revealed low CD8+ T-cell infiltration and weak interferon gamma signaling, suggesting an immunologically inactive or "immune desert" tumor microenvironment. Clonal evolution analysis showed that the POLE p.S297F mutation initiated hypermutation and clonal diversification in the primary tumor. In contrast, metastatic lesions exhibited POLE loss and activation of the BRAFV600E::PIK3CD pathway, leading to progress and immune evasion. These findings highlight a distinct evolutionary trajectory of POLE-mutated EC under immunosuppressive conditions in this case and underscore the need for tailored oncological surveillance and treatment strategies in transplant recipients.