Genetic predictors of unexpected recurrence in low-risk endometrial cancer: A comprehensive genomic analysis reveals FGFR2 as a risk factor and a rare fatal POLE-mutated recurrence

Abstract

Objective

Endometrial cancer is the most common gynecological malignancy in high-income countries. While early-stage endometrial cancer generally has a favorable prognosis, a small proportion of low-risk patients experience unexpected recurrence. This study aimed to identify molecular factors contributing to recurrence in stage 1 A grade 1–2 low-risk endometrioid endometrial cancer.

Methods

We performed next-generation sequencing (NGS) on tumor samples from 19 patients who experienced recurrence despite favorable clinicopathological features and compared them with six control patients without recurrence. Results were also compared to a matched cohort of low-risk endometrial cancers from The Cancer Genome Atlas (TCGA) database.

Results

Mutations in PTEN, PIK3CA, ARID1A, and FGFR2 were the most frequent in the recurrence group. FGFR2 mutations were exclusive to the recurrence group (9/19, 47.4 %) and absent in the non-recurrent group (0/6), a difference approaching statistical significance (p = 0.0571). FGFR2 mutations were also significantly more prevalent in the recurrence cohort compared to the TCGA low-risk cohort (p = 0.0039). Prominent FGFR2 missense mutations included S252W, K659E, and N549K, which may drive oncogenesis and tumor progression. Among the recurrence group, a rare POLE-mutated tumor recurred unexpectedly and proved fatal, highlighting the potential for poor outcomes even in typically favorable molecular subtypes.

Conclusion

FGFR2 mutations may play a role in tumor recurrence in a subset of low-risk endometrial cancers, underscoring the importance of molecular profiling in identifying patients at risk. FGFR2 represents a potential therapeutic target, warranting further validation in larger cohorts to establish its clinical utility.