Distinct genomic subgroups and mutational patterns in undifferentiated/dedifferentiated endometrial carcinoma.

Abstract

Background: Endometrial cancer represents a significant global health challenge, with undifferentiated and dedifferentiated endometrial carcinoma (UDEC) being a particularly aggressive subset.

Methods: We employed whole-exome sequencing (WES) to comprehensively characterize the molecular landscape of 29 UDECs in a single institution cohort. We analyzed driver mutations, molecular subgroups, SWI/SNF complex, DNA mismatch repair (MMR) pathways, and somatic copy number alterations (SCNAs).

Results: We identified 5 (17%) ultramutated tumors, 14 (48%) DNA mismatch repair (MMR)-deficient tumors, and 10 (35%) mutation-low tumors in this cohort. Mutations in the SWI/SNF family and other driver genes are common, including PTEN, ARID1A, KMT2B, ARID1B, SMARCA4, and PIK3CA. Genomic inactivation of SWI/SNF complex genes occurred in 19 of 29 (66%) of cases, highlighting the frequent chromatin remodeling dysfunction in UDEC. We observed frequent homopolymer mutations in UDECs with MMR deficiency, with RPL22^K15Rfs*5 mutation found in 10 of 14 (71%) MMR-deficient tumors. Notably, ultramutated tumors demonstrated superior survival compared to the other two subtypes.

Conclusions: Our analysis revealed distinct architectures and actionable alterations in UDEC. The identification of molecular subgroups provides a promising framework for prognostic stratification. Collectively, our findings not only advance our understanding of UDEC biology but also illuminate potential translational applications.