Molecular subtypes and genomic landscape of undifferentiated and dedifferentiated endometrial cancer.

Objective: Undifferentiated and dedifferentiated endometrial carcinomas are rare and clinically aggressive variants of the disease. We sought to define the molecular subtypes and genetic alterations affecting cancer-related genes of these rare histologic endometrial cancer types.

Methods: Patients with undifferentiated/dedifferentiated endometrial cancer subjected to clinical tumor-normal panel sequencing between January 1, 2014, to June 1, 2023, were retrospectively identified, and relevant demographic and clinicopathologic data were extracted from medical records. All cases underwent central pathology review. Endometrial carcinomas with mixed histology and synchronous tumors were excluded. Genomic data including somatic mutations, copy number alterations, and microsatellite instability (MSI), in addition to immunohistochemistry results, were extracted and utilized for molecular subtyping.

Results: A total of 35 patients met inclusion criteria, with a median age at diagnosis of 60 years (range, 36 to 85). Of these, 16 (46%) were undifferentiated and 19 (54%) dedifferentiated, with undifferentiated being more frequently of International Federation of Obstetrics and Gynecology (FIGO) 2009 stage IV at diagnosis than dedifferentiated (7/16, 40% vs 3/19, 17%, p = .05). All 4 molecular subtypes were present, with the majority being MSI-high/mismatch repair-deficient (n = 25, 71%); the remaining cases were of POLE molecular subtype (n = 2, 6%), copy number (CN)-high/TP53abnormal (n = 3, 9%), and CN-low/no specific molecular profile (n = 5, 14%). The most recurrent genetic alterations were found in PTEN (26/35, 74%), ARID1A (26/35, 74%), PIK3CA (21/35, 60%) ARID1B (14/35, 40%), and SMARCA4 (9/35, 26%). Pathogenic mutations in chromatin remodeling genes, including ARID1A and ARID1B, were absent in endometrial cancers of CN-high/TP53abnormal subtype.

Conclusions: Undifferentiated/dedifferentiated endometrial cancers are heterogeneous at the molecular level; however, the majority are MSI-high/mismatch repair-deficient, which may have therapeutic implications. Loss-of-function alterations in chromatin remodeling genes were present in all molecular subtypes except CN-high/TP53 abnormal undifferentiated/dedifferentiated endometrial cancers.