KRAS-mutated endometrial carcinomas: a comprehensive analysis of clinicopathological and molecular profiles across histological subtypes.

Abstract

The Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations represent oncogenic drivers in endometrial carcinoma (EC), while their clinicopathological and genomic features across EC histological subtypes have not been fully defined. In a cohort of 612 ECs subjected to targeted sequencing were retrospectively enrolled and cases were screened for KRAS hotspot mutations. Clinicopathological characteristics and genomic landscapes were systematically analyzed. KRAS hotspot mutations were identified in 119 (19.4%) EC cases, including 9 mesonephric-like adenocarcinomas (MLA), 98 endometrioid carcinomas (EEC), and 12 other histological types. Although MLA patients were younger than EECs, they showed significantly advanced FIGO stage (P < 0.0001), along with distinct patterns of myometrial invasion and lymph node metastasis. The overall dominant KRAS variants were G12D (35.3%), G12V (21.8%), and G13D (21.0%). Notably, EECs with mucinous differentiation (MD) possessed a distinct mutational spectrum dominated by G12D (83.3%), which differed significantly from other subgroups (P < 0.0001). All MLA cases displayed microsatellite stability, with only one KRAS/PTEN and three KRAS/PIK3CA co-mutations. Mismatch repair deficiency (MMRd) was observed in 31 cases (31.6%) of EECs. All EECs with MD and/or squamous differentiation harbored KRAS-PTEN/PIK3CA co-mutations, whereas KRAS were mutually exclusive with TP53 and CTNNB1 alterations. KRAS-mutated ECs display prominent subtype-specific clinicopathological and genomic heterogeneity. The unique molecular signatures may provide novel insights to improve diagnostic accuracy and facilitate the development of targeted treatment strategies.