Comprehensive molecular and immunohistochemical profiling of endometrial carcinomas: Insights into subtype-specific characteristics.
Year: 2025
Type: article
Study design: Observational Study
Abstract: e17641 Background: Endometrial carcinomas exhibit significant molecular and histopathological heterogeneity. This study analyzes 171 samples to uncover subtype-specific alterations and potential therapeutic targets. Methods: The samples included endometrioid (N=96), serous (N=30), and other histological subtypes. Molecular profiling, performed using a semiconductor-based NGS platform at Datar Cancer Genetics, assessed mutations, amplifications, and fusions in key cancer genes. Tumor mutational burden (TMB), microsatellite instability (MSI), and PD-L1 expression were evaluated in a subset. Results: The most frequently mutated genes in the cohort were PTEN (41%) and TP53 (41%). Subtype analysis revealed distinct patterns: PTEN mutations were more prevalent in endometrioid tumors (52%) than in serous tumors (10%), while TP53 mutations dominated serous tumors (80%) compared to endometrioid tumors (25%). Other commonly mutated genes in endometrioid and serous subtypes included PIK3CA (33.3% vs 30%), KRAS (18.8% vs 13.3%). CTNNB1 had notable enrichment in endometrioid tumors (19.8%) as against serous (6.7%). Additional alterations in ARID1A , PIK3R1 , and FBXW7 were observed, with subtype-specific distributions indicating diverse oncogenic drivers. POLE mutations seen in 4.9% (7/143) identify hypermutated tumors with high immunogenic potential. Microsatellite instability (MSI) was observed in 25.2% of tumors (29/115). PDL1 expression positivity in 15.6%, (7/45) highlight subgroups potentially responsive to immune checkpoint inhibitors. TMB-High status was seen in 28.9% of cases (13/45). ER positivity (74.1%, 60/81) aligned with the hormonal dependency of many endometrioid carcinomas, while HER2 overexpression was detected in 13%. Tumor differentiation grades in the cohort (N=104) were 24% well-differentiated, 13.5% moderately differentiated, and 61.5% poorly differentiated. Poorly differentiated tumors, predominantly serous, showed high TP53 mutations and aggressive behavior. Well-differentiated tumors, mainly endometrioid, were enriched for PTEN and CTNNB1 mutations. Endometrioid tumors demonstrated frequent alterations in the PI3K / AKT signalling pathway, with mutations in PTEN , PIK3CA , and PIK3R1 collectively observed in a significant proportion of cases. Additionally, mutations in CTNNB1 and KRAS were more prevalent, indicating the involvement of Wnt/β-catenin and RAS signalling pathways in tumorigenesis. In contrast, serous tumors were predominantly driven by TP53 mutations and exhibited recurrent alterations in FBXW7 and PIK3CA , suggesting distinct oncogenic pathways. Conclusions: This analysis highlights the molecular and phenotypic diversity of endometrial carcinomas, emphasizing the need for routine molecular profiling beyond POLE , TP53 and MSI to enable personalized therapies.
Source: Journal of Clinical Oncology
Language: English
Subfield: Obstetrics and Gynecology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4410813446