In‐depth molecular profiling of the biphasic components of uterine carcinosarcomas

Abstract

Uterine carcinosarcoma is a clinically aggressive malignancy composed of a mix of carcinomatous and sarcomatous elements. We performed targeted next‐generation sequencing of 27 uterine cancer and sarcoma genes together with immunohistochemical analyses of selected proteins in 30 uterine carcinosarcomas. This included 13 cases in which the distinct carcinoma and sarcoma components were sequenced separately and 10 cases where the metastatic tumours were analysed in addition to the primary tumours. We identified non‐synonymous somatic mutations in 90% of the cases, with 27 of 30 cases (90%) harbouring TP53 alterations. The PI3K pathway was the most commonly mutated signalling pathway with mutations identified in PIK3CA, PTEN, PIK3R1, and/or PIK3R2 in two‐thirds of the cases. Mutations in FBXW7, PPP2R1A, ARID1A and KRAS were demonstrated in a minority of cases. In cases where the carcinomatous and sarcomatous components were separately analysed, most of the mutations identified were present in both components, indicating a common origin for the two components. Furthermore, the same TP53 alterations and/or PI3K pathway mutations seen in the primary tumours were also identified in the metastatic sites. Overall, carcinosarcomas exhibited heterogeneous molecular features that resemble the heterogeneity seen in endometrial carcinomas, with some showing endometrioid carcinoma‐like and others showing serous carcinoma‐like mutation profiles. While patients with serous‐like tumours presented more frequently with advanced‐stage disease compared to patients with endometrioid‐like tumours, there was no statistical difference in outcome between the two groups. Our results provide insights into the oncogenesis of uterine carcinosarcoma and identify targetable mutations that represent early oncogenic events. The findings of the different molecular types of uterine carcinosarcoma that parallel the different molecular types in endometrial carcinoma may have future treatment implications with targeted therapies.

Integrated Molecular Characterization of Uterine Carcinosarcoma

“…The mutations that we discovered in this study were reminiscent of what was reported in the far more common endometrial carcinomas. In addition, molecular features including DNA methylation, copy number and gene expression recapitulate the endometrial versus serous dichotomy observed in endometrial carcinomas, which was in line with a previous report studying genetic mutation (McConechy et al, 2015). This paper also identified concordant mutation profiles in microdissected carcinoma and sarcomatous components of primary tumors as well as between primary and metastatic lesions.…”

Genomic profiling identifies GPC5 amplification in association with sarcomatous transformation in a subset of uterine carcinosarcomas

“…In an earlier report, using a targeted sequencing approach to study the biphasic nature of uterine carcinosarcoma, we found identical mutations and similar mutational burdens in matched carcinoma and sarcoma components, consistent with a clonal relationship 2. Since uterine carcinosarcomas are essentially metaplastic high‐grade carcinomas, it may be reasonable to speculate that CNAs may be more prevalent than point mutations, based on extrapolation of the genomic profiling data from high‐grade serous carcinoma 4, 5.…”

The FOXA2 transcription factor is frequently somatically mutated in uterine carcinosarcomas and carcinomas

“…Molecular studies that analyzed the carcinoma and sarcoma components of individual tumors separately found evidence of shared alterations between each component in a majority of cases . Thus, the majority of UCSs are believed to be monoclonal in origin, resulting from a metaplastic transition of carcinoma cells to sarcoma cells .…”