Abstract
PurposeOvarian and uterine clear cell carcinomas (CCCs) are rare but associated with poor prognosis. This study explored RNA transcription patterns characteristic of these tumors.Experimental DesignRNA sequencing (RNA-seq) of 11 ovarian CCCs and five uterine CCCs was performed and compared to publicly available data from high grade serous ovarian cancers (HGSOCs). Ingenuity Pathway Analyses were performed. CIBERSORT analyses estimated relative fractions of 22 immune cell types in each RNA-seq sample. Sequencing data was correlated with PD-L1 immunohistochemical expression.ResultsRNA-seq revealed 1,613 downregulated and 1,212 upregulated genes (corrected p < 0.05, |FC |≥10) in ovarian CCC versus HGSOC. Two subgroups were identified in the ovarian CCC, characterized by ethnicity and expression differences in ARID1A. There were 3,252 differentially expressed genes between PD-L1+/− ovarian CCCs, revealing immune response, cell death, and DNA repair networks, negatively correlated with PD-L1 expression, whereas cellular proliferation networks positively correlated with expression. In clear cell ovarian versus clear cell uterine cancer, 1,607 genes were significantly upregulated, and 109 genes were significantly downregulated (corrected p < 0.05, |FC|≥10). Comparative pathway analysis of late and early stage ovarian CCCs revealed unique metabolic and PTEN pathways, whereas uterine CCCs had unique Wnt/Ca+, estrogen receptor, and CCR5 signaling. CIBERSORT analysis revealed that activated mast cells and regulatory T cell populations were relatively enriched in uterine CCCs. The PD-L1+ ovarian CCCs had enriched resting NK cells and memory B cell populations, while PD-L1− had enriched CD8 T-cells, monocytes, eosinophils, and activated dendritic cells.ConclusionsUnique transcriptional expression profiles distinguish clear cell uterine and ovarian cancers from each other and from other more common histologic subtypes. These insights may aid in devising novel therapeutics.
Highlights
Ovarian and uterine carcinomas are gynecologic malignancies with significantly associated morbidity and mortality
Mutations in TP53, PIK3CA, PRKC1, and KRAS oncogenes as well as ARID1A and PTEN tumor suppressor genes have been studied as key drivers of ovarian cell carcinoma (CCC), revealing therapeutic targets [7,8,9]
We found FOXA1 to be upregulated whereas COX15, COX17, FBXL2, and cytochrome genes (SCO1 and SCO2) were down regulated in ovarian CCC as compared to HGS tumors
Summary
Ovarian and uterine carcinomas are gynecologic malignancies with significantly associated morbidity and mortality. While other histologies display microarray gene expression patterns unique to their tissue of origin, CCCs show a remarkably similar gene expression pattern in the endometrium, kidney, and ovary [1, 2]. Both uterine and ovarian clear cell carcinoma are rare and have early metastasis, high risk of recurrence, and poor prognosis [3]. Given that these represent less than 5% of all uterine or ovarian cancers, optimal management strategies are extrapolated from more common histologies and incorporate comprehensive surgical staging and combination cytotoxic chemotherapy [4]. Two studies analyzing DNA from 39 ovarian CCCs or 16 uterine CCCs report on mutational loads, microsatellite stability, and frequency of pathologic somatic mutations [10, 11]
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