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Updated: Jul 27, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
A comprehensive molecular analysis of 113 primary ovarian clear cell carcinomas reveals common therapeutically
Ivana Stružinská1,2, Nikola Hájková3, Jan Hojný3
1Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic. ivana.struzinska@vfn.cz.
Background:
Molecular aberrations occurring in primary ovarian clear cell carcinoma (OCCC) can be of diagnostic, predictive, and prognostic significance. However, a complex molecular study including genomic and transcriptomic analysis of large number of OCCC has been lacking.
Methods:
113 pathologically confirmed primary OCCCs were analyzed using capture DNA NGS (100 cases; 727 solid cancer related genes) and RNA-Seq (105 cases; 147 genes) in order to describe spectra and frequency of genomic and transcriptomic alterations, as well as their prognostic and predictive significance.
Results:
The most frequent mutations were detected in genes ARID1A, PIK3CA, TERTp, KRAS, TP53, ATM, PPP2R1A, NF1, PTEN, and POLE (51,47,27,18,13,10,7,6,6, and 4%, respectively). TMB-High cases were detected in 9% of cases. Cases with POLEmut and/or MSI-High had better relapse-free survival. RNA-Seq revealed gene fusions in 14/105 (13%) cases, and heterogeneous expression pattern. The majority of gene fusions affected tyrosine kinase receptors (6/14; four of those were MET fusions) or DNA repair genes (2/14). Based on the mRNA expression pattern, a cluster of 12 OCCCs characterized by overexpression of tyrosine kinase receptors (TKRs) AKT3, CTNNB1, DDR2, JAK2, KIT, or PDGFRA (p < 0.00001) was identified.
Conclusions:
The current work has elucidated the complex genomic and transcriptomic molecular hallmarks of primary OCCCs. Our results confirmed the favorable outcomes of POLEmut and MSI-High OCCC. Moreover, the molecular landscape of OCCC revealed several potential therapeutical targets. Molecular testing can provide the potential for targeted therapy in patients with recurrent or metastatic tumors.
Insights
This study details the genomic and transcriptomic landscape of ovarian clear cell carcinoma (OCCC), identifying key mutations and gene fusions. Findings highlight POLE mutations and MSI-High status as favorable prognostic markers in OCCC.
Area of Science:
- Oncology
- Genomics
- Transcriptomics
Background:
- Ovarian clear cell carcinoma (OCCC) molecular aberrations are crucial for diagnosis, prediction, and prognosis.
- A comprehensive genomic and transcriptomic analysis of a large OCCC cohort was previously lacking.
Purpose of the Study:
- To elucidate the complex molecular hallmarks of primary OCCC through integrated genomic and transcriptomic analysis.
- To identify frequent mutations, gene fusions, and expression patterns.
- To assess the prognostic and predictive significance of these molecular alterations.
Main Methods:
- Analysis of 113 primary OCCCs using DNA Next-Generation Sequencing (NGS) and RNA-Sequencing (RNA-Seq).
- Targeted sequencing of 727 cancer-related genes and 147 genes for RNA-Seq.
- Identification of mutations, copy number alterations, gene fusions, and mRNA expression patterns.
Main Results:
- Frequent mutations observed in ARID1A, PIK3CA, TERTp, KRAS, and TP53.
- Tumor Mutational Burden (TMB)-High cases identified in 9% of OCCC.
- POLE mutations and/or MSI-High status correlated with improved relapse-free survival.
- Gene fusions detected in 13% of cases, predominantly affecting tyrosine kinase receptors (e.g., MET) and DNA repair genes.
- A distinct OCCC cluster characterized by tyrosine kinase receptor (TKR) overexpression was identified.
Conclusions:
- The study provides a comprehensive molecular portrait of primary OCCC.
- POLE mutations and MSI-High status are confirmed as favorable prognostic indicators.
- Identified molecular alterations represent potential therapeutic targets for recurrent or metastatic OCCC, enabling targeted therapy.
