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A comprehensive molecular analysis of 113 primary ovarian clear cell carcinomas reveals common therapeutically significant aberrations

I. Stružinská, N. Hájková, J. Hojný, E. Krkavcová, R. Michálková, J. Dvořák, K. Němejcová, R. Matěj, J. Laco, J. Drozenová, P. Fabian, J. Hausnerová, G. Méhes, P. Škapa, M. Švajdler, D. Cibula, F. Frühauf, MK. Bártů, P. Dundr

. 2023 ; 18 (1) : 72. [pub] 20230612

Language English Country England, Great Britain

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc23011074

Grant support
NV19-03-00007 Ministerstvo Zdravotnictví Ceské Republiky
BBMRI_CZ LM2023033 European Regional Development Fund

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.

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$a BACKGROUND: Molecular aberrations occurring in primary ovarian clear cell carcinoma (OCCC) can be of diagnostic, predictive, and prognostic significance. However, a complex molecular study including genomic and transcriptomic analysis of large number of OCCC has been lacking. METHODS: 113 pathologically confirmed primary OCCCs were analyzed using capture DNA NGS (100 cases; 727 solid cancer related genes) and RNA-Seq (105 cases; 147 genes) in order to describe spectra and frequency of genomic and transcriptomic alterations, as well as their prognostic and predictive significance. RESULTS: The most frequent mutations were detected in genes ARID1A, PIK3CA, TERTp, KRAS, TP53, ATM, PPP2R1A, NF1, PTEN, and POLE (51,47,27,18,13,10,7,6,6, and 4%, respectively). TMB-High cases were detected in 9% of cases. Cases with POLEmut and/or MSI-High had better relapse-free survival. RNA-Seq revealed gene fusions in 14/105 (13%) cases, and heterogeneous expression pattern. The majority of gene fusions affected tyrosine kinase receptors (6/14; four of those were MET fusions) or DNA repair genes (2/14). Based on the mRNA expression pattern, a cluster of 12 OCCCs characterized by overexpression of tyrosine kinase receptors (TKRs) AKT3, CTNNB1, DDR2, JAK2, KIT, or PDGFRA (p < 0.00001) was identified. CONCLUSIONS: The current work has elucidated the complex genomic and transcriptomic molecular hallmarks of primary OCCCs. Our results confirmed the favorable outcomes of POLEmut and MSI-High OCCC. Moreover, the molecular landscape of OCCC revealed several potential therapeutical targets. Molecular testing can provide the potential for targeted therapy in patients with recurrent or metastatic tumors.
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$a Hájková, Nikola $u Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
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$a Hojný, Jan $u Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
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$a Krkavcová, Eva $u Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
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$a Michálková, Romana $u Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
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$a Matěj, Radoslav $u Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic $u Department of Pathology, Faculty of Medicine, Charles University, University Hospital Kralovske Vinohrady, Prague, 3rd, Czech Republic $u Department of Pathology and Molecular Medicine, Third Faculty of Medicine, Charles University, Thomayer University Hospital, Prague, Czech Republic
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$a Laco, Jan $u The Fingerland Department of Pathology, Faculty of Medicine in Hradec Kralove, Charles University, University Hospital Hradec Kralove, Prague, Czech Republic
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$a Drozenová, Jana $u Department of Pathology, Faculty of Medicine, Charles University, University Hospital Kralovske Vinohrady, Prague, 3rd, Czech Republic
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$a Fabian, Pavel $u Department of Oncological Pathology, Masaryk Memorial Cancer Institute, Brno, Czech Republic
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$a Méhes, Gábor $u Department of Pathology, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary
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$a Škapa, Petr $u Department of Pathology and Molecular Medicine, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
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$a Švajdler, Marián $u Šikl's Department of Pathology, The Faculty of Medicine, Faculty Hospital in Pilsen, Charles University, Pilsen, Czech Republic
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$a Cibula, David $u Gynecologic Oncology Center, Department of Obstetrics and Gynecology, First Faculty of Medicine, Charles University in Prague, General University Hospital in Prague, Prague, Czech Republic
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$a Frühauf, Filip $u Gynecologic Oncology Center, Department of Obstetrics and Gynecology, First Faculty of Medicine, Charles University in Prague, General University Hospital in Prague, Prague, Czech Republic
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$a Bártů, Michaela Kendall $u Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
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$a Dundr, Pavel $u Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic. pavel.dundr@vfn.cz $u Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Studničkova 2, Prague 2, 12800, Czech Republic. pavel.dundr@vfn.cz $1 https://orcid.org/0000000289406124 $7 xx0080436
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