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.

Department of Oncological Pathology Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Pathology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Pathology 1st Faculty of Medicine Charles University and General University Hospital Prague Studničkova 2 Prague 2 12800 Czech Republic

Department of Pathology and Molecular Medicine 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Pathology and Molecular Medicine 3rd Faculty of Medicine Charles University Thomayer University Hospital Prague Czech Republic

Department of Pathology Faculty of Medicine Charles University University Hospital Kralovske Vinohrady Prague 3rd Czech Republic

Department of Pathology Faculty of Medicine University of Debrecen Debrecen 4032 Hungary

Department of Pathology University Hospital Brno and Medical Faculty Masaryk University Brno Czech Republic

Gynecologic Oncology Center Department of Obstetrics and Gynecology 1st Faculty of Medicine Charles University Prague General University Hospital Prague Prague Czech Republic

Šikl's Department of Pathology The Faculty of Medicine Faculty Hospital in Pilsen Charles University Pilsen Czech Republic

The Fingerland Department of Pathology Faculty of Medicine in Hradec Kralove Charles University University Hospital Hradec Kralove Prague Czech Republic

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Friedlander ML, Russell K, Millis S, Gatalica Z, Bender R, Voss A. Molecular Profiling of Clear Cell ovarian cancers: identifying potential treatment targets for clinical trials. Int J Gynecol Cancer. 2016;26:648–54. doi: 10.1097/IGC.0000000000000677. PubMed DOI PMC

Zhu C, Xu Z, Zhang T, Qian L, Xiao W, Wei H, et al. Updates of Pathogenesis, Diagnostic and therapeutic perspectives for ovarian Clear Cell Carcinoma. J Cancer. 2021;12:2295–316. doi: 10.7150/jca.53395. PubMed DOI PMC

Bolton KL, Chen D, de la Corona RI, Fu Z, Murali R, M, KB, et al. Molecular subclasses of clear cell ovarian carcinoma and their impact on disease behavior and outcomes. Clin Cancer Res. 2022 doi: 10.1158/1078-0432.CCR-21-3817. PubMed DOI PMC

Oliveira D, Schnack TH, Poulsen TS, Christiansen AP, Hogdall CK, Hogdall EV. Genomic sub-classification of Ovarian Clear Cell Carcinoma revealed by distinct mutational signatures. Cancers (Basel). 2021;13. 10.3390/cancers13205242. PubMed PMC

Liu H, Zhang Z, Chen L, Pang J, Wu H, Liang Z. Next-generation sequencing reveals a very low prevalence of deleterious mutations of homologous recombination repair genes and homologous recombination Deficiency in Ovarian Clear Cell Carcinoma. Front Oncol. 2021;11:798173. doi: 10.3389/fonc.2021.798173. PubMed DOI PMC

Shibuya Y, Tokunaga H, Saito S, Shimokawa K, Katsuoka F, Bin L, et al. Identification of somatic genetic alterations in ovarian clear cell carcinoma with next generation sequencing. Genes Chromosomes Cancer. 2018;57:51–60. doi: 10.1002/gcc.22507. PubMed DOI

Itamochi H, Oishi T, Oumi N, Takeuchi S, Yoshihara K, Mikami M, et al. Whole-genome sequencing revealed novel prognostic biomarkers and promising targets for therapy of ovarian clear cell carcinoma. Br J Cancer. 2017;117:717–24. doi: 10.1038/bjc.2017.228. PubMed DOI PMC

Maru Y, Tanaka N, Ohira M, Itami M, Hippo Y, Nagase H. Identification of novel mutations in japanese ovarian clear cell carcinoma patients using optimized targeted NGS for clinical diagnosis. Gynecol Oncol. 2017;144:377–83. doi: 10.1016/j.ygyno.2016.11.045. PubMed DOI

Murakami R, Matsumura N, Brown JB, Higasa K, Tsutsumi T, Kamada M, et al. Exome sequencing Landscape Analysis in Ovarian Clear Cell Carcinoma Shed Light on Key chromosomal regions and mutation gene networks. Am J Pathol. 2017;187:2246–58. doi: 10.1016/j.ajpath.2017.06.012. PubMed DOI

Sugino K, Tamura R, Nakaoka H, Yachida N, Yamaguchi M, Mori Y, et al. Germline and somatic mutations of homologous recombination-associated genes in japanese ovarian cancer patients. Sci Rep. 2019;9:17808. doi: 10.1038/s41598-019-54116-y. PubMed DOI PMC

Yin X, Bi R, Ma P, Zhang S, Zhang Y, Sun Y, et al. Multiregion whole-genome sequencing depicts intratumour heterogeneity and punctuated evolution in ovarian clear cell carcinoma. J Med Genet. 2020;57:605–9. doi: 10.1136/jmedgenet-2019-106418. PubMed DOI

Simila-Maarala J, Soovares P, Pasanen A, Ahvenainen T, Vahteristo P, Butzow R, et al. TCGA molecular classification in endometriosis-associated ovarian carcinomas: novel data on clear cell carcinoma. Gynecol Oncol. 2022;165:577–84. doi: 10.1016/j.ygyno.2022.03.016. PubMed DOI

Stewart CJ, Bowtell DD, Doherty DA, Leung YC. Long-term survival of patients with mismatch repair protein-deficient, high-stage ovarian clear cell carcinoma. Histopathology. 2017;70:309–13. doi: 10.1111/his.13040. PubMed DOI

Agostini A, Brunetti M, Davidson B, Goran Trope C, Heim S, Panagopoulos I, et al. Identification of novel cyclin gene fusion transcripts in endometrioid ovarian carcinomas. Int J Cancer. 2018;143:1379–87. doi: 10.1002/ijc.31418. PubMed DOI PMC

Earp MA, Raghavan R, Li Q, Dai J, Winham SJ, Cunningham JM, et al. Characterization of fusion genes in common and rare epithelial ovarian cancer histologic subtypes. Oncotarget. 2017;8:46891–9. doi: 10.18632/oncotarget.16781. PubMed DOI PMC

Alldredge J, Randall L, De Robles G, Agrawal A, Mercola D, Liu M, et al. Transcriptome analysis of ovarian and uterine clear cell malignancies. Front Oncol. 2020;10:598579. doi: 10.3389/fonc.2020.598579. PubMed DOI PMC

Fridley BL, Dai J, Raghavan R, Li Q, Winham SJ, Hou X, et al. Transcriptomic characterization of Endometrioid, clear cell, and High-Grade Serous Epithelial Ovarian Carcinoma. Cancer Epidemiol Biomarkers Prev. 2018;27:1101–9. doi: 10.1158/1055-9965.EPI-17-0728. PubMed DOI PMC

Nagasawa S, Ikeda K, Horie-Inoue K, Sato S, Itakura A, Takeda S, et al. Systematic identification of characteristic genes of ovarian Clear Cell Carcinoma compared with High-Grade Serous Carcinoma based on RNA-Sequencing. Int J Mol Sci. 2019;20. 10.3390/ijms20184330. PubMed PMC

Stany MP, Vathipadiekal V, Ozbun L, Stone RL, Mok SC, Xue H, et al. Identification of novel therapeutic targets in microdissected clear cell ovarian cancers. PLoS ONE. 2011;6:e21121. doi: 10.1371/journal.pone.0021121. PubMed DOI PMC

Winterhoff B, Hamidi H, Wang C, Kalli KR, Fridley BL, Dering J, et al. Molecular classification of high grade endometrioid and clear cell ovarian cancer using TCGA gene expression signatures. Gynecol Oncol. 2016;141:95–100. doi: 10.1016/j.ygyno.2016.02.023. PubMed DOI PMC

Cunningham JM, Winham SJ, Wang C, Weiglt B, Fu Z, Armasu SM, et al. DNA methylation profiles of ovarian Clear Cell Carcinoma. Cancer Epidemiol Biomarkers Prev. 2022;31:132–41. doi: 10.1158/1055-9965.EPI-21-0677. PubMed DOI PMC

Fadare O, Zhao C, Khabele D, Parkash V, Quick CM, Gwin K, et al. Comparative analysis of Napsin A, alpha-methylacyl-coenzyme A racemase (AMACR, P504S), and hepatocyte nuclear factor 1 beta as diagnostic markers of ovarian clear cell carcinoma: an immunohistochemical study of 279 ovarian tumours. Pathology. 2015;47:105–11. doi: 10.1097/PAT.0000000000000223. PubMed DOI

DeLair D, Oliva E, Köbel M, Macias A, Gilks CB, Soslow RA. Morphologic spectrum of immunohistochemically characterized clear cell carcinoma of the ovary: a study of 155 cases. Am J Surg Pathol. 2011;35:36–44. doi: 10.1097/PAS.0b013e3181ff400e. PubMed DOI

Köbel M, Kalloger SE, Carrick J, Huntsman D, Asad H, Oliva E, et al. A limited panel of immunomarkers can reliably distinguish between clear cell and high-grade serous carcinoma of the ovary. Am J Surg Pathol. 2009;33:14–21. doi: 10.1097/PAS.0b013e3181788546. PubMed DOI

Dundr P, Gregova M, Hojny J, Krkavcova E, Michalkova R, Nemejcova K, et al. Uterine cellular leiomyomas are characterized by common HMGA2 aberrations, followed by chromosome 1p deletion and MED12 mutation: morphological, molecular, and immunohistochemical study of 52 cases. Virchows Arch. 2022;480:281–91. doi: 10.1007/s00428-021-03217-z. PubMed DOI

Nishikimi K, Nakagawa K, Tate S, Matsuoka A, Iwamoto M, Kiyokawa T, et al. Uncommon human telomerase reverse transcriptase promoter mutations are Associated with Poor Survival in Ovarian Clear Cell Carcinoma. Am J Clin Pathol. 2018;149:352–61. doi: 10.1093/ajcp/aqx166. PubMed DOI

Chakravarty D, Gao JJ, Phillips S, Kundra R, Zhang HX, Wang JJ, et al. OncoKB: a Precision Oncology Knowledge Base. Jco Precis Oncol. 2017;1. 10.1200/PO.17.00011. PubMed PMC

Lopez-Nieva P, Fernandez-Navarro P, Grana-Castro O, Andres-Leon E, Santos J, Villa-Morales M et al. Detection of novel fusion-transcripts by RNA-Seq in T-cell lymphoblastic lymphoma. Sci Rep-Uk 2019; 9. https://doi:ARTN 5179. PubMed PMC

Khalique S, Lord CJ, Banerjee S, Natrajan R. Translational genomics of ovarian clear cell carcinoma. Semin Cancer Biol. 2020;61:121–31. doi: 10.1016/j.semcancer.2019.10.025. PubMed DOI

Amano T, Chano T, Yoshino F, Kimura F, Murakami T. Current position of the molecular therapeutic targets for ovarian Clear Cell Carcinoma: A literature review. Healthc (Basel). 2019;7. 10.3390/healthcare7030094. PubMed PMC

Shen JF, Peng Y, Wei LZ, Zhang W, Yang L, Lan L, et al. ARID1A Deficiency impairs the DNA damage checkpoint and sensitizes cells to PARP inhibitors. Cancer Discov. 2015;5:752–67. doi: 10.1158/2159-8290.Cd-14-0849. PubMed DOI PMC

Williamson CT, Miller R, Pemberton HN, Jones SE, Campbell J, Konde A, et al. ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A. Nat Commun. 2016;7:13837. doi: 10.1038/ncomms13837. PubMed DOI PMC

Fukumoto T, Park PH, Wu S, Fatkhutdinov N, Karakashev S, Nacarelli T, et al. Repurposing Pan-HDAC inhibitors for ARID1A-Mutated ovarian Cancer. Cell Rep. 2018;22:3393–400. doi: 10.1016/j.celrep.2018.03.019. PubMed DOI PMC

Bitler BG, Wu S, Park PH, Hai Y, Aird KM, Wang Y, et al. ARID1A-mutated ovarian cancers depend on HDAC6 activity. Nat Cell Biol. 2017;19:962–73. doi: 10.1038/ncb3582. PubMed DOI PMC

Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2010;141:1117–34. doi: 10.1016/j.cell.2010.06.011. PubMed DOI PMC

Plenker D, Bertrand M, de Langen AJ, Riedel R, Lorenz C, Scheel AH, et al. Structural alterations of MET trigger response to MET kinase inhibition in Lung Adenocarcinoma Patients. Clin Cancer Res. 2018;24:1337–43. doi: 10.1158/1078-0432.Ccr-17-3001. PubMed DOI

Reddy MM, Deshpande A, Sattler M. Targeting JAK2 in the therapy of myeloproliferative neoplasms. Expert Opin Ther Tar. 2012;16:313–24. doi: 10.1517/14728222.2012.662956. PubMed DOI PMC

Uterine sarcoma with KAT6B/A::KANSL1 fusion: a molecular and clinicopathological study on 9 cases

Uterine leiomyoma with RAD51B::NUDT3 fusion: a report of 2 cases