Exploring the somatic mutational landscape of ovarian cancer in Estonia

Authors

  • Mikk Tooming Department of Genetics and Personalized Medicine, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia; Department of Laboratory Genetics, Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia https://orcid.org/0000-0002-5201-4426
  • Kadri Rekker Department of Laboratory Genetics, Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia https://orcid.org/0009-0001-4548-5756
  • Kadri Toome Department of Laboratory Genetics, Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia https://orcid.org/0009-0007-5206-5737
  • Laura Roht Department of Clinical Genetics, Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia https://orcid.org/0000-0002-5727-6759
  • Piret Laidre Department of Clinical Genetics, Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia
  • Olga Fjodorova Department of Laboratory Genetics, Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia https://orcid.org/0009-0006-6276-9239
  • Ustina Šamarina Department of Laboratory Genetics, Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia https://orcid.org/0009-0008-7493-5112
  • Sander Pajusalu Department of Genetics and Personalized Medicine, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia; Department of Laboratory Genetics, Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia https://orcid.org/0000-0002-5435-0781
  • Mihkel Ilisson Department of Genetics and Personalized Medicine, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia; Department of Laboratory Genetics, Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia https://orcid.org/0000-0002-2228-9701
  • Pilleriin Peets Chair of Analytical Chemistry, Institute of Chemistry, University of Tartu, Tartu, Estonia https://orcid.org/0000-0002-7095-661X
  • Tõnu Jõgi Haematology and Oncology Clinic, Tartu University Hospital, Tartu, Estonia
  • Karin Klaup Haematology and Oncology Clinic, Tartu University Hospital, Tartu, Estonia
  • Kristiina Ojamaa Oncology and Haematology Clinic, North Estonian Medical Center, Tallinn, Estonia https://orcid.org/0000-0003-1990-5670
  • Eva-Maria Niine-Roolaht Oncology and Haematology Clinic, North Estonian Medical Center, Tallinn, Estonia
  • Piret Kaarde Oncology and Haematology Clinic, North Estonian Medical Center, Tallinn, Estonia
  • Elen Vettus Centre of Oncology, East Tallinn Central Hospital, Tallinn, Estonia https://orcid.org/0000-0001-7594-8865
  • Jüri Piirsoo Gynaecology Department, West Tallinn Central Hospital, Tallinn, Estonia
  • Helen Vahar Gynaecology Department, West Tallinn Central Hospital, Tallinn, Estonia
  • Katrin Õunap Department of Genetics and Personalized Medicine, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia; Department of Laboratory Genetics, Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia https://orcid.org/0000-0002-4594-6364
  • Tiina Kahre Department of Genetics and Personalized Medicine, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia; Department of Laboratory Genetics, Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia https://orcid.org/0009-0007-4399-354X

DOI:

https://doi.org/10.2340/1651-226X.2026.45612

Abstract

Background and purpose: This retrospective study provides Estonia’s first nationwide overview of pathogenic and likely pathogenic variants in ovarian cancer (OC) using routine tumor molecular profiling. The aim was to characterize the mutational landscape, identify clinically actionable alterations, and evaluate the integration of germline testing.
Patient/material and methods: A total of 339 OC tumor samples underwent next‑generation sequencing-based profiling. Clinical characteristics, histological subtype, and prior germline testing were recorded. Variants were classified according to clinical‑actionability levels, and homologous recombination deficiency (HRD) was assessed in high‑grade serous OC cases.
Results: The mean age at diagnosis was 62.4 ± 12.5 years, and high‑grade serous OC accounted for 82.0% of cases. Clinically actionable alterations (OncoKB Level 1&2) were detected in 37.5% of patients, most frequently involving BRCA1, BRCA2, KRAS, and BRAF. Additional therapeutic targets were identified across diverse biomarkers. HRD was present in 53.2% of tested high‑grade serous tumors. Germline testing had been performed in 41.9% of patients, revealing pathogenic or likely pathogenic variants in 22.5%, predominantly in BRCA1 and BRCA2.
Interpretation: This study outlines the mutational spectrum of OC in Estonia and demonstrates a substantial prevalence of actionable alterations and HRD. The findings highlight the value of comprehensive tumor profiling to support precision‑medicine approaches and improve individualized patient management in Estonia.

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References

WHO. WHO, cancer today [Internet]. 2026 [cited 2026 Feb 21]. Available from: https://gco.iarc.who.int/today/

Tervisestatistika ja terviseuuringute andmebaas. PK10: Pahaloomuliste kasvajate esmasjuhud paikme, soo ja vanuserühma järgi [Internet]. [cited 2025 Apr 14]. Available from: http://statistika.tai.ee/pxweb/et/Andmebaas/Andmebaas__02Haigestumus__04PahaloomulisedKasvajad/PK10.px/

Bell D, Berchuck A, Birrer M, Chien J, Cramer DW, Dao F, et al. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609–15. DOI: https://doi.org/10.1038/nature10166

Shih IM, Wang Y, Wang TL. The origin of ovarian cancer species and precancerous landscape. Am J Pathol. 2021;191(1):26–39. DOI: https://doi.org/10.1016/j.ajpath.2020.09.006

Daly MB, Pal T, Maxwell KN, Churpek J, Kohlmann W, AlHilli Z, et al. NCCN guidelines® insights: genetic/familial high-risk assessment: breast, ovarian, and pancreatic, version 3.2026. J Natl Compr Canc Netw [Internet]. 2026;(v3.2026). [cited 2026 Feb 2]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/genetics_bopp.pdf

Gressel GM, Frey MK, Norquist B, Senter L, Blank SV, Urban RR. Germline and somatic testing for ovarian cancer: an SGO clinical practice statement. Gynecol Oncol. 2024;181:170–8. DOI: https://doi.org/10.1016/j.ygyno.2023.12.010

Casaubon JT, Kashyap S, Regan JP. BRCA1 and BRCA2 mutations [Internet]. Treasure Island, FL: StatPearls Publishing; 2025 [cited 2026 Feb 21]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK470239/

Konstantinopoulos PA, Norquist B, Lacchetti C, Armstrong D, Grisham RN, Goodfellow PJ, et al. Germline and somatic tumor testing in epithelial ovarian cancer: ASCO guideline. J Clin Oncol. 2020;38(11):1222–45. DOI: https://doi.org/10.1200/JCO.19.02960

Barbosa A, Pinto P, Peixoto A, Guerra J, Pinto C, Santos C, et al. Gene panel tumor testing in ovarian cancer patients significantly increases the yield of clinically actionable germline variants beyond BRCA1/BRCA2. Cancers. 2020;12(10):2834. DOI: https://doi.org/10.3390/cancers12102834

Jang J, Kim Y, Kim JH, Cho SM, Lee KA. Cost-effectiveness analysis of germline and somatic BRCA testing in patients with advanced ovarian cancer. Ann Lab Med. 2023;43(1):73–81. DOI: https://doi.org/10.3343/alm.2023.43.1.73

Andrikopoulou A, Zografos E, Apostolidou K, Kyriazoglou A, Papatheodoridi AM, Kaparelou M, et al. Germline and somatic variants in ovarian carcinoma: a next-generation sequencing (NGS) analysis. Front Oncol. 2022;12:1030786. DOI: https://doi.org/10.3389/fonc.2022.1030786

Frugtniet B, Morgan S, Murray A, Palmer-Smith S, White R, Jones R, et al. The detection of germline and somatic BRCA1/2 genetic variants through parallel testing of patients with high-grade serous ovarian cancer: a national retrospective audit. BJOG. 2022;129(3):433–42. DOI: https://doi.org/10.1111/1471-0528.16975

Vos JR, Fakkert IE, de Hullu JA, van Altena AM, Sie AS, Ouchene H, et al. Universal tumor DNA BRCA1/2 testing of ovarian cancer: prescreening PARPi treatment and genetic predisposition. J Natl Cancer Inst. 2020;112(2):161–9. DOI: https://doi.org/10.1093/jnci/djz138

Mosele MF, Westphalen CB, Stenzinger A, Barlesi F, Bayle A, Bièche I, et al. Recommendations for the use of next-generation sequencing (NGS) for patients with advanced cancer in 2024: a report from the ESMO Precision Medicine Working Group. Ann Oncol. 2024;35(7):588–606. DOI: https://doi.org/10.1016/j.annonc.2024.04.005

Tavares V, Marques IS, de Melo IG, Assis J, Pereira D, Medeiros R. Paradigm shift: a comprehensive review of ovarian cancer management in an era of advancements. Int J Mol Sci. 2024;25(3):1845. DOI: https://doi.org/10.3390/ijms25031845

Carrick DM, Mehaffey MG, Sachs MC, Altekruse S, Camalier C, Chuaqui R, et al. Robustness of next generation sequencing on older formalin-fixed paraffin-embedded tissue. PLoS One. 2015;10(7):e0127353. DOI: https://doi.org/10.1371/journal.pone.0127353

Edsjö A, Russnes HG, Lehtiö J, Tamborero D, Hovig E, Stenzinger A, et al. High-throughput molecular assays for inclusion in personalised oncology trials – state-of-the-art and beyond. J Intern Med. 2024;295(6):785–803. DOI: https://doi.org/10.1111/joim.13785

Caruso G, Weroha SJ, Cliby W. Ovarian cancer: a review. JAMA. 2025;334(14):1278–91. DOI: https://doi.org/10.1001/jama.2025.9495

Giro A, Herrmann T, Bauer A, Pinard C, Godiveau M, Passildas J, et al. Predictive and prognostic factors in epithelial ovarian cancer: a review. Indian J Gynecol Oncolog. 2025;23(1):45. DOI: https://doi.org/10.1007/s40944-025-00964-8

Nero C, Ciccarone F, Pietragalla A, Duranti S, Daniele G, Salutari V,

et al. Ovarian cancer treatments strategy: focus on PARP inhibitors and immune check point inhibitors. Cancers. 2021;13(6):1298. DOI: https://doi.org/10.3390/cancers13061298

Cui M, Xia Q, Zhang X, Yan W, Meng D, Xie S, et al. Development and validation of a tumor mutation burden-related immune prognostic signature for ovarian cancers. Front Genet. 2022;12:688207. DOI: https://doi.org/10.3389/fgene.2021.688207

O’Malley DM, Krivak TC, Kabil N, Munley J, Moore KN. PARP inhibitors in ovarian cancer: a review. Target Oncol. 2023;18(4):471–503. DOI: https://doi.org/10.1007/s11523-023-00970-w

Watkins JA, Irshad S, Grigoriadis A, Tutt AN. Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers. Breast Canc Res. 2014;16(3):211. DOI: https://doi.org/10.1186/bcr3670

Morand S, Devanaboyina M, Staats H, Stanbery L, Nemunaitis J. Ovarian cancer immunotherapy and personalized medicine. Int J Mol Sci. 2021;22(12):6532. DOI: https://doi.org/10.3390/ijms22126532

Colombo N, Coleman RL, Wu X, Köse F, Wenham RM, Sebastianelli A, et al. 2022-RA-657-ESGO ENGOT-ov65/KEYNOTE-B96: phase 3, randomized, double-blind study of pembrolizumab versus placebo plus paclitaxel with optional bevacizumab for platinum-resistant recurrent ovarian cancer. Int J Gynecol Cancer. 2022;32:A251. DOI: https://doi.org/10.1136/ijgc-2022-ESGO.538

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–23. DOI: https://doi.org/10.1038/gim.2015.30

den Dunnen JT, Dalgleish R, Maglott DR, Hart RK, Greenblatt MS, McGowan-Jordan J, et al. HGVS recommendations for the description of sequence variants: 2016 update. Hum Mutat. 2016;37(6):564–9. DOI: https://doi.org/10.1002/humu.22981

Čerina D, Matković V, Katić K, Belac Lovasić I, Šeparović R, Canjko I, et al. Comprehensive genomic profiling in the management of ovarian cancer – national results from croatia. J Pers Med. 2022;12(7):1176. DOI: https://doi.org/10.3390/jpm12071176

Ammous-Boukhris N, Abdelmaksoud-Dammak R, Ben Kridis W, Ben-Ayed-Guerfali D, Shtaiwi Abed A, Guidara S, et al. Germline and somatic mutational variants of Tunisian high grade serous ovarian cancer identified by next-generation sequencing. BMC Cancer. 2025;25:1542. DOI: https://doi.org/10.1186/s12885-025-14989-x

Tooming M, Toome K, Rekker K, Roht L, Laidre P, Fjodorova O, et al. Exploring the hereditary genetic mutational landscape of breast and ovarian cancer in Estonia. Sci Rep. 2026;16(1):13373. Available from: https://www.nature.com/articles/s41598-026-43459-y DOI: https://doi.org/10.1038/s41598-026-43459-y

Nilbert M. The promises of precision medicine – voices from the Nordics. Acta Oncol. 2025;64:775–7. DOI: https://doi.org/10.2340/1651-226X.2025.43987

Imoto K, Yamamoto H, Ohkawa C, Shimada N, Ikuzawa R, Takeda H, et al. An approach for improvement of the accuracy of cancer gene panel testing. Int J Clin Oncol. 2024;29(5):571–81. DOI: https://doi.org/10.1007/s10147-024-02483-6

Jantus-Lewintre E, Rappa A, Ruano D, van Egmond D, Gallach S, Gozuyasli D, et al. Multicenter in-house evaluation of an amplicon-based next−generation sequencing panel for comprehensive molecular profiling. Mol Diagn Ther. 2025;29(2):249–61. DOI: https://doi.org/10.1007/s40291-024-00766-2

Fieuws C, Van der Meulen J, Proesmans K, De Jaeghere EA, Loontiens S, Van Dorpe J, et al. Identification of potentially actionable genetic variants in epithelial ovarian cancer: a retrospective cohort study. npj Precis Onc. 2024;8(1):1–9. DOI: https://doi.org/10.1038/s41698-024-00565-2

Veneziani AC, Gonzalez-Ochoa E, Alqaisi H, Madariaga A, Bhat G, Rouzbahman M, et al. Heterogeneity and treatment landscape of ovarian carcinoma. Nat Rev Clin Oncol. 2023;20(12):820–42. DOI: https://doi.org/10.1038/s41571-023-00819-1

Smith LE, Padilla JL, Licor A, Steinkamp MP, Lagutina IV, Guo Y, et al. Novel p53 reactivators that are synergistic with olaparib for the treatment of gynecologic cancers with mutant p53. Transl Oncol. 2025;61:102522. DOI: https://doi.org/10.1016/j.tranon.2025.102522

El-Bahrawy M. Ovarian cancer pathology. In: Farghaly SA, editor. Advances in diagnosis and management of ovarian cancer. Cham: Springer International Publishing; 2022. p. 57–85. DOI: https://doi.org/10.1007/978-3-031-09169-8_5

Kelliher L, Yoeli-Bik R, Schweizer L, Lengyel E. Molecular changes driving low-grade serous ovarian cancer and implications for treatment. Int J Gynecol Cancer. 2024;34(10):1630–8. DOI: https://doi.org/10.1136/ijgc-2024-005305

Shim YS, Kim JH, Seo S-S, Kang S, Park SY, Lim MC. Landscape of genomic alterations and clinical outcomes in low-grade serous ovarian cancer in Korea. Gynecol Oncol Rep. 2025;61:101934. DOI: https://doi.org/10.1016/j.gore.2025.101934

Koczkowska M, Zuk M, Gorczynski A, Ratajska M, Lewandowska M, Biernat W, et al. Detection of somatic BRCA1/2 mutations in ovarian cancer – next‐generation sequencing analysis of 100 cases. Cancer Med. 2016;5(7):1640–6. DOI: https://doi.org/10.1002/cam4.748

Leitsalu L, Palover M, Sikka TT, Reigo A, Kals M, Pärn K, et al. Genotype-first approach to the detection of hereditary breast and ovarian cancer risk, and effects of risk disclosure to biobank participants. Eur J Hum Genet. 2021;29(3):471–81. DOI: https://doi.org/10.1038/s41431-020-00760-2

Jürgens H, Roht L, Leitsalu L, Nõukas M, Palover M, Nikopensius T, et al. Precise, genotype-first breast cancer prevention: experience with transferring monogenic findings from a population biobank to the clinical setting. Front Genet. 2022;13:881100. DOI: https://doi.org/10.3389/fgene.2022.881100

Tamboom K, Kaasik K, Aršavskaja J, Tekkel M, Lilleorg A, Padrik P, et al. BRCA1 mutations in women with familial or early-onset breast cancer and BRCA2 mutations in familial cancer in Estonia. Hered Cancer Clin Pract. 2010;8(1):4. DOI: https://doi.org/10.1186/1897-4287-8-4

Landen CN, Molinero L, Hamidi H, Sehouli J, Miller A, Moore KN, et al. Influence of genomic landscape on cancer immunotherapy for newly diagnosed ovarian cancer: biomarker analyses from the IMagyn050 randomized clinical trial. Clin Cancer Res. 2023;29(9):1698–707. DOI: https://doi.org/10.1158/1078-0432.CCR-22-2032

European Medicines Agency (EMA). European Medicines Agency (EMA) – olaparib [Internet]. 2026 [cited 2026 Mar 22]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/lynparza

Peng Y, Yang Q. Targeting KRAS in gynecological malignancies. FASEB J. 2024;38(19):e70089. DOI: https://doi.org/10.1096/fj.202401734R

Villegas-Vazquez EY, Marín-Carrasco FP, Reyes-Hernández OD, Báez-González AS, Bustamante-Montes LP, Padilla-Benavides T, et al. Revolutionizing ovarian cancer therapy by drug repositioning for accelerated and cost-effective treatments. Front Oncol. 2025;14:1514120. DOI: https://doi.org/10.3389/fonc.2024.1514120

Meric-Bernstam F, Makker V, Oaknin A, Oh DY, Banerjee S, González-Martín A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: primary results from the DESTINY-PanTumor02 phase II trial. J Clin Oncol. 2024;42(1):47–58. DOI: https://doi.org/10.1200/JCO.23.02005

Kuzbari Z, Bandlamudi C, Loveday C, Garrett A, Mehine M, George A, et al. Germline-focused analysis of tumour-detected variants in 49,264 cancer patients: ESMO Precision Medicine Working Group recommendations. Ann Oncol. 2023;34(3):215–27. DOI: https://doi.org/10.1016/j.annonc.2022.12.003

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2026-05-18

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Tooming, M., Rekker, K., Toome, K., Roht, L., Laidre, P., Fjodorova, O., … Kahre, T. (2026). Exploring the somatic mutational landscape of ovarian cancer in Estonia. Acta Oncologica, 65, 422–429. https://doi.org/10.2340/1651-226X.2026.45612

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Vol. 65 (2026): Acta Oncologica

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Copyright (c) 2026 Mikk Tooming, Kadri Rekker, Kadri Toome, Laura Roht, Piret Laidre, Olga Fjodorova, Ustina Šamarina, Sander Pajusalu, Mihkel Ilisson, Pilleriin Peets, Tõnu Jõgi, Karin Klaup, Kristiina Ojamaa, Eva-Maria Niine-Roolaht, Piret Kaarde, Elen Vettus, Jüri Piirsoo, Helen Vahar, Katrin Õunap, Tiina Kahre

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