Concerning the dismal prognosis of chemoresistant patients with epithelial ovarian carcinoma (EOC), we aimed to follow up the findings of a previous whole-exome sequencing study using an orthogonal Sanger sequencing on the same patients and a separate set of 127 EOC patients (N = 177, all fresh frozen tumor samples). We focused on TP53 as a frequently mutated gene relevant for chemosensitivity, included KRAS as an additional therapeutically relevant target, complemented the study with transcript levels of both genes, and compared results with clinical parameters. All variants in TP53 and KRAS detected by exome sequencing were confirmed. KRAS mutated patients had significantly more frequent FIGO stages I or II (p = .002) and other than high-grade serous tumor subtypes (nonHGSCs) (p < .001), which was connected with lower KRAS transcript levels (p = .004). Patients with nonHGSC subtypes had less frequent TP53 mutations (p = .002). Carriers of TP53 variants disrupting the DNA binding loop had significantly longer platinum-free intervals than the rest (p = .037). Tumors bearing nonsense, frameshift, or splice site TP53 variants had a significantly lower TP53 transcript level, while those with missense variants had significantly higher levels than wild types (p < .001). The normalized intratumoral TP53 and KRAS transcript levels were correlated, and patients with co-mutated genes had poorer overall survival than others (p = .015). Protein levels of both genes significantly correlated with their respective transcripts (p = .028 and p = .001, respectively). Our study points to KRAS as a target for future therapy of nonHGSCs and reveals the prognostic value of TP53 variants in the DNA binding loop.

Biomedical Center Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic

Department of Gynecology and Obstetrics 3rd Faculty of Medicine Charles University and University Hospital Královské Vinohrady Prague Czech Republic

Department of Gynecology and Obstetrics Faculty of Medicine and University Hospital in Pilsen Charles University Pilsen Czech Republic

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

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

Toxicogenomics Unit National Institute of Public Health Prague Czech Republic

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Cabasag CJ, Fagan PJ, Ferlay J, Vignat J, Laversanne M, Liu L, van der Aa MA, Bray F, Soerjomataram I.. Ovarian cancer today and tomorrow: a global assessment by world region and human development index using GLOBOCAN 2020. Intl J Cancer. 2022;151(9):1535–16. doi: 10.1002/ijc.34002. PubMed DOI

Matulonis UA, Sood AK, Fallowfield L, Howitt BE, Sehouli J, Karlan BY. Ovarian cancer. Nat Rev Dis Primers. 2016;2(1):16061. doi: 10.1038/nrdp.2016.61. PubMed DOI PMC

Matz M, Coleman MP, Carreira H, Salmerón D, Chirlaque MD, Allemani C, Bouzbid S, Hamdi-Chérif M, Zaidi Z, Bah E, et al. Worldwide comparison of ovarian cancer survival: histological group and stage at diagnosis (CONCORD-2). Gynecologic Oncol. 2017;144(2):396–404. doi: 10.1016/j.ygyno.2016.11.019. PubMed DOI PMC

Kim A, Ueda Y, Naka T, Enomoto T. Therapeutic strategies in epithelial ovarian cancer. J Exp Clin Cancer Res. 2012;31(1):14. doi: 10.1186/1756-9966-31-14. PubMed DOI PMC

Ovarian cancer survival rates | Ovarian cancer prognosis. [Accessed 2024 Feb 15]. https://www.cancer.org/cancer/types/ovarian-cancer/detection-diagnosis-staging/survival-rates.html.

Lheureux S, Gourley C, Vergote I, Oza AM. Epithelial ovarian cancer. Lancet. 2019;393(10177):1240–1253. doi: 10.1016/S0140-6736(18)32552-2. PubMed DOI

Lisio MA, Fu L, Goyeneche A, Gao ZH, Telleria C. High-grade serous ovarian cancer: basic sciences, clinical and therapeutic standpoints. IJMS. 2019;20(4):952. doi: 10.3390/ijms20040952. PubMed DOI PMC

Cortez AJ, Tudrej P, Kujawa KA, Lisowska KM. Advances in ovarian cancer therapy. Cancer Chemother Pharmacol. 2018;81(1):17–38. doi: 10.1007/s00280-017-3501-8. PubMed DOI PMC

O’Sullivan Coyne G, Chen AP, Meehan R, Doroshow JH. Parp inhibitors in reproductive system cancers: current use and developments. Drugs. 2017;77(2):113–130. doi: 10.1007/s40265-016-0688-7. PubMed DOI PMC

Banerjee S, Gonzalez-Martin A, Harter P, Lorusso D, Moore KN, Oaknin A, Ray-Coquard I. First-line PARP inhibitors in ovarian cancer: summary of an ESMO open - cancer horizons round-table discussion. ESMO Open. 2020;5(6):e001110. doi: 10.1136/esmoopen-2020-001110. PubMed DOI PMC

Chartron E, Theillet C, Guiu S, Jacot W. Targeting homologous repair deficiency in breast and ovarian cancers: biological pathways, preclinical and clinical data. Crit Rev In Oncol/Hematol. 2019;133:58–73. doi: 10.1016/j.critrevonc.2018.10.012. PubMed DOI

Rojas V, Hirshfield KM, Ganesan S, Rodriguez-Rodriguez L. Molecular characterization of epithelial ovarian cancer: implications for diagnosis and treatment. IJMS. 2016;17(12):2113. doi: 10.3390/ijms17122113. PubMed DOI PMC

Goyal G, Fan T, Silberstein PT. Hereditary cancer syndromes: utilizing DNA repair deficiency as therapeutic target. Fam Cancer. 2016;15(3):359–366. doi: 10.1007/s10689-016-9883-7. PubMed DOI PMC

Hlaváč V, Holý P, Václavíková R, Rob L, Hruda M, Mrhalová M, Černaj P, Bouda J, Souček P. Whole-exome sequencing of epithelial ovarian carcinomas differing in resistance to platinum therapy. Life Sci Alliance. 2022;5(12):e202201551. doi: 10.26508/lsa.202201551. PubMed DOI PMC

Norquist BM, Brady MF, Harrell MI, Walsh T, Lee MK, Gulsuner S, Bernards SS, Casadei S, Burger RA, Tewari KS, et al. Mutations in homologous recombination genes and outcomes in ovarian carcinoma patients in GOG 218: an NRG oncology/gynecologic oncology group study. Clin Cancer Res. 2018;24(4):777–783. doi: 10.1158/1078-0432.CCR-17-1327. PubMed DOI PMC

Zhang H, Liu T, Zhang Z, Payne SH, Zhang B, McDermott JE, Zhou J-Y, Petyuk VA, Chen L, Ray D, et al. Integrated proteogenomic characterization of human high-grade serous ovarian cancer. Cell. 2016;166(3):755–765. doi: 10.1016/j.cell.2016.05.069. PubMed DOI PMC

Li C, Bonazzoli E, Bellone S, Choi J, Dong W, Menderes G, Altwerger G, Han C, Manzano A, Bianchi A, et al. Mutational landscape of primary, metastatic, and recurrent ovarian cancer reveals c-MYC gains as potential target for BET inhibitors. Proc Natl Acad Sci USA. 2019;116(2):619–624. doi: 10.1073/pnas.1814027116. PubMed DOI PMC

de Witte CJ, Kutzera J, van Hoeck A, Nguyen L, Boere IA, Jalving M, Ottevanger PB, van Schaik-van de Mheen C, Stevense M, Kloosterman WP, et al. Distinct genomic profiles are associated with treatment response and survival in ovarian cancer. Cancers (Basel). 2022;14(6):1511. doi: 10.3390/cancers14061511. PubMed DOI PMC

Pejovic T, Fitch K, Mills G. Ovarian cancer recurrence: “Is the definition of platinum resistance modified by PARP inhibitors and other intervening treatments?” Cancer Drug Resist. 2022;5:451–458. doi: 10.20517/cdr.2021.138. PubMed DOI PMC

Nasioudis D, Fernandez ML, Wong N, Powell DJ Jr, Mills GB, Westin S, Fader AN, Carey MS, Simpkins F. The spectrum of MAPK-ERK pathway genomic alterations in gynecologic malignancies: opportunities for novel therapeutic approaches. Gynecologic Oncol. 2023;177:86–94. doi: 10.1016/j.ygyno.2023.08.007. PubMed DOI

Therachiyil L, Anand A, Azmi A, Bhat A, Korashy HM, Uddin S. Role of RAS signaling in ovarian cancer. F1000Res. 2022;11:1253. doi: 10.12688/f1000research.126337.1. PubMed DOI PMC

Peres LC, Cushing-Haugen KL, Köbel M, Harris HR, Berchuck A, Rossing MA, Schildkraut JM, Doherty JA. Invasive epithelial ovarian cancer survival by histotype and disease stage. JNCI: j Natl Cancer Inst. 2019;111(1):60–68. doi: 10.1093/jnci/djy071. PubMed DOI PMC

Stewart J, Cunningham N, Banerjee S. New therapies for clear cell ovarian carcinoma. Int J Gynecological Cancer. 2023;33(3):385–393. doi: 10.1136/ijgc-2022-003704. PubMed DOI

Tang D, Kang R. Glimmers of hope for targeting oncogenic KRAS-G12D. Cancer Gene Ther. 2023;30:391–393. doi: 10.1038/s41417-022-00561-3. PubMed DOI

Kim D, Herdeis L, Rudolph D, Zhao Y, Böttcher J, Vides A, Ayala-Santos CI, Pourfarjam Y, Cuevas-Navarro A, Xue JY, et al. Pan-KRAS inhibitor disables oncogenic signalling and tumour growth. Nature. 2023;619(7968):160–166. doi: 10.1038/s41586-023-06123-3. PubMed DOI PMC

Nakajima EC, Drezner N, Li X, Mishra-Kalyani PS, Liu Y, Zhao H, Bi Y, Liu J, Rahman A, Wearne E, et al. Fda approval summary: sotorasib for KRAS G12C-mutated metastatic NSCLC. Clin Cancer Res. 2022;28(8):1482–1486. doi: 10.1158/1078-0432.CCR-21-3074. PubMed DOI PMC

Dhillon S. Adagrasib: first approval. Drugs. 2023;83(3):275–285. doi: 10.1007/s40265-023-01839-y. PubMed DOI

Brachova P, Mueting SR, Carlson MJ, Goodheart MJ, Button AM, Mott SL, Dai D, Thiel KW, Devor EJ, Leslie KK. Tp53 oncomorphic mutations predict resistance to platinum- and taxane-based standard chemotherapy in patients diagnosed with advanced serous ovarian carcinoma. Int J Oncol. 2015;46(2):607–618. doi: 10.3892/ijo.2014.2747. PubMed DOI PMC

Peuget S, Zhou X, Selivanova G. Translating p53-based therapies for cancer into the clinic. Nat Rev Cancer. 2024;24(3):192–215. doi: 10.1038/s41568-023-00658-3. PubMed DOI

Dong ZY, Zhong WZ, Zhang XC, Su J, Xie Z, Liu SY, Tu H-Y, Chen H-J, Sun Y-L, Zhou Q, et al. Potential predictive value of TP53 and KRAS mutation status for response to PD-1 blockade immunotherapy in lung adenocarcinoma. Clin Cancer Res. 2017;23(12):3012–3024. doi: 10.1158/1078-0432.CCR-16-2554. PubMed DOI

Gu M, Xu T, Chang P. Kras/lkb1 and KRAS/TP53 co-mutations create divergent immune signatures in lung adenocarcinomas. Ther Adv Med Oncol. 2021;13:17588359211006950. doi: 10.1177/17588359211006950. PubMed DOI PMC

Datta J, Bianchi A, De Castro Silva I, Deshpande NU, Cao LL, Mehra S, Singh S, Rafie C, Sun X, Chen X, et al. Distinct mechanisms of innate and adaptive immune regulation underlie poor oncologic outcomes associated with KRAS-TP53 co-alteration in pancreatic cancer. Oncogene. 2022;41(28):3640–3654. doi: 10.1038/s41388-022-02368-w. PubMed DOI

André F, Arnedos M, Baras AS, Baselga J, Bedard PL, Berger MF, Bierkens M, Calvo F, Cerami E, Chakravarty D, et al. Aacr project GENIE: powering precision medicine through an international consortium. Cancer Discov. 2017;7(8):818–831. doi: 10.1158/2159-8290.CD-17-0151. PubMed DOI PMC

Rechsteiner M, Zimmermann AK, Wild PJ, Caduff R, von Teichman A, Fink D, Moch H, Noske A. Tp53 mutations are common in all subtypes of epithelial ovarian cancer and occur concomitantly with KRAS mutations in the mucinous type. Exp And Mol Pathol. 2013;95(2):235–241. doi: 10.1016/j.yexmp.2013.08.004. PubMed DOI

Soberanis Pina P, Lheureux S. Overcoming PARP inhibitor resistance in ovarian cancer. Int J Gynecological Cancer. 2023;33(3):364–376. doi: 10.1136/ijgc-2022-003698. PubMed DOI

Coelho R, Tozzi A, Disler M, Lombardo F, Fedier A, López MN, Freuler F, Jacob F, Heinzelmann-Schwarz V. Overlapping gene dependencies for PARP inhibitors and carboplatin response identified by functional CRISPR-Cas9 screening in ovarian cancer. Cell Death Dis. 2022;13(10):909. doi: 10.1038/s41419-022-05347-x. PubMed DOI PMC

McMullen M, Karakasis K, Madariaga A, Oza AM. Overcoming platinum and PARP-inhibitor resistance in ovarian cancer. Cancers. 2020;12(6):1607. doi: 10.3390/cancers12061607. PubMed DOI PMC

Friedlander M, Trimble E, Tinker A, Alberts D, Avall-Lundqvist E, Brady M, Harter P, Pignata S, Pujade-Lauraine E, Sehouli J, et al. Clinical trials in recurrent ovarian cancer. Int J Gynecological Cancer. 2011;21(4):771–775. doi: 10.1097/IGC.0b013e31821bb8aa. PubMed DOI

Soucek P, Anzenbacher P, Skoumalova I, Dvorak M. Expression of cytochrome P450 genes in CD34+ hematopoietic stem and progenitor cells. Stem Cells. 2005;23(9):1417–1422. doi: 10.1634/stemcells.2005-0066. PubMed DOI

Elsnerova K, Mohelnikova-Duchonova B, Cerovska E, Ehrlichova M, Gut I, Rob L, Skapa P, Hruda M, Bartakova A, Bouda J, et al. Gene expression of membrane transporters: importance for prognosis and progression of ovarian carcinoma. Oncol Rep. 2016;35(4):2159–2170. doi: 10.3892/or.2016.4599. PubMed DOI

Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, Mueller R, Nolan T, Pfaffl MW, Shipley GL, et al. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem. 2009;55(4):611–622. doi: 10.1373/clinchem.2008.112797. PubMed DOI

Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-delta delta C(T)) method. Methods. 2001;25(4):402–408. doi: 10.1006/meth.2001.1262. PubMed DOI

Untergasser A, Cutcutache I, Koressaar T, Ye J, Faircloth BC, Remm M, Rozen SG. Primer3—new capabilities and interfaces. Nucleic Acids Res. 2012;40(15):e115–e115. doi: 10.1093/nar/gks596. PubMed DOI PMC

Mohammad AI, Obeed Allah M, Ali E, Krus I, Šůsová S, Tesařová T, Rob L, Hruda M, Bouda J, Bartáková A, Mrhalová M, et al. Functional validation of somatic variability in TP53 and KRAS for prediction of platinum sensitivity and prognosis in epithelial ovarian carcinoma patients. Int J Cancer. 2024, PREPRINT (Version 1) available at Research Square]. Oct 22. 155(1):104–116. doi: 10.1002/ijc.34908. PubMed DOI