Functional validation of somatic variability in TP53 and KRAS for prediction of platinum sensitivity and prognosis in epithelial ovarian carcinoma patients
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 froz...
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Taylor & Francis Group
2025-12-01
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| Series: | Cancer Biology & Therapy |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/15384047.2025.2543105 |
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| author | Al Obeed Allah Mohammad Ali Esraa Krus Ivona Holý Petr Haničinec Vojtěch Ambrozkiewicz Filip Rob Lukáš Hruda Martin Mrhalová Marcela Kopečková Kateřina Bartáková Alena Bouda Jiří Spálenková Alžběta Souček Pavel Václavíková Radka |
| author_facet | Al Obeed Allah Mohammad Ali Esraa Krus Ivona Holý Petr Haničinec Vojtěch Ambrozkiewicz Filip Rob Lukáš Hruda Martin Mrhalová Marcela Kopečková Kateřina Bartáková Alena Bouda Jiří Spálenková Alžběta Souček Pavel Václavíková Radka |
| author_sort | Al Obeed Allah Mohammad |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-cfb25425d58b4b9eaa2384a416c87ca0 |
| institution | Kabale University |
| issn | 1538-4047 1555-8576 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
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| series | Cancer Biology & Therapy |
| spelling | doaj-art-cfb25425d58b4b9eaa2384a416c87ca02025-08-20T03:41:22ZengTaylor & Francis GroupCancer Biology & Therapy1538-40471555-85762025-12-0126110.1080/15384047.2025.2543105Functional validation of somatic variability in TP53 and KRAS for prediction of platinum sensitivity and prognosis in epithelial ovarian carcinoma patientsAl Obeed Allah Mohammad0Ali Esraa1Krus Ivona2Holý Petr3Haničinec Vojtěch4Ambrozkiewicz Filip5Rob Lukáš6Hruda Martin7Mrhalová Marcela8Kopečková Kateřina9Bartáková Alena10Bouda Jiří11Spálenková Alžběta12Souček Pavel13Václavíková Radka14Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech RepublicBiomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech RepublicToxicogenomics Unit, National Institute of Public Health, Prague, Czech RepublicBiomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech RepublicBiomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech RepublicBiomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech RepublicDepartment of Gynecology and Obstetrics, Third Faculty of Medicine, Charles University and University Hospital Královské Vinohrady, Prague, Czech RepublicDepartment of Gynecology and Obstetrics, Third Faculty of Medicine, Charles University and University Hospital Královské Vinohrady, Prague, Czech RepublicDepartment of Pathology and Molecular Medicine, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech RepublicDepartment of Oncology and Molecular Medicine, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech RepublicDepartment of Gynecology and Obstetrics, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czech RepublicDepartment of Gynecology and Obstetrics, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czech RepublicBiomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech RepublicBiomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech RepublicBiomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech RepublicConcerning 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.https://www.tandfonline.com/doi/10.1080/15384047.2025.2543105Epithelial ovarian carcinomaplatinum sensitivityTP53KRASvarianttranscript expression |
| spellingShingle | Al Obeed Allah Mohammad Ali Esraa Krus Ivona Holý Petr Haničinec Vojtěch Ambrozkiewicz Filip Rob Lukáš Hruda Martin Mrhalová Marcela Kopečková Kateřina Bartáková Alena Bouda Jiří Spálenková Alžběta Souček Pavel Václavíková Radka Functional validation of somatic variability in TP53 and KRAS for prediction of platinum sensitivity and prognosis in epithelial ovarian carcinoma patients Cancer Biology & Therapy Epithelial ovarian carcinoma platinum sensitivity TP53 KRAS variant transcript expression |
| title | Functional validation of somatic variability in TP53 and KRAS for prediction of platinum sensitivity and prognosis in epithelial ovarian carcinoma patients |
| title_full | Functional validation of somatic variability in TP53 and KRAS for prediction of platinum sensitivity and prognosis in epithelial ovarian carcinoma patients |
| title_fullStr | Functional validation of somatic variability in TP53 and KRAS for prediction of platinum sensitivity and prognosis in epithelial ovarian carcinoma patients |
| title_full_unstemmed | Functional validation of somatic variability in TP53 and KRAS for prediction of platinum sensitivity and prognosis in epithelial ovarian carcinoma patients |
| title_short | Functional validation of somatic variability in TP53 and KRAS for prediction of platinum sensitivity and prognosis in epithelial ovarian carcinoma patients |
| title_sort | functional validation of somatic variability in tp53 and kras for prediction of platinum sensitivity and prognosis in epithelial ovarian carcinoma patients |
| topic | Epithelial ovarian carcinoma platinum sensitivity TP53 KRAS variant transcript expression |
| url | https://www.tandfonline.com/doi/10.1080/15384047.2025.2543105 |
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