Functional validation of somatic variability in TP53 and KRAS for prediction of platinum sensitivity and prognosis in epithelial ovarian carcinoma patients

Background: Concerning the dismal prognosis of chemoresistant patients with epithelial ovarian carcinoma (EOC), we aimed to validate the findings of a previous whole exome sequencing study on 50 patients using an orthogonal Sanger sequencing method on the same patients and a separate set of 127 EOC patients (N=177). Methods: We focused on TP53 as a frequently mutated gene relevant for chemosensitivity, included KRAS as an additional therapeutically relevant target, complemented study with transcript levels of both genes, and compared results with clinical parameters. Results: All variants in TP53 and KRAS detected by exome sequencing were confirmed. KRAS mutated patients had significantly more frequently FIGO stages I or II (p=0.007) and other than high-grade serous tumor subtypes (nonHGSCs) (p<0.001), which was connected with lower KRAS transcript levels (p=0.004). Patients with nonHGSCs harboring TP53 missense variants disrupting the DNA binding loop had significantly poorer platinum-free interval than the rest (p=0.008). 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<0.001). The normalized intratumoral TP53 and KRAS transcript levels were correlated, and three patients with both genes co-mutated had extremely poor survival. Conclusions: 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.