Somatic Alterations in TP53 and KRAS and Their Functional Impact in Epithelial Ovarian Cancer

In light of the bleak outlook for chemotherapy-resistant epithelial ovarian carcinoma (EOC) patients, we set out to corroborate the observations from an earlier whole-exome sequencing investigation by performing orthogonal Sanger sequencing on the identical patient cohort, along with an additional independent set of 127 EOC cases (n = 177, exclusively fresh frozen tumor specimens). Our emphasis was on TP53, a recurrently altered gene with implications for chemosensitivity, while KRAS was included as a supplementary therapeutic target; we further augmented the work with transcriptional expression data for both genes and assessed associations with clinical characteristics. Every TP53 and KRAS alteration uncovered by exome sequencing was verified. Individuals bearing KRAS mutations presented with a markedly higher prevalence of FIGO stages I or II (P = .002) and non-high-grade serous histological categories (nonHGSCs) (P < .001), which corresponded with diminished KRAS transcript abundance (P = .004). Those with non-HGSC classifications exhibited TP53 mutations less often (P = .002). Subjects carrying TP53 alterations that disturb the DNA binding loop experienced considerably prolonged platinum-free intervals relative to all other patients (P = .037). Tumor samples harboring nonsense, frameshift, or splice site TP53 alterations displayed markedly reduced TP53 transcript abundance, whereas samples with missense alterations showed significantly elevated levels in comparison to wild-type counterparts (P < .001). Normalized intratumoral transcript levels of TP53 and KRAS showed a correlation, and patients whose tumors harbored concurrent mutations in both genes had inferior overall survival compared with the remaining cohort (P = .015). Protein expression levels for both genes correlated meaningfully with their corresponding transcript measurements (P = .028 and P = .001, respectively). Our work designates KRAS as a candidate for forthcoming therapeutic strategies targeting non-HGSCs and highlights the prognostic relevance of TP53 alterations within the DNA-binding loop.