Abstract
Individual mutations in the tumor suppressor TP53 alter p53 protein function. Some mutations create a non-functional protein, whereas others confer oncogenic activity, which we term ‘oncomorphic’. Since mutations in TP53 occur in nearly all ovarian tumors, the objective of this study was to determine the relationship of oncomorphic TP53 mutations with patient outcomes in advanced serous ovarian cancer patients. Clinical and molecular data from 264 high-grade serous ovarian cancer patients uniformly treated with standard platinum- and taxane-based adjuvant chemotherapy were downloaded from The Cancer Genome Atlas (TCGA) portal. Additionally, patient samples were obtained from the University of Iowa and individual mutations were analyzed in ovarian cancer cell lines. Mutations in the TP53 were annotated and categorized as oncomorphic, loss of function (LOF), or unclassified. Associations between mutation types, chemoresistance, recurrence, and progression-free survival (PFS) were calculated. Oncomorphic TP53 mutations were present in 21.3% of ovarian cancers in the TCGA dataset. Patients with oncomorphic TP53 mutations demonstrated significantly worse PFS, a 60% higher risk of recurrence (HR=1.60, 95% confidence intervals 1.09, 2.33, p=0.015), and higher rates of platinum resistance (χ2 test p=0.0024) when compared with single nucleotide mutations not categorized as oncomorphic. Furthermore, tumors containing oncomorphic TP53 mutations displayed unique protein expression profiles, and some mutations conferred increased clonogenic capacity in ovarian cancer cell models. Our study reveals that oncomorphic TP53 mutations are associated with worse patient outcome. These data suggest that future studies should take into consideration the functional consequences of TP53 mutations when determining treatment options.
Highlights
Epithelial ovarian cancer is the most deadly of the gynecologic malignancies and the fifth leading cause of cancer‐related death among women [1]
Using stringent criteria to define oncomorphic TP53 mutations, we evaluated the relationship of oncomorphic p53 expression with progression‐free survival (PFS), risk of recurrence, and response to standard platinum and taxane chemotherapy
The median PFS for the study population was 13.8 months, and median overall survival was 30.2 months, which is consistent with reported outcomes in the full The Cancer Genome Atlas (TCGA) ovarian cancer data set [3]
Summary
Epithelial ovarian cancer is the most deadly of the gynecologic malignancies and the fifth leading cause of cancer‐related death among women [1]. There has been an improvement in the 5‐year survival of patients diagnosed with advanced disease, the long‐term survival rate remains poor at 30% [1]. Low survival can be attributed to the insidious nature of ovarian cancer progression, resulting in late diagnosis. 75% of cases involve metastases to the abdominal cavity (FIGO stages III‐IV) at the time of diagnosis [2]. An additional complication contributing to low survival is the high rate of chemoresistance [1]. The ability to predict the patients at highest risk for rapid disease progression would allow clinicians to optimize therapy up front using more aggressive regimens
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