TP53 mutations in high grade serous ovarian cancer and impact on clinical outcomes: a comparison of next generation sequencing and bioinformatics analyses

Abstract

ObjectiveMutations in TP53 are found in the majority of high grade serous ovarian cancers, leading to gain of function or loss of function of its protein product, p53, involved in oncogenesis. There have been conflicting reports as to the impact of the type of these on prognosis. We aim to further elucidate this relationship in our cohort of patients.Methods229 patients with high grade serous ovarian cancer underwent tumor profiling through an institutional molecular screening program with targeted next generation sequencing. TP53 mutations were classified using methods previously described in the literature. Immunohistochemistry on formalin-fixed paraffin embedded tissue was used to assess for TP53 mutation. Using divisive hierarchal clustering, we generated patient clusters with similar clinicopathologic characteristics to investigate differences in outcomes.ResultsSix different classification schemes of TP53 mutations were studied. These did not show an association with first platinum-free interval or overall survival. Next generation sequencing reliably predicted mutation in 80% of cases, similar to the proportion detected by immunohistochemistry. Divisive hierarchical clustering generated four main clusters, with cluster 3 having a significantly worse prognosis (p<0.0001; log-rank test). This cluster had a higher concentration of gain of function mutations and these patients were less likely to have undergone optimal debulking surgery.ConclusionsDifferent classifications of TP53 mutations did not show an impact on outcomes in this study. Immunohistochemistry was a good predictor for TP53 mutation. Cluster analysis showed that a subgroup of patients with gain of function mutations (cluster 3) had a worse prognosis.

Phase II Trial of Cabozantinib in Recurrent/Metastatic Endometrial Cancer: A Study of the Princess Margaret, Chicago, and California Consortia (NCI9322/PHL86)

“…We recently described discrepancies in identification of TP53 mutation in high grade serous ovarian cancer using targeted sequencing versus standard immunohistochemistry. (46) It is likely that both histological misclassification and the use of less sensitive sequencing approaches both contributed to the lower than anticipated rate of TP53 mutation (63%) in our serous histology cohort. Finally, correlative molecular studies were completed in archival tumor samples which may not accurately reflect the mutational status of tumors at time of recurrence and after treatment with chemotherapy or radiation.…”

TP53 structural variants in metastatic prostatic carcinoma

“…Pathogenic mutations in TP53 result in either loss of p53 expression or its ability to bind to DNA response elements. A subset of TP53 mutations result in gain of oncogenic function or mutations with dominant negative effect with accumulation of mutant protein at high levels [24] and some of these have also been associated with development of chemoresistance [25].…”

Mechanisms of High-Grade Serous Carcinogenesis in the Fallopian Tube and Ovary: Current Hypotheses, Etiologic Factors, and Molecular Alterations

“…TP53 mutations are heterogeneous and occur at almost every codon in the DNA-binding domain of the gene [ 91 ]. While loss of function of p53 promotes tumorigenesis, TP53 mutations may also lead to the development of gain of function (oncomorphic) p53 proteins, which also promote tumorigenesis [ 91 , 92 ]. Oncomorphic TP53 mutations have been found to be present in 21.3% of ovarian cancers [ 91 ].…”