TP53 hotspot mutations as immunoreactive neoantigens define a signature with differential survival outcomes in advanced ovarian cancer

Abstract

Abstract Background Hotspot mutations (HSM) in TP53 (R175, Y220, G245; R248, R273) have been recognized as potential immunoreactive neoantigens able to achieve intratumoral T cell responses in advanced ovarian cancer, particularly in high-grade serous ovarian cancer (HGSOC). The purpose of this study was to assess if HSM, Non-HSM (missense non-HSM) and Other (INDELs, stop gained, splice site) somatic mutations in TP53, confer differential survival outcomes. Presence of circulating p53-autoantibodies (p53-AAbs) was also tested and correlated with TP53 mutation spectra. Methods A series of 83 patients (71 HGSOC) with advanced (III-IV stage, G2-3) ovarian cancer, treated with primary debulking surgery and platinum-based therapy, were retrospectively enrolled. Characterization of TP53 mutations in chemo-naive tumours was performed with a targeted next-generation sequencing approach. An ELISA kit was used to detect p53-AAbs. Platinum-free interval (PFI), progression-free survival (PFS) and Overall survival (OS) were compared using Kaplan-Meier, Log-rank test and Cox proportional hazard models (adjusted for age, stage, serous subtype, residual tumour). Results Somatic mutations in TP53 were found in 74.7% of patients; among them, 71% was -p53-AAbs and 29% was +p53-AAbs. The repertoire of TP53 mutations was significantly different according to p53-AAbs (p\xa0=\xa00.005), with prevalence of Other mutations (50%) in patients -p53-AAbs. In multivariate analysis (WT as the ref. category), patients with: i) Non-HSM mutations had reduced PFI (p\xa0=\xa00.026), PFS (p\xa0=\xa00.014) and OS (p\xa0=\xa00.048); ii) Other mutations had reduced PFI (p\xa0=\xa00.002) and PFS (p\xa0=\xa00.007), but not OS (p\xa0=\xa00.062); iii) HSM mutations were not associated with PFI (p\xa0=\xa00.605), PFS (p\xa0=\xa00.681) and OS (p\xa0=\xa00.437). Conclusions Molecular profile of chemo-naive tumours in advanced ovarian cancer showed different outcomes coupled to specific TP53 signatures. A more aggressive mutational profile in TP53 was observed in patients without p53-AAbs. Non-synonymous mutated neoantigens arised from tumour clones, appear to be critical to identify patients best suited to immunotherapy. Further investigations in the tumour microenvironment are needed to confirm these preliminary findings. Legal entity responsible for the study Giorgio Giorda. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.