Clonal Evolution of TP53 c.375+1G>A Mutation in Pre- and Post- Neo-Adjuvant Chemotherapy (NACT) Tumor Samples in High-Grade Serous Ovarian Cancer (HGSOC).

Marica Garziera,Sara Gagno,Loredana Romanato,Giuseppe Toffoli,Fabrizio Ecca,Roberto Sorio,Vincenzo Canzonieri,Erika Cecchin,Giorgio Giorda,Elena De Mattia,Elena Poletto,Simona Scalone,Rossana Roncato

doi:10.3390/cells8101186

Abstract

Carboplatin/paclitaxel is the reference regimen in the treatment of advanced high-grade serous ovarian cancer (HGSOC) in neo-adjuvant chemotherapy (NACT) before interval debulking surgery (IDS). To identify new genetic markers of platinum-resistance, next-generation sequencing (NGS) analysis of 26 cancer-genes was performed on paired matched pre- and post-NACT tumor and blood samples in a patient with stage IV HGSOC treated with NACT-IDS, showing platinum-refractory/resistance and poor prognosis. Only the TP53 c.375+1G>A somatic mutation was identified in both tumor samples. This variant, associated with aberrant splicing, was in trans configuration with the 72Arg allele of the known germline polymorphism TP53 c.215C>G (p. Pro72Arg). In the post-NACT tumor sample we observed the complete expansion of the TP53 c.375+1G>A driver mutant clone with somatic loss of the treatment-sensitive 72Arg allele. NGS results were confirmed with Sanger method and immunostaining for p53, BRCA1, p16, WT1, and Ki-67 markers were evaluated. This study showed that (i) the splice mutation in TP53 was present as an early driver mutation at diagnosis; (ii) the mutational profile was shared in pre- and post-NACT tumor samples; (iii) the complete expansion of a single dominant mutant clone through loss of heterozygosity (LOH) had occurred, suggesting a possible mechanism of platinum-resistance in HGSOC under the pressure of NACT.

Highlights

Epithelial ovarian cancer is the most lethal malignancy of the female genital tract and the eighth leading cause of cancer-related death in 2018, among women worldwide [1]
Patients with trans configuration of the TP53 variants identified by next-generation sequencing (NGS) in the tumor are at high risk of mutation selection by Neo-adjuvant chemotherapy (NACT) based on platinum/paclitaxel combination therapy
This study reports, in a patient with stage IV high-grade serous ovarian cancer (HGSOC) characterized by poor response to treatment and prognosis, that the TP53 c.375+1G>A somatic mutation affecting a consensus splice donor (SD) site in intron 4 flanking region was an early mutational event, and it was shared in the tumor before and after NACT

Summary

Introduction

Epithelial ovarian cancer is the most lethal malignancy of the female genital tract and the eighth leading cause of cancer-related death in 2018, among women worldwide [1]. Most patients receive a diagnosis at an advanced stage (III–IV) of the disease because of a lack of specific symptoms, ending in a poor prognosis with a five-year survival rate of only 45% [3]. Despite an initial good response to platinum-based chemotherapy relapse seems unavoidable, with ~70% of patients experiencing disease recurrence in the first two years since diagnosis and requiring further treatments [4]. Primary debulking surgery (PDS), followed by platinum-based chemotherapy, is the standard treatment for advanced ovarian cancer, including HGSOC. Neo-adjuvant chemotherapy (NACT) based on a platinum/taxane combination, prior to interval debulking surgery (IDS), is an alternative treatment option in patients with stage III–IV advanced ovarian cancer who are not candidates for PDS, due to unresectable disease and/or poor performance status [7,8].

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