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Open AccessCase Report

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)

1
Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico (CRO), IRCCS, 33081 Aviano, Italy
2
Gynecological Oncology Unit, Centro di Riferimento Oncologico (CRO), IRCCS, 33081 Aviano, Italy
3
Medical Oncology Unit C, Centro di Riferimento Oncologico (CRO), IRCCS, 33081 Aviano, Italy
4
Medical Oncology, “Santa Maria della Misericordia” University Hospital, ASUIUD, 33100 Udine, Italy
5
Pathology Unit, Centro di Riferimento Oncologico (CRO), IRCCS, 33081 Aviano, Italy
6
Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy
*
Author to whom correspondence should be addressed.
V. Canzonieri and G. Toffoli share last authorship.
Cells 2019, 8(10), 1186; https://doi.org/10.3390/cells8101186
Received: 20 August 2019 / Revised: 22 September 2019 / Accepted: 30 September 2019 / Published: 1 October 2019
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Ovarian Cancer)
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. View Full-Text
Keywords: HGSOC; NACT; NGS; TP53; chemoresistance HGSOC; NACT; NGS; TP53; chemoresistance
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Garziera, M.; Cecchin, E.; Giorda, G.; Sorio, R.; Scalone, S.; De Mattia, E.; Roncato, R.; Gagno, S.; Poletto, E.; Romanato, L.; Ecca, F.; Canzonieri, V.; Toffoli, G. 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). Cells 2019, 8, 1186.

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