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)

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 c...

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Bibliographic Details
Published in:Cells (Basel, Switzerland) Switzerland), 2019-10, Vol.8 (10), p.1186
Main Authors: Garziera, Marica, Cecchin, Erika, Giorda, Giorgio, Sorio, Roberto, Scalone, Simona, De Mattia, Elena, Roncato, Rossana, Gagno, Sara, Poletto, Elena, Romanato, Loredana, Ecca, Fabrizio, Canzonieri, Vincenzo, Toffoli, Giuseppe
Format: Article
Language:English
Subjects:
Alleles
BRCA1 protein
Cancer therapies
Carboplatin
Case Report
chemoresistance
Chemotherapy
Genes
Genetic markers
Genomics
Heterozygosity
hgsoc
Loss of heterozygosity
Medical prognosis
Mutants
Mutation
nact
Next-generation sequencing
ngs
Ovarian cancer
p53 Protein
Paclitaxel
Patients
Platinum
Software
Surgery
tp53
Tumors
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Summary: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 c.375+1G>A somatic mutation was identified in both tumor samples. This variant, associated with aberrant splicing, was in configuration with the 72Arg allele of the known germline polymorphism c.215C>G (p. Pro72Arg). In the post-NACT tumor sample we observed the complete expansion of the 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 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.
ISSN:2073-4409
2073-4409
DOI:10.3390/cells8101186