Identifying cancer drivers and actionable mutations is critical for precision oncology. In epithelial ovarian cancer (EOC) the majority of mutations lack biological or clinical validation. We fully characterized 43 lines of Patient-Derived Xenografts (PDXs) and performed copy number analysis and whole exome sequencing of 12 lines derived from naïve, high grade EOCs. Pyrosequencing allowed quantifying mutations in the source tumours. Drug response was assayed on PDX Derived Tumour Cells (PDTCs) and in vivo on PDXs. We identified a PIK3R1W624R variant in PDXs from a high grade serous EOC. Allele frequencies of PIK3R1W624R in all the passaged PDXs and in samples of the source tumour suggested that it was truncal and thus possibly a driver mutation. After inconclusive results in silico analyses, PDTCs and PDXs allowed the showing actionability of PIK3R1W624R and addiction of PIK3R1W624R carrying cells to inhibitors of the PI3K/AKT/mTOR pathway. It is noteworthy that PIK3R1 encodes the p85α regulatory subunit of PI3K, that is very rarely mutated in EOC. The PIK3R1W624R mutation is located in the cSH2 domain of the p85α that has never been involved in oncogenesis. These data show that patient-derived models are irreplaceable in their role of unveiling unpredicted driver and actionable variants in advanced ovarian cancer.

PIK3R1W624R Is an Actionable Mutation in High Grade Serous Ovarian Carcinoma

D'Ambrosio, Concetta;Arigoni, Maddalena;Capellero, Sonia;Di Nardo, Giovanna;Berrino, Enrico;Calogero, Raffaele A;Valabrega, Giorgio;Di Renzo, Maria Flavia;Olivero, Martina
2020-01-01

Abstract

Identifying cancer drivers and actionable mutations is critical for precision oncology. In epithelial ovarian cancer (EOC) the majority of mutations lack biological or clinical validation. We fully characterized 43 lines of Patient-Derived Xenografts (PDXs) and performed copy number analysis and whole exome sequencing of 12 lines derived from naïve, high grade EOCs. Pyrosequencing allowed quantifying mutations in the source tumours. Drug response was assayed on PDX Derived Tumour Cells (PDTCs) and in vivo on PDXs. We identified a PIK3R1W624R variant in PDXs from a high grade serous EOC. Allele frequencies of PIK3R1W624R in all the passaged PDXs and in samples of the source tumour suggested that it was truncal and thus possibly a driver mutation. After inconclusive results in silico analyses, PDTCs and PDXs allowed the showing actionability of PIK3R1W624R and addiction of PIK3R1W624R carrying cells to inhibitors of the PI3K/AKT/mTOR pathway. It is noteworthy that PIK3R1 encodes the p85α regulatory subunit of PI3K, that is very rarely mutated in EOC. The PIK3R1W624R mutation is located in the cSH2 domain of the p85α that has never been involved in oncogenesis. These data show that patient-derived models are irreplaceable in their role of unveiling unpredicted driver and actionable variants in advanced ovarian cancer.
2020
9
2
442
459
https://www.mdpi.com/2073-4409/9/2/442
PDX derived tumour cells; PI3K; PIK3R1; Patient-Derived xenografts; ovarian cancer
D'Ambrosio, Concetta; Erriquez, Jessica; Arigoni, Maddalena; Capellero, Sonia; Mittica, Gloria; Ghisoni, Eleonora; Borella, Fulvio; Katsaros, Dionyssios; Privitera, Silvana; Ribotta, Marisa; Maldi, Elena; Di Nardo, Giovanna; Berrino, Enrico; Venesio, Tiziana; Ponzone, Riccardo; Vaira, Marco; Hall, Douglas; Jimenez-Linan, Mercedes; Paterson, Anna L; Calogero, Raffaele A; Brenton, James D; Valabrega, Giorgio; Di Renzo, Maria Flavia; Olivero, Martina
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1732854
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