L Beltrame1, M Di Marino1, R Fruscio2, E Calura3, B Chapman4, L Clivio1, F Sina2, C Mele5, P Iatropoulos5, T Grassi2, V Fotia6, C Romualdi3, P Martini3, M Noris5, L Paracchini1, I Craparotta1, M Petrillo7, R Milani2, P Perego8, A Ravaggi9, A Zambelli10, E Ronchetti11, M D'Incalci12, S Marchini1. 1. Department of Oncology, Centro di Ricerche Cliniche per le Malattie Rare 'ALDO e CELE DACCO'', IRCCS 'Mario Negri' Institute for Pharmacological Research, Milano. 2. Clinic of Obstetrics and Gynecology, University of Milano-Bicocca, San Gerardo Hospital, Monza. 3. Department of Biology, University of Padova, Padova, Italy. 4. Bioinformatics Core, Harvard School of Public Health, Boston, USA. 5. Department of Molecular Medicine Laboratory, Immunology and Genetic of Rare Diseases and Organ Transplantation, Centro di Ricerche Cliniche per le Malattie Rare 'ALDO e CELE DACCO'', IRCCS 'Mario Negri' Institute for Pharmacological Research, Milano. 6. PhD Program in Experimental Medicine, University of Pavia, Pavia. 7. Gynecologic Oncology Unit, Catholic University of the Sacred Heart, Rome. 8. Department of Pathology, University of Milano-Bicocca, San Gerardo Hospital, Monza. 9. Division of Gynecologic Oncology, 'Angelo Nocivelli' Institute of Molecular Medicine, University of Brescia, Brescia. 10. Unit of Medical Oncology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo. 11. Laboratory of Experimental Oncology and Pharmacogenomics, IRCCS Salvatore Maugeri Foundation, Pavia, Italy. 12. Department of Oncology, Centro di Ricerche Cliniche per le Malattie Rare 'ALDO e CELE DACCO'', IRCCS 'Mario Negri' Institute for Pharmacological Research, Milano maurizio.dincalci@marionegri.it.
Abstract
BACKGROUND: The majority of patients with stage III-IV epithelial ovarian cancer (EOC) relapse after initially responding to platinum-based chemotherapy, and develop resistance. The genomic features involved in drug resistance are unknown. To unravel some of these features, we investigated the mutational profile of genes involved in pathways related to drug sensitivity in a cohort of matched tumors obtained at first surgery (Ft-S) and second surgery (Sd-S). PATIENTS AND METHODS: Matched biopsies (33) taken at Ft-S and Sd-S were selected from the 'Pandora' tumor tissue collection. DNA libraries for 65 genes were generated using the TruSeq Custom Amplicon kit and sequenced on MiSeq (Illumina). Data were analyzed using a high-performance cluster computing platform (Cloud4CARE project) and independently validated. RESULTS: A total of 2270 somatic mutations were identified (89.85% base substitutions 8.19% indels, and 1.92% unknown). Homologous recombination (HR) genes and TP53 were mutated in the majority of Ft-S, while ATM, ATR, TOP2A and TOP2B were mutated in the entire dataset. Only 2% of mutations were conserved between matched Ft-S and Sd-S. Mutations detected at second surgery clustered patients in two groups characterized by different mutational profiles in genes associated with HR, PI3K, miRNA biogenesis and signal transduction. CONCLUSIONS: There was a low level of concordance between Ft-S and Sd-S in terms of mutations in genes involved in key processes of tumor growth and drug resistance. This result suggests the importance of future longitudinal analyses to improve the clinical management of relapsed EOC.
BACKGROUND: The majority of patients with stage III-IV epithelial ovarian cancer (EOC) relapse after initially responding to platinum-based chemotherapy, and develop resistance. The genomic features involved in drug resistance are unknown. To unravel some of these features, we investigated the mutational profile of genes involved in pathways related to drug sensitivity in a cohort of matched tumors obtained at first surgery (Ft-S) and second surgery (Sd-S). PATIENTS AND METHODS: Matched biopsies (33) taken at Ft-S and Sd-S were selected from the 'Pandora' tumor tissue collection. DNA libraries for 65 genes were generated using the TruSeq Custom Amplicon kit and sequenced on MiSeq (Illumina). Data were analyzed using a high-performance cluster computing platform (Cloud4CARE project) and independently validated. RESULTS: A total of 2270 somatic mutations were identified (89.85% base substitutions 8.19% indels, and 1.92% unknown). Homologous recombination (HR) genes and TP53 were mutated in the majority of Ft-S, while ATM, ATR, TOP2A and TOP2B were mutated in the entire dataset. Only 2% of mutations were conserved between matched Ft-S and Sd-S. Mutations detected at second surgery clustered patients in two groups characterized by different mutational profiles in genes associated with HR, PI3K, miRNA biogenesis and signal transduction. CONCLUSIONS: There was a low level of concordance between Ft-S and Sd-S in terms of mutations in genes involved in key processes of tumor growth and drug resistance. This result suggests the importance of future longitudinal analyses to improve the clinical management of relapsed EOC.
Authors: F Guffanti; M F Alvisi; A Anastasia; F Ricci; M Chiappa; A Llop-Guevara; V Serra; R Fruscio; A Degasperi; S Nik-Zainal; M R Bani; M Lupia; R Giavazzi; E Rulli; G Damia Journal: Br J Cancer Date: 2021-11-03 Impact factor: 7.640
Authors: S Balendran; S Liebmann-Reindl; A S Berghoff; T Reischer; N Popitsch; C B Geier; L Kenner; P Birner; B Streubel; M Preusser Journal: J Neurooncol Date: 2017-05-11 Impact factor: 4.130
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