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1. Figure S4 from BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors

Author

Silvia Giordano, Simona Corso, Caterina Marchiò, Alessandro Ferrero, Marco F. Amisano, Gian Luca Baiocchi, Maurizio Degiuli, Giovanni De Manzoni, Uberto Fumagalli, Maria Antista, Federica Morano, Michele Prisciandaro, Andrea Sartore-Bianchi, Salvatore Siena, Antonino Musolino, Alba Llop-Guevara, Benedetta Pellegrino, Violeta Serra, Elisabetta Puliga, Irene M. Maina, Daniela Conticelli, Cristina Migliore, Daniel Moya-Rull, Salvatore Ribisi, Claudia Orrù, Enrico Berrino, Dario Romagnoli, Loris De Cecco, Matteo Benelli, Sara E. Bellomo, Filippo Pietrantonio, Sabrina Rizzolio, and Annalisa Petrelli

Abstract

A gastric cancer PDX model carrying two LOF mutations in the ATM gene is not responsive to olaparib.

Published
2023

2. Figure S6 from BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors

Author

Silvia Giordano, Simona Corso, Caterina Marchiò, Alessandro Ferrero, Marco F. Amisano, Gian Luca Baiocchi, Maurizio Degiuli, Giovanni De Manzoni, Uberto Fumagalli, Maria Antista, Federica Morano, Michele Prisciandaro, Andrea Sartore-Bianchi, Salvatore Siena, Antonino Musolino, Alba Llop-Guevara, Benedetta Pellegrino, Violeta Serra, Elisabetta Puliga, Irene M. Maina, Daniela Conticelli, Cristina Migliore, Daniel Moya-Rull, Salvatore Ribisi, Claudia Orrù, Enrico Berrino, Dario Romagnoli, Loris De Cecco, Matteo Benelli, Sara E. Bellomo, Filippo Pietrantonio, Sabrina Rizzolio, and Annalisa Petrelli

Abstract

MLH1 KO cells do not display MSI.

Published
2023

3. Supplementary Table S2 from BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors

Author

Silvia Giordano, Simona Corso, Caterina Marchiò, Alessandro Ferrero, Marco F. Amisano, Gian Luca Baiocchi, Maurizio Degiuli, Giovanni De Manzoni, Uberto Fumagalli, Maria Antista, Federica Morano, Michele Prisciandaro, Andrea Sartore-Bianchi, Salvatore Siena, Antonino Musolino, Alba Llop-Guevara, Benedetta Pellegrino, Violeta Serra, Elisabetta Puliga, Irene M. Maina, Daniela Conticelli, Cristina Migliore, Daniel Moya-Rull, Salvatore Ribisi, Claudia Orrù, Enrico Berrino, Dario Romagnoli, Loris De Cecco, Matteo Benelli, Sara E. Bellomo, Filippo Pietrantonio, Sabrina Rizzolio, and Annalisa Petrelli

Abstract

Molecular, histological and pathological features of the 57 metastatic gastric cancer patients included in the retrospective analysis

Published
2023

4. Supplementary Methods from BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors

Author

Silvia Giordano, Simona Corso, Caterina Marchiò, Alessandro Ferrero, Marco F. Amisano, Gian Luca Baiocchi, Maurizio Degiuli, Giovanni De Manzoni, Uberto Fumagalli, Maria Antista, Federica Morano, Michele Prisciandaro, Andrea Sartore-Bianchi, Salvatore Siena, Antonino Musolino, Alba Llop-Guevara, Benedetta Pellegrino, Violeta Serra, Elisabetta Puliga, Irene M. Maina, Daniela Conticelli, Cristina Migliore, Daniel Moya-Rull, Salvatore Ribisi, Claudia Orrù, Enrico Berrino, Dario Romagnoli, Loris De Cecco, Matteo Benelli, Sara E. Bellomo, Filippo Pietrantonio, Sabrina Rizzolio, and Annalisa Petrelli

Abstract

Supplementary Methods

Published
2023

5. BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors

Author

Annalisa Petrelli, Sabrina Rizzolio, Filippo Pietrantonio, Sara E. Bellomo, Matteo Benelli, Loris De Cecco, Dario Romagnoli, Enrico Berrino, Claudia Orrù, Salvatore Ribisi, Daniel Moya-Rull, Cristina Migliore, Daniela Conticelli, Irene M. Maina, Elisabetta Puliga, Violeta Serra, Benedetta Pellegrino, Alba Llop-Guevara, Antonino Musolino, Salvatore Siena, Andrea Sartore-Bianchi, Michele Prisciandaro, Federica Morano, Maria Antista, Uberto Fumagalli, Giovanni De Manzoni, Maurizio Degiuli, Gian Luca Baiocchi, Marco F. Amisano, Alessandro Ferrero, Caterina Marchiò, Simona Corso, Silvia Giordano, Institut Català de la Salut, [Petrelli A, Rizzolio S] Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy. [Pietrantonio F] Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. [Bellomo SE] Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy. Department of Oncology, University of Torino, Candiolo, Italy. [Benelli M] Bioinformatics Unit, Oncology Department, Nuovo Ospedale-Santo Stefano, Prato, Italy. [De Cecco L] Molecular Mechanisms Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. [Serra V, Llop-Guevara A] Experimental Therapeutics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
fenómenos genéticos::variación genética::mutación::mutación de la línea germinal [FENÓMENOS Y PROCESOS], Cancer Research, neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias gástricas [ENFERMEDADES], Otros calificadores::/uso terapéutico [Otros calificadores], Medicaments antineoplàstics - Ús terapèutic, acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos [COMPUESTOS QUÍMICOS Y DROGAS], Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Other subheadings::Other subheadings::/drug therapy [Other subheadings], Genetic Phenomena::Genetic Variation::Mutation::Germ-Line Mutation [PHENOMENA AND PROCESSES], Anomalies cromosòmiques, Estómac - Càncer - Tractament, Oncology, Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Stomach Neoplasms [DISEASES], Other subheadings::/therapeutic use [Other subheadings], Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents [CHEMICALS AND DRUGS], Estómac - Càncer - Aspectes genètics
Abstract

Mutations; Gastric cancers; PARP inhibitors Mutacions; Càncers gàstrics; Inhibidors de PARP Mutaciones; Cánceres gástricos; Inhibidores de PARP Despite negative results of clinical trials conducted on the overall population of patients with gastric cancer, PARP inhibitor (PARPi) therapeutic strategy still might represent a window of opportunity for a subpopulation of patients with gastric cancer. An estimated 7% to 12% of gastric cancers exhibit a mutational signature associated with homologous recombination (HR) failure, suggesting that these patients could potentially benefit from PARPis. To analyze responsiveness of gastric cancer to PARPi, we exploited a gastroesophageal adenocarcinoma (GEA) platform of patient-derived xenografts (PDX) and PDX-derived primary cells and selected 10 PDXs with loss-of-function mutations in HR pathway genes. Cell viability assays and preclinical trials showed that olaparib treatment was effective in PDXs harboring BRCA2 germline mutations and somatic inactivation of the second allele. Olaparib responsive tumors were sensitive to oxaliplatin as well. Evaluation of HR deficiency (HRD) and mutational signatures efficiently stratified responder and nonresponder PDXs. A retrospective analysis on 57 patients with GEA showed that BRCA2 inactivating variants were associated with longer progression-free survival upon platinum-based regimens. Five of 7 patients with BRCA2 germline mutations carried the p.K3326* variant, classified as “benign.” However, familial history of cancer, the absence of RAD51 foci in tumor cells, and a high HRD score suggest a deleterious effect of this mutation in gastric cancer. In conclusion, PARPis could represent an effective therapeutic option for BRCA2-mutated and/or high HRD score patients with GEA, including patients with familial intestinal gastric cancer. This work was funded by the Italian Association for Cancer Research (AIRC), IG 20210 and IG 27531 to S. Giordano; IG 23624 to F. Pietrantonio; IG 21770 to S. Corso. FPRC 5×1000 2015 Min. Salute “Strategy” to SG; Fondazione Piemontese per la Ricerca sul Cancro (FPRC) 5×1000 MS2017 PTCRC-intra 2020 to S. Giordano; Ricerca Locale Dept. Oncology 2021 to S. Corso; Italian Ministry of Health-Ricerca Corrente 2022–23. B. Pellegrino was supported by ESMO with a Clinical Translational Fellowship aid supported by Roche and received research grants from GOIRC. Fondazione CR Firenze to M. Benelli.

Published
2023

6. Figure S2 from BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors

Author

Silvia Giordano, Simona Corso, Caterina Marchiò, Alessandro Ferrero, Marco F. Amisano, Gian Luca Baiocchi, Maurizio Degiuli, Giovanni De Manzoni, Uberto Fumagalli, Maria Antista, Federica Morano, Michele Prisciandaro, Andrea Sartore-Bianchi, Salvatore Siena, Antonino Musolino, Alba Llop-Guevara, Benedetta Pellegrino, Violeta Serra, Elisabetta Puliga, Irene M. Maina, Daniela Conticelli, Cristina Migliore, Daniel Moya-Rull, Salvatore Ribisi, Claudia Orrù, Enrico Berrino, Dario Romagnoli, Loris De Cecco, Matteo Benelli, Sara E. Bellomo, Filippo Pietrantonio, Sabrina Rizzolio, and Annalisa Petrelli

Abstract

BRCA2 LOF mutations in the GEA PDX models used in pre-clinical trials.

Published
2023

7. Data from BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors

Author

Silvia Giordano, Simona Corso, Caterina Marchiò, Alessandro Ferrero, Marco F. Amisano, Gian Luca Baiocchi, Maurizio Degiuli, Giovanni De Manzoni, Uberto Fumagalli, Maria Antista, Federica Morano, Michele Prisciandaro, Andrea Sartore-Bianchi, Salvatore Siena, Antonino Musolino, Alba Llop-Guevara, Benedetta Pellegrino, Violeta Serra, Elisabetta Puliga, Irene M. Maina, Daniela Conticelli, Cristina Migliore, Daniel Moya-Rull, Salvatore Ribisi, Claudia Orrù, Enrico Berrino, Dario Romagnoli, Loris De Cecco, Matteo Benelli, Sara E. Bellomo, Filippo Pietrantonio, Sabrina Rizzolio, and Annalisa Petrelli

Abstract

Despite negative results of clinical trials conducted on the overall population of patients with gastric cancer, PARP inhibitor (PARPi) therapeutic strategy still might represent a window of opportunity for a subpopulation of patients with gastric cancer. An estimated 7% to 12% of gastric cancers exhibit a mutational signature associated with homologous recombination (HR) failure, suggesting that these patients could potentially benefit from PARPis. To analyze responsiveness of gastric cancer to PARPi, we exploited a gastroesophageal adenocarcinoma (GEA) platform of patient-derived xenografts (PDX) and PDX-derived primary cells and selected 10 PDXs with loss-of-function mutations in HR pathway genes. Cell viability assays and preclinical trials showed that olaparib treatment was effective in PDXs harboring BRCA2 germline mutations and somatic inactivation of the second allele. Olaparib responsive tumors were sensitive to oxaliplatin as well. Evaluation of HR deficiency (HRD) and mutational signatures efficiently stratified responder and nonresponder PDXs. A retrospective analysis on 57 patients with GEA showed that BRCA2 inactivating variants were associated with longer progression-free survival upon platinum-based regimens. Five of 7 patients with BRCA2 germline mutations carried the p.K3326* variant, classified as “benign.” However, familial history of cancer, the absence of RAD51 foci in tumor cells, and a high HRD score suggest a deleterious effect of this mutation in gastric cancer. In conclusion, PARPis could represent an effective therapeutic option for BRCA2-mutated and/or high HRD score patients with GEA, including patients with familial intestinal gastric cancer.Significance:PARP inhibition is a potential strategy for treating patients with gastric cancer with mutated BRCA2 or homologous repair deficiency, including patients with familial intestinal gastric cancer, for whom BRCA2 germline testing should be recommended.

Published
2023

8. Figure S3 from BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors

Author

Silvia Giordano, Simona Corso, Caterina Marchiò, Alessandro Ferrero, Marco F. Amisano, Gian Luca Baiocchi, Maurizio Degiuli, Giovanni De Manzoni, Uberto Fumagalli, Maria Antista, Federica Morano, Michele Prisciandaro, Andrea Sartore-Bianchi, Salvatore Siena, Antonino Musolino, Alba Llop-Guevara, Benedetta Pellegrino, Violeta Serra, Elisabetta Puliga, Irene M. Maina, Daniela Conticelli, Cristina Migliore, Daniel Moya-Rull, Salvatore Ribisi, Claudia Orrù, Enrico Berrino, Dario Romagnoli, Loris De Cecco, Matteo Benelli, Sara E. Bellomo, Filippo Pietrantonio, Sabrina Rizzolio, and Annalisa Petrelli

Abstract

Familial history of cancers of the GEA patients carrying BRCA2 germline LOF mutations.

Published
2023

9. Supplementary Table S1 from BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors

Author

Silvia Giordano, Simona Corso, Caterina Marchiò, Alessandro Ferrero, Marco F. Amisano, Gian Luca Baiocchi, Maurizio Degiuli, Giovanni De Manzoni, Uberto Fumagalli, Maria Antista, Federica Morano, Michele Prisciandaro, Andrea Sartore-Bianchi, Salvatore Siena, Antonino Musolino, Alba Llop-Guevara, Benedetta Pellegrino, Violeta Serra, Elisabetta Puliga, Irene M. Maina, Daniela Conticelli, Cristina Migliore, Daniel Moya-Rull, Salvatore Ribisi, Claudia Orrù, Enrico Berrino, Dario Romagnoli, Loris De Cecco, Matteo Benelli, Sara E. Bellomo, Filippo Pietrantonio, Sabrina Rizzolio, and Annalisa Petrelli

Abstract

HRD and mutational signature scores in PDXs used in the preclinical trials

Published
2023

10. Supplementary Table S3 from BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors

Author

Silvia Giordano, Simona Corso, Caterina Marchiò, Alessandro Ferrero, Marco F. Amisano, Gian Luca Baiocchi, Maurizio Degiuli, Giovanni De Manzoni, Uberto Fumagalli, Maria Antista, Federica Morano, Michele Prisciandaro, Andrea Sartore-Bianchi, Salvatore Siena, Antonino Musolino, Alba Llop-Guevara, Benedetta Pellegrino, Violeta Serra, Elisabetta Puliga, Irene M. Maina, Daniela Conticelli, Cristina Migliore, Daniel Moya-Rull, Salvatore Ribisi, Claudia Orrù, Enrico Berrino, Dario Romagnoli, Loris De Cecco, Matteo Benelli, Sara E. Bellomo, Filippo Pietrantonio, Sabrina Rizzolio, and Annalisa Petrelli

Abstract

LOF mutations and clinical characteristics of patients carrying HR gene variants

Published
2023

11. Figure S8 from BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors

Author

Silvia Giordano, Simona Corso, Caterina Marchiò, Alessandro Ferrero, Marco F. Amisano, Gian Luca Baiocchi, Maurizio Degiuli, Giovanni De Manzoni, Uberto Fumagalli, Maria Antista, Federica Morano, Michele Prisciandaro, Andrea Sartore-Bianchi, Salvatore Siena, Antonino Musolino, Alba Llop-Guevara, Benedetta Pellegrino, Violeta Serra, Elisabetta Puliga, Irene M. Maina, Daniela Conticelli, Cristina Migliore, Daniel Moya-Rull, Salvatore Ribisi, Claudia Orrù, Enrico Berrino, Dario Romagnoli, Loris De Cecco, Matteo Benelli, Sara E. Bellomo, Filippo Pietrantonio, Sabrina Rizzolio, and Annalisa Petrelli

Abstract

RAD51 assay predicts PARPi response in Gastric Cancer PDX models.

Published
2023

12. Figure S1 from BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors

Author

Silvia Giordano, Simona Corso, Caterina Marchiò, Alessandro Ferrero, Marco F. Amisano, Gian Luca Baiocchi, Maurizio Degiuli, Giovanni De Manzoni, Uberto Fumagalli, Maria Antista, Federica Morano, Michele Prisciandaro, Andrea Sartore-Bianchi, Salvatore Siena, Antonino Musolino, Alba Llop-Guevara, Benedetta Pellegrino, Violeta Serra, Elisabetta Puliga, Irene M. Maina, Daniela Conticelli, Cristina Migliore, Daniel Moya-Rull, Salvatore Ribisi, Claudia Orrù, Enrico Berrino, Dario Romagnoli, Loris De Cecco, Matteo Benelli, Sara E. Bellomo, Filippo Pietrantonio, Sabrina Rizzolio, and Annalisa Petrelli

Abstract

HR gene mutations in GEA models used in in vitro and in vivo experiments.

Published
2023

13. Figure S7 from BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors

Author

Silvia Giordano, Simona Corso, Caterina Marchiò, Alessandro Ferrero, Marco F. Amisano, Gian Luca Baiocchi, Maurizio Degiuli, Giovanni De Manzoni, Uberto Fumagalli, Maria Antista, Federica Morano, Michele Prisciandaro, Andrea Sartore-Bianchi, Salvatore Siena, Antonino Musolino, Alba Llop-Guevara, Benedetta Pellegrino, Violeta Serra, Elisabetta Puliga, Irene M. Maina, Daniela Conticelli, Cristina Migliore, Daniel Moya-Rull, Salvatore Ribisi, Claudia Orrù, Enrico Berrino, Dario Romagnoli, Loris De Cecco, Matteo Benelli, Sara E. Bellomo, Filippo Pietrantonio, Sabrina Rizzolio, and Annalisa Petrelli

Abstract

MLH1 gene knock-out abrogates responsiveness to olaparib in CAPAN-1 cells.

Published
2023

14. Figure S5 from BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors

Author

Silvia Giordano, Simona Corso, Caterina Marchiò, Alessandro Ferrero, Marco F. Amisano, Gian Luca Baiocchi, Maurizio Degiuli, Giovanni De Manzoni, Uberto Fumagalli, Maria Antista, Federica Morano, Michele Prisciandaro, Andrea Sartore-Bianchi, Salvatore Siena, Antonino Musolino, Alba Llop-Guevara, Benedetta Pellegrino, Violeta Serra, Elisabetta Puliga, Irene M. Maina, Daniela Conticelli, Cristina Migliore, Daniel Moya-Rull, Salvatore Ribisi, Claudia Orrù, Enrico Berrino, Dario Romagnoli, Loris De Cecco, Matteo Benelli, Sara E. Bellomo, Filippo Pietrantonio, Sabrina Rizzolio, and Annalisa Petrelli

Abstract

Microsatellite instability (MSI) evaluation in the GTR0264 and GTR0324 tumors.

Published
2023

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