The preservation of pathogenic BRCA1/2 germline mutations in tumor tissues is usually not questioned, while it remains unknown whether these interact with somatic genotypes for patient outcome. Herein we compared germline and tumor genotypes in operable triple-negative breast cancer (TNBC) and evaluated their combined effects on prognosis. We analyzed baseline germline and primary tumor genotype data obtained by Sanger and Next Generation Sequencing in 194 TNBC patients. We also performed multiple tests interrogating the preservation of germline mutations in matched tumors and breast tissue from carriers with available material. Patients had been treated within clinical trials with adjuvant anthracyclines-taxanes based chemotherapy. We identified 50 (26%) germline mutation carriers (78% in BRCA1) and 136 (71%) tumors with somatic mutations (83% in TP53). Tumor mutation patterns differed between carriers and non-carriers (P<0.001); PIK3CA mutations were exclusively present in non-carriers (P=0.007). Germline BRCA1/2 mutations were not detected in matched tumors and breast tissues from 14 out of 33 (42%) evaluable carriers. Microsatellite markers revealed tumor loss of the germline mutant allele in one case only. Tumors that had lost the germline mutation demonstrated a higher incidence of somatic TP53 mutations as compared to tumors with preserved germline mutations (P=0.036). Germline mutation status significantly interacted with tumor TP53 mutations for patient disease-free survival (interaction P=0.026): In non-carriers, tumor TP53 mutations did not affect outcome; In carriers, those with mutated TP53 tumors experienced more relapses compared to those with wild-type TP53 tumors (36% vs. 9% relapse rate, respectively). In conclusion, we show that loss of germline BRCA1/2 mutations is not a rare event in TNBC. This finding, the observed differences in tumor genotypes with respect to germline status and the prognostic interaction between germline BRCA1-related and tumor TP53 mutation status prompt for combined germline and tumor genotyping for the classification of TNBC, particularly in the context of clinical trials evaluating synthetic lethality drugs.
American journal of cancer research. 2017 Jan 01*** epublish ***
Vassiliki Kotoula, Florentia Fostira, Kyriaki Papadopoulou, Paraskevi Apostolou, Eleftheria Tsolaki, Georgios Lazaridis, Kyriaki Manoussou, Flora Zagouri, Dimitrios Pectasides, Ioannis Vlachos, Ioannis Tikas, Sotiris Lakis, Irene Konstantopoulou, George Pentheroudakis, Helen Gogas, Pavlos Papakostas, Christos Christodoulou, Dimitrios Bafaloukos, Evangelia Razis, Vasilios Karavasilis, Christina Bamias, Drakoulis Yannoukakos, George Fountzilas
Department of Pathology, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of MedicineThessaloniki, Greece; Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of ThessalonikiThessaloniki, Greece., Molecular Diagnostics Laboratory, INRASTES, National Center for Scientific Research NCSR Demokritos Athens, Greece., Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki Thessaloniki, Greece., Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine Thessaloniki, Greece., Section of Biostatistics, Hellenic Cooperative Oncology Group, Data Office Athens, Greece., Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens School of Medicine Athens, Greece., Oncology Section, Second Department of Internal Medicine, Hippokration Hospital Athens, Greece., Molecular Diagnostics Laboratory, INRASTES, National Center for Scientific Research NCSR DemokritosAthens, Greece; DIANA-Lab, Department of Computer and Communication Engineering, University of ThessalyVolos, Greece., Department of Medical Oncology, Ioannina University Hospital Ioannina, Greece., First Department of Medicine, Laiko General Hospital, National and Kapodistrian University of Athens School of Medicine Athens, Greece., Oncology Unit, Hippokration Hospital Athens, Greece., Second Department of Medical Oncology, Metropolitan Hospital Piraeus, Greece., First Department of Medical Oncology, Metropolitan Hospital Piraeus, Greece., Third Department of Medical Oncology, Hygeia Hospital Athens, Greece., National and Kapodistrian University of Athens, Medical School, Department of Hygiene, Epidemiology and Medical Statistics Athens, Greece., Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of ThessalonikiThessaloniki, Greece; Aristotle University of ThessalonikiThessaloniki, Greece.