title: The fate of BRCA1-related germline mutations in triple-negative breast tumors.
abstract: The preservation of pathogenicBRCA1/2germline 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% inBRCA1) and 136 (71%) tumors with somatic mutations (83% inTP53). Tumor mutation patterns differed between carriers and non-carriers (P<0.001);PIK3CAmutations were exclusively present in non-carriers (P=0.007). GermlineBRCA1/2mutations 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 somaticTP53mutations as compared to tumors with preserved germline mutations (P=0.036). Germline mutation status significantly interacted with tumorTP53mutations for patient disease-free survival (interaction P=0.026): In non-carriers, tumorTP53mutations did not affect outcome; In carriers, those with mutatedTP53tumors experienced more relapses compared to those with wild-typeTP53tumors (36% vs. 9% relapse rate, respectively). In conclusion, we show that loss of germlineBRCA1/2mutations 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 tumorTP53mutation status prompt for combined germline and tumor genotyping for the classification of TNBC, particularly in the context of clinical trials evaluating synthetic lethality drugs.
authors.affiliation: 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.
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Kotoula
authors.affiliation: Molecular Diagnostics Laboratory, INRASTES, National Center for Scientific Research NCSR Demokritos Athens, Greece.
authors.forename: Florentia
authors.initials: F
authors.lastname: Fostira
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki Thessaloniki, Greece.
authors.forename: Kyriaki
authors.initials: K
authors.lastname: Papadopoulou
authors.affiliation: Molecular Diagnostics Laboratory, INRASTES, National Center for Scientific Research NCSR Demokritos Athens, Greece.
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Apostolou
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki Thessaloniki, Greece.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Tsolaki
authors.affiliation: Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine Thessaloniki, Greece.
authors.forename: Georgios
authors.initials: G
authors.lastname: Lazaridis
authors.affiliation: Section of Biostatistics, Hellenic Cooperative Oncology Group, Data Office Athens, Greece.
authors.forename: Kyriaki
authors.initials: K
authors.lastname: Manoussou
authors.affiliation: Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens School of Medicine Athens, Greece.
authors.forename: Flora
authors.initials: F
authors.lastname: Zagouri
authors.affiliation: Oncology Section, Second Department of Internal Medicine, Hippokration Hospital Athens, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Pectasides
authors.affiliation: Molecular Diagnostics Laboratory, INRASTES, National Center for Scientific Research NCSR DemokritosAthens, Greece; DIANA-Lab, Department of Computer and Communication Engineering, University of ThessalyVolos, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Vlachos
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki Thessaloniki, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Tikas
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki Thessaloniki, Greece.
authors.forename: Sotiris
authors.initials: S
authors.lastname: Lakis
authors.affiliation: Molecular Diagnostics Laboratory, INRASTES, National Center for Scientific Research NCSR Demokritos Athens, Greece.
authors.forename: Irene
authors.initials: I
authors.lastname: Konstantopoulou
authors.affiliation: Department of Medical Oncology, Ioannina University Hospital Ioannina, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Pentheroudakis
authors.affiliation: First Department of Medicine, Laiko General Hospital, National and Kapodistrian University of Athens School of Medicine Athens, Greece.
authors.forename: Helen
authors.initials: H
authors.lastname: Gogas
authors.affiliation: Oncology Unit, Hippokration Hospital Athens, Greece.
authors.forename: Pavlos
authors.initials: P
authors.lastname: Papakostas
authors.affiliation: Second Department of Medical Oncology, Metropolitan Hospital Piraeus, Greece.
authors.forename: Christos
authors.initials: C
authors.lastname: Christodoulou
authors.affiliation: First Department of Medical Oncology, Metropolitan Hospital Piraeus, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Bafaloukos
authors.affiliation: Third Department of Medical Oncology, Hygeia Hospital Athens, Greece.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Razis
authors.affiliation: Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine Thessaloniki, Greece.
authors.forename: Vasilios
authors.initials: V
authors.lastname: Karavasilis
authors.affiliation: National and Kapodistrian University of Athens, Medical School, Department of Hygiene, Epidemiology and Medical Statistics Athens, Greece.
authors.forename: Christina
authors.initials: C
authors.lastname: Bamias
authors.affiliation: Molecular Diagnostics Laboratory, INRASTES, National Center for Scientific Research NCSR Demokritos Athens, Greece.
authors.forename: Drakoulis
authors.initials: D
authors.lastname: Yannoukakos
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of ThessalonikiThessaloniki, Greece; Aristotle University of ThessalonikiThessaloniki, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Fountzilas
keywords: BRCA1; BRCA2; TNBC; TP53; adjuvant chemotherapy; germline; haploinsufficiency; mutant-LOH; mutation reversion; somatic