Vassiliki Kotoula1,2, Kyriaki Papadopoulou3, Ioannis Tikas4, Florentia Fostira5, Eleni Vrettou4, Sofia Chrisafi3, Elena Fountzilas6,7, Georgia-Angeliki Koliou8, Paraskevi Apostolou5, Konstantinos Papazisis9, Thomas Zaramboukas4, Anthoula Asimaki-Vlachopoulou10, Spyros Miliaras11, Ananias Ananiadis12, Christos Poulios4, Ioannis Natsiopoulos13, Aris Tsiftsoglou12, Efterpi Demiri14, George Fountzilas3,15,16. 1. Department of Pathology, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, University Campus, bld. 17b, 54124, Thessaloníki, Greece. vkotoula@auth.gr. 2. Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloníki, Greece. vkotoula@auth.gr. 3. Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloníki, Greece. 4. Department of Pathology, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, University Campus, bld. 17b, 54124, Thessaloníki, Greece. 5. Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research NCSR Demokritos, Athens, Greece. 6. Second Department of Medical Oncology, Euromedica General Clinic of Thessaloniki, Thessaloníki, Greece. 7. European University of Cyprus, Nicosia, Cyprus. 8. Section of Biostatistics, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece. 9. Department of Medical Oncology, Interbalkan European Medical Center, Thessaloníki, Greece. 10. Histopathology and Cytology Laboratory, Thessaloníki, Greece. 11. First Department of Surgery, Papageorgiou Hospital, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloníki, Greece. 12. Department of Surgery, St. Luke's Hospital, Thessaloníki, Greece. 13. Department of Breast Surgery, Interbalkan European Medical Center, Thessaloníki, Greece. 14. Department of Plastic Surgery, Papageorgiou Hospital, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloníki, Greece. 15. Aristotle University of Thessaloniki, Thessaloníki, Greece. 16. German Oncology Center, Limassol, Cyprus.
Abstract
PURPOSE: The genomic status of non-malignant tissues from carriers of pathogenic germline BRCA1/2 (gBRCA1/2) variants may reveal information towards individualized prophylaxis. We performed spatiotemporal tissue genotype comparisons in a real-life cohort of gBRCA1/2 carriers of Greek origin, who underwent multiple risk-reducing/prophylactic surgeries at various time points. METHODS: Fifty-three women (median age 36 years) within cancer families were observed for up to 37.5 years; 43 were cancer carriers and 10 were healthy carriers. Histology review and genotyping were performed for 187 paraffin tissues (average: 3.5 per carrier) including 46 carcinomas (40 breast) and 141 non-malignant breast and gynecological samples. RESULTS: High allelic imbalance (AI) and somatic pathogenic TP53 variants were present in cancer carriers only (p values < 0.0001). High AI was associated with gBRCA1/2 indels (p < 0.0001) and gBRCA2 alterations (p = 0.0109). Somatic (pathogenic) variants were infrequently shared between non-malignant tissues and matched carcinomas. Aberrations of gBRCA1 variant heterozygosity were noticed in tissues from cancer carriers only (13/43, 30.2%). These pertained to classic LOH (neoplastic lesions in 9/43 carriers, 20.9%) and under-representation of the germline variants (5 samples, 4 non-malignant, all in the breast). Both aberrations coexisted in matched samples in one case. Over time, germline variant heterozygosity prevailed in non-malignant tissues; intra-carrier genomic alterations were aggravated (21.1%), ameliorated (26.3%) or remained stable. CONCLUSION: This real-life case study supports the need to address tissue genotypes from prophylactic surgeries in combination with polygenic scores towards personalized prophylaxis. To this end, knowing the traditionally classified pathogenic potential of a gBRCA1/2 variant may not be enough.
PURPOSE: The genomic status of non-malignant tissues from carriers of pathogenic germline BRCA1/2 (gBRCA1/2) variants may reveal information towards individualized prophylaxis. We performed spatiotemporal tissue genotype comparisons in a real-life cohort of gBRCA1/2 carriers of Greek origin, who underwent multiple risk-reducing/prophylactic surgeries at various time points. METHODS: Fifty-three women (median age 36 years) within cancer families were observed for up to 37.5 years; 43 were cancer carriers and 10 were healthy carriers. Histology review and genotyping were performed for 187 paraffin tissues (average: 3.5 per carrier) including 46 carcinomas (40 breast) and 141 non-malignant breast and gynecological samples. RESULTS: High allelic imbalance (AI) and somatic pathogenic TP53 variants were present in cancer carriers only (p values < 0.0001). High AI was associated with gBRCA1/2 indels (p < 0.0001) and gBRCA2 alterations (p = 0.0109). Somatic (pathogenic) variants were infrequently shared between non-malignant tissues and matched carcinomas. Aberrations of gBRCA1 variant heterozygosity were noticed in tissues from cancer carriers only (13/43, 30.2%). These pertained to classic LOH (neoplastic lesions in 9/43 carriers, 20.9%) and under-representation of the germline variants (5 samples, 4 non-malignant, all in the breast). Both aberrations coexisted in matched samples in one case. Over time, germline variant heterozygosity prevailed in non-malignant tissues; intra-carrier genomic alterations were aggravated (21.1%), ameliorated (26.3%) or remained stable. CONCLUSION: This real-life case study supports the need to address tissue genotypes from prophylactic surgeries in combination with polygenic scores towards personalized prophylaxis. To this end, knowing the traditionally classified pathogenic potential of a gBRCA1/2 variant may not be enough.
Authors: Oluwadamilola Motunaryo Fayanju; Carolyn R T Stoll; Susan Fowler; Graham A Colditz; Julie A Margenthaler Journal: Ann Surg Date: 2014-12 Impact factor: 12.969
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