title: Spectrum and frequencies of BRCA1/2 mutations in Bulgarian high risk breast cancer patients.
abstract: BACKGROUND
  About 3885 women are diagnosed with breast cancer and 1285 die from the disease each year in Bulgaria. However no genetic testing to identify the mutations in high-risk families has been provided so far.
  
  
  METHODS
  We evaluated 200 Bulgarian women with primary invasive breast cancer and with personal/ family history of breast cancer for the presence of unequivocally damaging germline mutations in BRCA1/2 using Sanger sequencing.
  
  
  RESULTS
  Of the 200 patients, 39 (19.5 %) carried a disease predisposing mutation, including 28 (14 %) with a BRCA1 mutation and 11 (5.5 %) with a BRCA2 mutation. At BRCA1, 6 different mutations were identified, including 2 frameshifts, 1 nonsense and 1 missense that had been previously reported (c.5030_5033delCTAA, c.5263_5264insC, c.4603G > T, c.181 T > G), and 2 frameshifts, which were novel to this study (c.464delA, c.5397_5403delCCCTTGG). At BRCA2, 7 different frameshift mutations were identified, including 5 previously reported (5851_5854delAGTT, c.5946delT, c.5718_5719delCT, c.7910_7914delCCTTT,c.9098_9099insA) and 2 novel (c.8532_8533delAA, c.9682delA). A BRCA1 mutation was found in 18.4 % of women diagnosed with breast cancer at/or under the age of 40 compared to 11.2 % of women diagnosed at a later age; a BRCA2 mutation was found in 4 % of women diagnosed at/or under the age of 40 compared to 6.5 % of women diagnosed at a later age. A mutation was present in 26.8 % patients with a positive family history and in 14.4 % of women with a negative family history. The most prevalent mutation observed in 22 patients (11 %) was BRCA1 c.5263_5264insC, a known Slavic mutation with founder effect in Eastern European and AJ communities. Other recurrent mutations were BRCA2 c.9098-9099insA (2 %), BRCA1 c.181T > G (1 %) and BRCA2 c.5851_5854delAGTT (1 %). Notably, BRCA1 c.5263_5264insC represented 56 % of all mutations identified in this series. Of the 22 patients with BRCA1 c.5263_5264insC, 9 were diagnosed with early onset breast cancer, 11 with TNBCs, 4 with bilateral breast cancer, and 6 with both breast and ovarian cancer.
  
  
  CONCLUSIONS
  This is the first comprehensive study of the BRCA1/2 mutation spectrum in Bulgaria and will assist the establishment of efficient protocols for genetic testing and individualized risk assessment for Bulgarian breast/ovarian cancer patients and healthy individuals at a high-risk.
authors.affiliation: Molecular Medicine Center, Medical University of Sofia, 2 Zdrave str., 1431, Sofia, Bulgaria.|Department of Medical Chemistry and Biochemistry, Medical Faculty, Medical University of Sofia, 2 Zdrave str., 1431, Sofia, Bulgaria.
authors.forename: Rumyana Ivanova
authors.initials: RI
authors.lastname: Dodova
authors.affiliation: Molecular Medicine Center, Medical University of Sofia, 2 Zdrave str., 1431, Sofia, Bulgaria. mitkova@mmcbg.org.|Department of Medical Chemistry and Biochemistry, Medical Faculty, Medical University of Sofia, 2 Zdrave str., 1431, Sofia, Bulgaria. mitkova@mmcbg.org.
authors.forename: Atanaska Velichkova
authors.initials: AV
authors.lastname: Mitkova
authors.affiliation: Molecular Medicine Center, Medical University of Sofia, 2 Zdrave str., 1431, Sofia, Bulgaria.|Department of Medical Chemistry and Biochemistry, Medical Faculty, Medical University of Sofia, 2 Zdrave str., 1431, Sofia, Bulgaria.
authors.forename: Daniela Rosenova
authors.initials: DR
authors.lastname: Dacheva
authors.affiliation: Molecular Medicine Center, Medical University of Sofia, 2 Zdrave str., 1431, Sofia, Bulgaria.
authors.forename: Lina Basam
authors.initials: LB
authors.lastname: Hadjo
authors.affiliation: General and Clinical Pathology Clinic, University Hospital "Alexandrovska", 1 Georgi Sofiiski str., 1431, Sofia, Bulgaria.|Department of General and Clinical Pathology, Medical University of Sofia, 1 Georgi Sofiiski str., 1431, Sofia, Bulgaria.
authors.forename: Alexandrina Ivanova
authors.initials: AI
authors.lastname: Vlahova
authors.affiliation: Clinic of Medical Oncology (Chemotherapy), Specialized Hospital for Active Treatment in Oncology, 6 "Plovdivsko pole" str., 1756, Sofia, Bulgaria.
authors.forename: Margarita Stoyanova Taushanova
authors.initials: MST
authors.lastname: -Hadjieva
authors.affiliation: Clinic of Medical Oncology (Chemotherapy), Specialized Hospital for Active Treatment in Oncology, 6 "Plovdivsko pole" str., 1756, Sofia, Bulgaria.
authors.forename: Spartak Stoyanov
authors.initials: SS
authors.lastname: Valev
authors.affiliation: Molecular Medicine Center, Medical University of Sofia, 2 Zdrave str., 1431, Sofia, Bulgaria.
authors.forename: Marija Mitko
authors.initials: MM
authors.lastname: Caulevska
authors.affiliation: Molecular Medicine Center, Medical University of Sofia, 2 Zdrave str., 1431, Sofia, Bulgaria.
authors.forename: Stanislava Dimitrova
authors.initials: SD
authors.lastname: Popova
authors.affiliation: Molecular Medicine Center, Medical University of Sofia, 2 Zdrave str., 1431, Sofia, Bulgaria.|Department of Medical Chemistry and Biochemistry, Medical Faculty, Medical University of Sofia, 2 Zdrave str., 1431, Sofia, Bulgaria.
authors.forename: Ivan Emilov
authors.initials: IE
authors.lastname: Popov
authors.affiliation: General and Clinical Pathology Clinic, University Hospital "Alexandrovska", 1 Georgi Sofiiski str., 1431, Sofia, Bulgaria.|Department of General and Clinical Pathology, Medical University of Sofia, 1 Georgi Sofiiski str., 1431, Sofia, Bulgaria.
authors.forename: Tihomir Iliichev
authors.initials: TI
authors.lastname: Dikov
authors.affiliation: Department of Surgery, University Hospital "Tsaritsa Yoana - ISUL", 8 "Byalo more" str., 1527, Sofia, Bulgaria.|Medical Faculty, 8 "Byalo more" str., 1527, Sofia, Bulgaria.
authors.forename: Theophil Angelov
authors.initials: TA
authors.lastname: Sedloev
authors.affiliation: Department of General and Liver-Pancreatic Surgery, University Hospital "Alexandrovska", 1 Georgi Sofiiski str., 1431, Sofia, Bulgaria.|Medical Faculty, Medical University of Sofia, 1 Georgi Sofiiski str., 1431, Sofia, Bulgaria.
authors.forename: Atanas Stefanov
authors.initials: AS
authors.lastname: Ionkov
authors.affiliation: Clinic of Medical Oncology (Chemotherapy), Specialized Hospital for Active Treatment in Oncology, 6 "Plovdivsko pole" str., 1756, Sofia, Bulgaria.
authors.forename: Konstanta Velinova
authors.initials: KV
authors.lastname: Timcheva
authors.affiliation: General and Clinical Pathology Clinic, University Hospital "Alexandrovska", 1 Georgi Sofiiski str., 1431, Sofia, Bulgaria.|Department of General and Clinical Pathology, Medical University of Sofia, 1 Georgi Sofiiski str., 1431, Sofia, Bulgaria.
authors.forename: Svetlana Liubomirova
authors.initials: SL
authors.lastname: Christova
authors.affiliation: Molecular Medicine Center, Medical University of Sofia, 2 Zdrave str., 1431, Sofia, Bulgaria.
authors.forename: Ivo Marinov
authors.initials: IM
authors.lastname: Kremensky
authors.affiliation: Molecular Medicine Center, Medical University of Sofia, 2 Zdrave str., 1431, Sofia, Bulgaria.|Department of Medical Chemistry and Biochemistry, Medical Faculty, Medical University of Sofia, 2 Zdrave str., 1431, Sofia, Bulgaria.
authors.forename: Vanio Ivanov
authors.initials: VI
authors.lastname: Mitev
authors.affiliation: Molecular Medicine Center, Medical University of Sofia, 2 Zdrave str., 1431, Sofia, Bulgaria.|Department of Medical Chemistry and Biochemistry, Medical Faculty, Medical University of Sofia, 2 Zdrave str., 1431, Sofia, Bulgaria.
authors.forename: Radka Petrova
authors.initials: RP
authors.lastname: Kaneva
mesh_terms: D000328:Adult; D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000208:ethnology / Q000235:genetics* / Q000473:pathology*; D002031:Bulgaria / Q000208:ethnology; D005260:Female; D018703:Founder Effect; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D057285:Precision Medicine; D017422:Sequence Analysis, DNA
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human