Vol 27, No 2 (2022)
Research paper
Published online: 2022-03-10

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The highest frequency of BRCA1 c.3700_3704del detected among Albanians from Kosovo

Ivana Maleva Kostovska1, Simona Jakovchevska1, Milena Jakimovska Özdemir1, Sanja Kiprijanovska1, Katerina Kubelka-Sabit23, Dzengis Jasar23, Marina Iljovska4, Emilija Lazareva4, Snezhana Smichkoska4, Dijana Plaseska-Karanfilska1
Rep Pract Oncol Radiother 2022;27(2):303-309.


Background: The spectrum of BRCA1 and BRCA2 mutations varies among populations; however, some mutations may be frequent in particular ethnic groups due to the “founder” effect. The c.3700_3704del mutation was previously described as a recurrent BRCA1 variant in Eastern European countries. This study aimed to investigate the frequency of c.3700_3704del BRCA1 mutation in Albanian breast and ovarian cancer patients from North Macedonia and Kosovo.

Materials and methods: A total of 327 patients with invasive breast and/or ovarian cancer (111 Albanian women from North Macedonia and 216 from Kosovo) were screened for 13 recurrent BRCA1/2 mutations. Targeted NGS with a panel of 94 cancer-associated genes including BRCA1 and BRCA2 was performed in a selected group of 118 patients.

Results: We have identified 21 BRCA1/2 pathogenic variants, 17 (14 BRCA1 and 3 BRCA2) in patients from Kosovo (7.9%) and 4 (1 BRCA1 and 3 BRCA2) in patients from North Macedonia (3.6%). All BRCA1/2 mutations were found in one patient each, except for c.3700_3704del BRCA1 mutation which was observed in 14 unrelated families, all except one originating from Kosovo. The c.3700_3704del mutation accounts for 93% of BRCA1 mutation positive cases and is present with a frequency of 6% among breast cancer patients from Kosovo.

Conclusions: This is the first report of BRCA1/2 mutations among breast and ovarian cancer patients from Kosovo. The finding that BRCA1 c.3700_3704del represents a founder mutation in Kosovo with the highest worldwide reported frequency supports the implementation of fast and low-cost screening protocol, regardless of the family history and even a pilot population-based screening in at-risk population.

Key words: BRCA1; c.3700_3704del; founder mutation; breast cancer; Kosovo

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  1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3): 209–249.
  2. Fackenthal JD, Olopade OI. Breast cancer risk associated with BRCA1 and BRCA2 in diverse populations. Nat Rev Cancer. 2007; 7(12): 937–948.
  3. Ramus SJ, Gayther SA. The contribution of BRCA1 and BRCA2 to ovarian cancer. Mol Oncol. 2009; 3(2): 138–150.
  4. Antoniou A, Pharoah PDP, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003; 72(5): 1117–1130.
  5. Tafe LJ, Datto MB, Palomaki GE, et al. CAP/ACMG Biochemical and Molecular Genetics Resource Committee. Molecular testing for the BRCA1 and BRCA2 Ashkenazi Jewish founder mutations: a report on the College of American Pathologists proficiency testing surveys. Genet Med. 2015; 17(1): 58–62.
  6. Janavičius R. Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control. EPMA J. 2010; 1(3): 397–412.
  7. Jakimovska M, Maleva Kostovska I, Popovska-Jankovic K, et al. BRCA1 and BRCA2 germline variants in breast cancer patients from the Republic of Macedonia. Breast Cancer Res Treat. 2018; 168(3): 745–753.
  8. Laitman Y, Friebel TM, Yannoukakos D, et al. The spectrum of BRCA1 and BRCA2 pathogenic sequence variants in Middle Eastern, North African, and South European countries. Hum Mutat. 2019; 40(11): e1–e23.
  9. Brozek I, Cybulska C, Ratajska M, et al. Prevalence of the most frequent BRCA1 mutations in Polish population. J Appl Genet. 2011; 52(3): 325–330.
  10. Foretova L, Machackova E, Navratilova M, et al. BRCA1 and BRCA2 mutations in women with familial or early-onset breast/ovarian cancer in the Czech Republic. Hum Mutat. 2004; 23(4): 397–398.
  11. Górski B, Byrski T, Huzarski T, et al. Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer. Am J Hum Genet. 2000; 66(6): 1963–1968.
  12. Konstantopoulou I, Tsitlaidou M, Fostira F, et al. High prevalence of BRCA1 founder mutations in Greek breast/ovarian families. Clin Genet. 2014; 85(1): 36–42.
  13. Machackova E, Foretova L, Lukesova M, et al. Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer. BMC Cancer. 2008; 8: 140.
  14. Ratajska M, Brozek I, Senkus-Konefka E, et al. BRCA1 and BRCA2 point mutations and large rearrangements in breast and ovarian cancer families in Northern Poland. Oncol Rep. 2008; 19(1): 263–268.
  15. Takahashi H, Behbakht K, McGovern PE, et al. Mutation analysis of the BRCA1 gene in ovarian cancers. Cancer Res. 1995; 55(14): 2998–3002.
  16. Maleva I, Madjunkova S, Bozhinovski G, et al. Genetic variation of the brca1 and brca2 genes in macedonian patients. Balkan J Med Genet. 2012; 15(Suppl): 81–85.
  17. Richards S, Aziz N, Bale S, et al. ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015; 17(5): 405–424.
  18. Шубин ВП, Логинова АН, Поспехова НИ, et al. Особенности спектра и частота мутаций в гене BRCA1 при раке яичников в Республике Мордовии. Медицинская генетика. 2011; 10(1): 19–24.
  19. Grudinina NA, Golubkov VI, Tikhomirova OS, et al. [Prevalence of widespread BRCA1 gene mutations in patients with familial breast cancer from St. Petersburg]. Genetika. 2005; 41(3): 405–410.
  20. Pohlreich P, Zikan M, Stribrna J, et al. High proportion of recurrent germline mutations in the BRCA1 gene in breast and ovarian cancer patients from the Prague area. Breast Cancer Res. 2005; 7(5): R728–R736.
  21. Brozek I, Ochman K, Debniak J, et al. High frequency of BRCA1/2 germline mutations in consecutive ovarian cancer patients in Poland. Gynecol Oncol. 2008; 108(2): 433–437.
  22. Domagala P, Jakubowska A, Jaworska-Bieniek K, et al. Prevalence of Germline Mutations in Genes Engaged in DNA Damage Repair by Homologous Recombination in Patients with Triple-Negative and Hereditary Non-Triple-Negative Breast Cancers. PLoS One. 2015; 10(6): e0130393.
  23. Koczkowska M, Zuk M, Gorczynski A, et al. Detection of somatic BRCA1/2 mutations in ovarian cancer - next-generation sequencing analysis of 100 cases. Cancer Med. 2016; 5(7): 1640–1646.
  24. Pogoda K, Niwińska A, Sarnowska E, et al. Effects of Germline Mutations on Triple-Negative Breast Cancer Prognosis. J Oncol. 2020; 2020: 8545643.
  25. Fostira F, Kostantopoulou I, Apostolou P, et al. One in three highly selected Greek patients with breast cancer carries a loss-of-function variant in a cancer susceptibility gene. J Med Genet. 2020; 57(1): 53–61.
  26. Bergthorsson JT, Ejlertsen B, Olsen JH, et al. BRCA1 and BRCA2 mutation status and cancer family history of Danish women affected with multifocal or bilateral breast cancer at a young age. J Med Genet. 2001; 38(6): 361–368.
  27. Goidescu IG, Caracostea G, Eniu DT, et al. Prevalence of deleterious mutations among patients with breast cancer referred for multigene panel testing in a Romanian population. Clujul Med. 2018; 91(2): 157–165.
  28. Hoyer J, Vasileiou G, Uebe S, et al. Addition of triple negativity of breast cancer as an indicator for germline mutations in predisposing genes increases sensitivity of clinical selection criteria. BMC Cancer. 2018; 18(1): 926.
  29. Yazici H, Bitisik O, Akisik E, et al. BRCA1 and BRCA2 mutations in Turkish breast/ovarian families and young breast cancer patients. Br J Cancer. 2000; 83(6): 737–742.
  30. Zidekova D, Waczulikova I, Dolesova L, et al. Rapid screening test of most frequent BRCA1/BRCA2 pathogenic variants in the NGS era. Neoplasma. 2018; 65(2): 309–315.

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