Original article| Volume 207, ISSUE 5, P195-205, May 2014

Comprehensive BRCA1 and BRCA2 mutational profile in Lithuania

  • Ramūnas Janavičius
    Corresponding author.
    Department of Molecular and Regenerative Medicine, Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santariškių Klinikos, Vilnius, Lithuania

    State Research Institute, Innovative Medicine Center, Vilnius, Lithuania
    Search for articles by this author
  • Vilius Rudaitis
    Clinics of Internal, Family Medicine and Oncology, Faculty of Medicine, Vilnius University, Vilnius, Lithuania

    Department of Gynecology, Centre of Women's Physiology and Pathology, Vilnius University Hospital Santariškių Klinikos, Vilnius, Lithuania
    Search for articles by this author
  • Ugnius Mickys
    National Center of Pathology, Vilnius, Lithuania
    Search for articles by this author
  • Pavel Elsakov
    State Research Institute, Innovative Medicine Center, Vilnius, Lithuania

    Public Institution Centro Poliklinika, Vilnius, Lithuania
    Search for articles by this author
  • Laimonas Griškevičius
    Department of Molecular and Regenerative Medicine, Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santariškių Klinikos, Vilnius, Lithuania

    Clinics of Internal, Family Medicine and Oncology, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
    Search for articles by this author
      There is limited knowledge about the BRCA1/2 mutational profile in Lithuania. We aimed to define the full BRCA1 and BRCA2 mutational spectrum and the clinically relevant prevalence of these gene mutations in Lithuania. A data set of 753 unrelated probands, recruited through a clinical setting, was used and consisted of 380 female breast cancer cases, 213 epithelial ovarian cancer cases, 20 breast and ovarian cancer cases, and 140 probands with positive family history of breast or ovarian cancer. A comprehensive mutation analysis of the BRCA1/2 genes by high resolution melting analysis coupled with Sanger sequencing and multiplex ligation-dependent probe amplification analysis was performed. Genetic analysis revealed 32 different pathogenic germline BRCA1/2 mutations: 20 in the BRCA1 gene and 12 in the BRCA2 gene, including four different large genomic rearrangements in the BRCA1 gene. In all, 10 novel BRCA1/2 mutations were found. Nine different recurrent BRCA1 mutations and two recurrent BRCA2 mutations were identified, which comprised 90.4% of all BRCA1/2 mutations. BRCA1 exon 1–3 deletion and BRCA2 c.658_659del are reported for the first time as recurrent mutations, pointing to a possible Baltic founder effect. Approximately 7% of breast cancer and 22% of ovarian cancer patients without family history and an estimated 0.5–0.6% of all Lithuanian women were found to be carriers of mutations in the BRCA1 or BRCA2 gene.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Cancer Genetics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Balmana J.
        • Diez O.
        • Castiglione M.
        BRCA in breast cancer: ESMO clinical recommendations.
        Ann Oncol. 2009; 20: 19-20
        • Kurian A.W.
        • Sigal B.M.
        • Plevritis S.K.
        Survival analysis of cancer risk reduction strategies for BRCA1/2 mutation carriers.
        J Clin Oncol. 2010; 28: 222-231
        • Trainer A.H.
        • Meiser B.
        • Watts K.
        • et al.
        Moving toward personalized medicine: treatment-focused genetic testing of women newly diagnosed with ovarian cancer.
        Int J Gynecol Cancer. 2010; 20: 704-716
        • Trainer A.H.
        • Lewis C.R.
        • Tucker K.
        • et al.
        The role of BRCA mutation testing in determining breast cancer therapy.
        Nat Rev Clin Oncol. 2010; 7: 708-717
        • Nathanson K.L.
        • Domchek S.M.
        Therapeutic approaches for women predisposed to breast cancer.
        Ann Rev Med. 2011; 62: 295-306
        • Robson M.
        • Offit K.
        Clinical practice. Management of an inherited predisposition to breast cancer.
        N Engl J Med. 2007; 357: 154-162
        • De Greve J.
        • Sermijn E.
        • De Brakeleer S.
        • et al.
        Hereditary breast cancer: from bench to bedside.
        Curr Opin Oncol. 2008; 20: 605-613
        • Granader E.J.
        • Dwamena B.
        • Carlos R.C.
        MRI and mammography surveillance of women at increased risk for breast cancer: recommendations using an evidence-based approach.
        Acad Radiol. 2008; 15: 1590-1595
        • Kauff N.D.
        • Domchek S.M.
        • Friebel T.M.
        • et al.
        Risk-reducing salpingo-oophorectomy for the prevention of BRCA1− and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study.
        J Clin Oncol. 2008; 26: 1331-1337
        • Rebbeck T.R.
        • Kauff N.D.
        • Domchek S.M.
        Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers.
        J Natl Cancer Inst. 2009; 101: 80-87
        • Evans D.G.
        • Baildam A.D.
        • Anderson E.
        • et al.
        Risk reducing mastectomy: outcomes in 10 European centres.
        J Med Genet. 2009; 46: 254-258
        • Tutt A.
        • Robson M.
        • Garber J.E.
        • et al.
        Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial.
        Lancet. 2010; 376: 235-244
        • Byrski T.
        • Dent R.
        • Blecharz P.
        • et al.
        Results of a phase II open-label, non-randomized trial of cisplatin chemotherapy in patients with BRCA1-positive metastatic breast cancer.
        Breast Cancer Res. 2012; 14: R110
        • Janavičius R.
        Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control.
        EPMA J. 2010; 1: 397-412
        • Gronwald J.
        • Elsakov P.
        • Gorski B.
        • et al.
        High incidence of 4153delA BRCA1 gene mutations in Lithuanian breast- and breast-ovarian cancer families.
        Breast Cancer Res Treat. 2005; 94: 111-113
        • Janavičius R.
        • Pepalytė I.
        • Kučinskas V.
        Novel and common BRCA1 mutations in familial breast/ovarian cancer patients from Lithuania.
        Breast Cancer Res Treat. 2009; 117: 467-469
        • Elsakov P.
        • Kurtinaitis J.
        • Petraitis S.
        • et al.
        The contribution of founder mutations in BRCA1 to breast and ovarian cancer in Lithuania.
        Clin Genet. 2010; 78: 373-376
        • Csokay B.
        • Tihomirova L.
        • Stengrevics A.
        • et al.
        Strong founder effects in BRCA1 mutation carrier breast cancer patients from Latvia. Mutation in brief no. 258.
        Hum Mutat. 1999; 14: 92
        • Tikhomirova L.
        • Sinicka O.
        • Smite D.
        • et al.
        High prevalence of two BRCA1 mutations, 4154delA and 5382insC, in Latvia.
        Fam Cancer. 2005; 4: 77-84
        • Gorski 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: 1963-1968
        • Oszurek O.
        • Gorski B.
        • Gronwald J.
        • et al.
        Founder mutations in the BRCA1 gene in west Belarusian breast-ovarian cancer families.
        Clin Genet. 2001; 60: 470-471
        • Uglanitsa N.
        • Oszurek O.
        • Uglanitsa K.
        • et al.
        The contribution of founder mutations in BRCA1 to breast cancer in Belarus.
        Clin Genet. 2010; 78: 377-380
        • Sokolenko A.P.
        • Rozanov M.E.
        • Mitiushkina N.V.
        • et al.
        Founder mutations in early-onset, familial and bilateral breast cancer patients from Russia.
        Fam Cancer. 2007; 6: 281-286
        • Suspitsin E.N.
        • Sherina N.Y.
        • Ponomariova D.N.
        • et al.
        High frequency of BRCA1, but not CHEK2 or NBS1 (NBN), founder mutations in Russian ovarian cancer patients.
        Hered Cancer Clin Pract. 2009; 7: 5
        • Mavaddat N.
        • Barrowdale D.
        • Andrulis I.L.
        • et al.
        Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).
        Cancer Epidemiol Biomarkers Prev. 2012; 21: 134-147
        • De Leeneer K.
        • Coene I.
        • Poppe B.
        • et al.
        Rapid and sensitive detection of BRCA1/2 mutations in a diagnostic setting: comparison of two high-resolution melting platforms.
        Clin Chem. 2008; 54: 982-989
        • Janavicius R.
        • Rudaitis V.
        • Feng B.J.
        • et al.
        Haplotype analysis and ancient origin of the BRCA1 c.4035delA Baltic founder mutation.
        Eur J Med Genet. 2013; 56: 125-130
        • Plakhins G.
        • Irmejs A.
        • Gardovskis A.
        • et al.
        Genotype-phenotype correlations among BRCA1 4153delA and 5382insC mutation carriers from Latvia.
        BMC Med Genet. 2011; 12: 147
        • Thompson D.
        • Easton D.
        Variation in BRCA1 cancer risks by mutation position.
        Cancer Epidemiol Biomarkers Prev. 2002; 11: 329-336
        • Konstantopoulou I.
        • Rampias T.
        • Ladopoulou A.
        • et al.
        Greek BRCA1 and BRCA2 mutation spectrum: two BRCA1 mutations account for half the carriers found among high-risk breast/ovarian cancer patients.
        Breast Cancer Res Treat. 2008; 107: 431-441
        • Neuhausen S.L.
        • Mazoyer S.
        • Friedman L.
        • et al.
        Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study.
        Am J Hum Genet. 1996; 58: 271-280
        • Hamel N.
        • Feng B.J.
        • Foretova L.
        • et al.
        On the origin and diffusion of BRCA1 c.5266dupC (5382insC) in European populations.
        Eur J Hum Genet. 2010; 19: 300-306
        • Kaufman B.
        • Laitman Y.
        • Gronwald J.
        • et al.
        Haplotype of the C61G BRCA1 mutation in Polish and Jewish individuals.
        Genet Test Mol Biomarkers. 2009; 13: 465-469
        • Kucinskas L.
        • Juzenas S.
        • Sventoraityte J.
        • et al.
        Prevalence of C282Y, H63D, and S65C mutations in hereditary HFE-hemochromatosis gene in Lithuanian population.
        Ann Hematol. 2012; 91: 491-495
        • Einbeigi Z.
        • Bergman A.
        • Meis-Kindblom J.M.
        • et al.
        Occurrence of both breast and ovarian cancer in a woman is a marker for the BRCA gene mutations: a population-based study from western Sweden.
        Fam Cancer. 2007; 6: 35-41
        • Krajc M.
        • Teugels E.
        • Zgajnar J.
        • et al.
        Five recurrent BRCA1/2 mutations are responsible for cancer predisposition in the majority of Slovenian breast cancer families.
        BMC Med Genet. 2008; 9: 83
        • Wagner T.M.
        • Moslinger R.A.
        • Muhr D.
        • et al.
        BRCA1-related breast cancer in Austrian breast and ovarian cancer families: specific BRCA1 mutations and pathological characteristics.
        Int J Cancer. 1998; 77: 354-360
        • Carvalho M.A.
        • Marsillac S.M.
        • Karchin R.
        • et al.
        Determination of cancer risk associated with germ line BRCA1 missense variants by functional analysis.
        Cancer Res. 2007; 67: 1494-1501
        • Hastings V.
        • Tomiak E.
        • Smith S.
        • et al.
        BRCA1 variant of unknown significance (ACMG category 3) in 2 unrelated Polish/Ukrainian families.
        Curr Oncol. 2012; 19: e96
        • Spearman A.D.
        • Sweet K.
        • Zhou X.P.
        • et al.
        Clinically applicable models to characterize BRCA1 and BRCA2 variants of uncertain significance.
        J Clin Oncol. 2008; 26: 5393-5400
        • Spurdle A.B.
        • Lakhani S.R.
        • Healey S.
        • et al.
        Clinical classification of BRCA1 and BRCA2 DNA sequence variants: the value of cytokeratin profiles and evolutionary analysis—a report from the kConFab Investigators.
        J Clin Oncol. 2008; 26: 1657-1663
        • 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.
        Human Mutat. 2004; 23: 397-398
        • 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
        • 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: 433-437
        • Iyevleva A.G.
        • Suspitsin E.N.
        • Kroeze K.
        • et al.
        Non-founder BRCA1 mutations in Russian breast cancer patients.
        Cancer Lett. 2010; 298: 258-263
        • 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: 263-268
        • Kurian A.W.
        BRCA1 and BRCA2 mutations across race and ethnicity: distribution and clinical implications.
        Curr Opin Obstet Gynecol. 2010; 22: 72-78
        • Warner E.
        • Foulkes W.
        • Goodwin P.
        • et al.
        Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer.
        J Natl Cancer Inst. 1999; 91: 1241-1247
        • Metcalfe K.A.
        • Poll A.
        • Royer R.
        • et al.
        Screening for founder mutations in BRCA1 and BRCA2 in unselected Jewish women.
        J Clin Oncol. 2010; 28: 387-391
        • Gorski B.
        • Jakubowska A.
        • Huzarski T.
        • et al.
        A high proportion of founder BRCA1 mutations in Polish breast cancer families.
        Int J Cancer. 2004; 110: 683-686
        • Brozek I.
        • Cybulska C.
        • Ratajska M.
        • et al.
        Prevalence of the most frequent BRCA1 mutations in Polish population.
        J Appl Genet. 2011; 52: 325-330
        • Antoniou A.C.
        • Cunningham A.P.
        • Peto J.
        • et al.
        The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions.
        Br J Cancer. 2008; 98: 1457-1466
        • Weitzel J.N.
        • Lagos V.I.
        • Cullinane C.A.
        • et al.
        Limited family structure and BRCA gene mutation status in single cases of breast cancer.
        JAMA. 2007; 297: 2587-2595
      1. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian v.1.2013. Accessed October 1, 2013.