Advertisement

Clinicopathologic features and genetic characteristics of the BRCA1/2 mutation in Turkish breast cancer patients

      Highlights

      • The BRCA1/2 mutations were evaluated with clinicopathological features and genetic characteristics in 603 Turkish breast cancer patients.
      • The c.5266dupC mutation is one of the most frequently reported mutations in BRCA1 and the most common BRCA2 gene mutations in the present study were c.8940delA and c.9097dupA.
      • The variants based on classification categories identified in our cohort, 14 variants seem to be unique to the Turkish population.
      • Additionally, among the cases screened for BRCA1/2, 7 variants were detected with uncertain significance.
      • These results could contribute to management of the breast cancer patients.

      Abstract

      The aim of this study was to identify the frequency and spectrum of germline BRCA1/2 pathogenic alterations in a cohort of patients with breast carcinoma. In this study, a total of 603 breast cancer subjects from Turkey were screened for BRCA1/BRCA2 mutations using HDA and Sanger sequencing. In the present study, 21 BRCA1 and BRCA2 pathogenic variants were detected in 30 patients and BRCA1/2 mutations were significantly associated with a family history of breast/ovarian cancer. Analysis of overall survival for BRCA1/BRCA2 mutation carriers showed a trend for poor overall survival only in BRCA1 carriers, although this was not statistically significant in BRCA1 and BRCA2 mutation carriers. The c.5266dupC mutation is one of the most frequently reported mutations in BRCA1 and was identified in five breast cancer patients in our study. The most common BRCA2 gene mutations in the present study were c.8940delA and c.9097dupA, which were found in seven patients. We found mostly BRCA1 and BRCA2 mutation carriers in those patients who showed hormone-positive features. In conclusion, our data showed differences in the distribution of the mutation spectrum of BRCA1 and BRCA2 in Turkey.

      Keywords

      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:

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

      References

        • Ferlay J.
        • Soerjomataram I.
        • Dikshit R.
        • et al.
        Cancer incidence and mortality worldwide: sources, methods and major patterns in globocan.
        Int J Cancer J Int du Cancer. 2012; 136 (2015): E359-E386
        • Ly D.
        • Forman D.
        • Ferlay J.
        • Brinton L.A.
        • Cook M.B
        An international comparison of male and female breast cancer incidence rates.
        Int J Cancer. 2013; 132: 1918-1926
        • Neilson H.K.
        • Farris M.S.
        • Stone C.R.
        • et al.
        Moderate-vigorous recreational physical activity and breast cancer risk, stratified by menopause status: a systematic review and meta-analysis.
        Menopause. 2017; 24 (Mar): 322-344
        • Monninkhof E.M.
        • Elias S.G.
        • Vlems F.A.
        • et al.
        TFPAC physical activity and breast cancer: a systematic review.
        Epidemiology. 2007; 18: 137-157
        • Carmichael A.R.
        • Bates T
        Obesity and breast cancer: a review of the literature.
        Breast. 2004; 3: 85-92
        • Wang J.
        • Yang D.L.
        • Chen Z.Z.
        • Gou B.F
        Associations of body mass index with cancer incidence among populations, genders, and menopausal status: a systematic review and meta-analysis.
        Cancer Epidemiol. 2016; 42: 1-8
        • Cao W.M.
        • Gao Y.
        • Yang H.J.
        • et al.
        Novel germline mutations and unclassified variants of BRCA1 and BRCA2 genes in chinese women with familial breast/ovarian cancer.
        BMC Cancer BMC Cancer. 2016; 16: 64
        • Kuusisto K.M.
        • Bebel A.
        • Vihinen M.
        • et al.
        Screening for BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1 mutations in highrisk finnish BRCA1/2-founder mutation-negative breast and/or ovarian cancer individuals.
        Breast Cancer Res. 2011; 13: R20
        • Rashid M.U.
        • Muhammad N.
        • Faisal S.
        • et al.
        Constitutional CHEK2 mutations are infrequent in early-onset and familial breast/ovarian cancer patients from Pakistan.
        BMC Cancer. 2013; 13: 312
        • Rashid M.U.
        • Muhammad N.
        • Faisal S.
        • et al.
        Deleterious rad51c germline mutations rarely predispose to breast and ovarian cancer in Pakistan.
        Breast Cancer Res Treat. 2014; 145: 775-784
        • Koumpis C.
        • Dimitrakakis C.
        • Antsaklis A.
        • et al.
        Prevalence of BRCA1 and BRCA2 mutations in unselected breast cancer patients from Greece.
        Hered Cancer Clin Pract. 2011; 9: 10
        • Scully R.
        • Ganesan S.
        • Vlasakova K.
        • et al.
        Genetic analysis of BRCA1 function in a defined tumor cell line.
        Mol Cell. 1999; 4: 1093-1099
        • Chen S.
        • Parmigiani G.
        Meta-analysis of BRCA1 and BRCA2 penetrance.
        J Clin Oncol. 2007; 25: 1329e33
        • Levy-Lahad E.
        • Friedman E.
        Cancer risks among BRCA1 and BRCA2 mutation carriers.
        Br J Cancer. 2007; 96: 11-15
        • Ferrone C.R.
        • Levine D.A.
        • Tang L.H.
        • et al.
        BRCA germline mutations in jewish patients with pancreatic adenocarcinoma.
        J Clin Oncol. 2009; 27: 433-438
        • Bolf E.L.
        • Sprague B.L.
        • Carr F.E
        A linkage between thyroid and breast cancer: a common etiology?.
        Cancer Epidemiol Biomarkers Prev. 2019; 28: 643-649
        • Mehta A.
        • Vasudevan S.
        • Sharma S.K.
        • et al.
        Germline BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance associated with breast/ovarian cancer: a report from North India.
        Cancer Manag Res. 2018; 10: 6505-6516
        • Roy R.
        • Chun J.
        • Powell S.N
        BRCA1 and BRCA2: different roles in a common pathway of genome protection.
        Nat Rev Cancer. 2012; 12: 68-78
        • Niravath P.
        • Cakar B.
        • Ellis M
        The role of genetic testing in the selection of therapy for breast cancer: a review.
        JAMA Oncol. 2017; 3: 262-268
        • AlHilli M.M.
        • Al-Hilli Z.
        Perioperative management of women undergoing risk-reducing surgery for hereditary breast and ovarian cancer.
        J Minim Invasive Gynecol. 2019; 26: 253-265
      1. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN guidelines) genetic/familial high-risk assessment: breast and ovarian. Available at:https://www.nccn.org/professionals/physiciangls/pdf/genetics_screening.pdf. Accessed March 10, 2017.

        • Weigelt B.
        • Comino-Méndez I.
        • Bruijn I.
        • et al.
        Diverse BRCA1 and BRCA2 reversion mutations in circulating cell-free dna of therapy-resistant breast or ovarian cancer.
        Clin Cancer Res. 2017; 23: 6708-6720
        • Lagos-Jaramillo V.I.
        • Press M.F.
        • Ricker C.N.
        • et al.
        Pathological characteristics of BRCA-associated breast cancers in hispanics.
        Breast Cancer Res Treat. 2011; 130: 281-289
        • M1 Wu
        • C Mao
        • Chen Q.
        • et al.
        Serum p53 protein and anti-p53 antibodies are associated with increased cancer risk: a case-control study of 569 patients and 879 healthy controls.
        Mol Biol Rep. 2010; 37: 339-343
        • Evans D.G.
        • Lalloo F.
        • Howell S.
        • et al.
        Low prevalence of HER2 positivity amongst BRCA1 and BRCA2 mutation carriers and in primary BRCA screens.
        Breast Cancer Res Treat. 2016; 155: 597-601
        • Comen E.
        • Davids M.
        • Kirchhoff T.
        • et al.
        Relative contributions of BRCA1 and BRCA2 mutations to “triple-negative” breast cancer in ashkenazi women.
        Breast Cancer Res Treat. 2011; 129: 185-190
        • Chen H.
        • Wu J.
        • Zhang Z.
        • et al.
        Association between brca status and triple-negative breast cancer: a meta-analysis.
        Front Pharmacol. 2018; 9: 909
        • Siegel R.L.
        • Miller K.D.
        • Jemal A
        Cancer statistics.
        CA Cancer J Clin. 2017; 67: 7-30
        • Ferlay J.
        • Soerjomataram I.
        • Ervik M.
        • Dikshit R.
        • Eser S.
        • Mathers C.
        • et al.
        GLOBOCAN.
        Int J Cancer. 2012; 136 (2015): E359-E3586
        • F1 Girardi
        • DR1 Barnes
        • D1 Barrowdale
        • et al.
        Risks of breast or ovarian cancer in BRCA1 or BRCA2 predictive test negatives: findings from the embrace study.
        Genet Med. 2018; 22: 1575-1582
        • Egeli U.
        • Cecener G.
        • Tunca B.
        • Tasdelen I
        Novel germline BRCA1 and BRCA2 mutations in turkish women with breast and/or ovarian cancer and their relatives.
        Cancer Invest. 2006; 24: 484-491
        • Claus E.B.
        • Schildkraut J.M.
        • Thompson W.D.
        • Risch N.J
        The genetic attributable risk of breast and ovarian cancer.
        Cancer. 1996; 77: 2318-2324
        • Lebo M.S.
        • Zakoor K.R.
        • Chun K.
        • et al.
        Canadian open genetics repository working group. data sharing as a national quality improvement program: reporting on BRCA1 and BRCA2 variant-interpretation comparisons through the canadian open genetics repository (COGR).
        Genet Med. 2018; 20: 294-302
      2. NCCN Guidelines Version 1. 2018Genetic/Familial high-risk assessment: Breast and ovarian. https://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf. Accessed online 11/17/17.

        • Antoniou A.
        • Pharoah P.D.
        • 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: 1117e1130
        • 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. 2011; 19: 300-306
        • Burcoş T.
        • Cimponeriu D.
        • Ion D.A.
        • et al.
        Analysis of several BRCA1 and BRCA2 mutations in a hospital-based series of unselected breast cancer cases.
        Chirurgia (Bucur). 2013; 108: 468-472
        • Hartwig M.
        • Janiszewska H.
        • Bąk A.
        • et al.
        Prevalence of the BRCA1 c.68_69delAG (BIC: 185delAG) mutation in women with breast cancer from north-central Poland and a review of the literature on other regions of the country.
        Contemp Oncol (Pozn). 2013; 17: 34-37
        • L1 Negura
        • N Uhrhammer
        • Negura A.
        • et al.
        Complete brca mutation screening in breast and ovarian cancer predisposition families from a North-Eastern Romanian population.
        Fam Cancer. 2010; 9: 519-523
        • 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. 2011; 19: 300-306
        • 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: 1640-1646
        • Younes N.
        • Zayed H.
        Genetic epidemiology of ovarian cancer in the 22 arab countries: a systematic review.
        Gene. 2019; 684: 154-164
        • Wojcik P.
        • Jasiowka M.
        • Strycharz E.
        • et al.
        Recurrent mutations of BRCA1, BRCA2 and PALB2 in the population of breast and ovarian cancer patients in Southern Poland.
        Hered Cancer Clin Pract. 2016; 14: 5
        • Janavičius R.
        Founder BRCA1/2 mutations in europe: implications for hereditary breast–ovarian cancer prevention and control.
        EPMA J. 2010; 1: 397-412
        • Alyahri N.
        • Abdi S.
        • Khan W.
        • et al.
        Novel associations between BRCA1 variants C.181 t>g (Rs28897672) and ovarian crisk in saudi females.
        J Med Biochem. 2019; 38: 13-21
        • Goidescu I.G.
        • Caracostea G.
        • Eniu D.T.
        • Stamatian F.V
        Prevalence of deleterious mutations among patients with breast cancer referred for multigene panel testing in a romanian population.
        Clujul Med. 2018; 91: 157-165
      3. Goidescu I., Eniu D.T., Caracostea G., Cruciat Gh, Stamatian F. Associations of pathogenic mutations responsible for breast cancer risk with histology and immunohistochemistry in Romanian population2018; 26: 165–176.

        • Brose M.S.
        • Volpe P.
        • Paul K.
        • et al.
        Characterization of two novel BRCA1 germ-line mutations involving splice donor sites.
        Genet Test. 2004; 8: 133-138
        • Li M.
        • Zhang J.
        • Ouyang T.
        • et al.
        Incidence of BRCA1 somatic mutations and response to neoadjuvant chemotherapy in chinese women with triple-negative breast cancer.
        Gene. 2016; 584: 26-30
        • Apessos A.
        • Agiannitopoulos K.
        • Pepe G.
        • et al.
        Comprehensive brca mutation analysis in the greek population. Experience from a single clinical diagnostic center.
        Cancer Genet. 2018; 220: 1-12
        • Trujillano D.
        • Weiss M.E.
        • Schneider J.
        • et al.
        Next-generation sequencing of the BRCA1 and BRCA2 genes for the genetic diagnostics of hereditary breast and/or ovarian cancer.
        J Mol Diagn. 2015; 17: 162-170
        • Sharon E.
        • Plon Diana M.
        • Eccles Douglas E.
        • et al.
        Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results.
        Hum Mutat. 2008; 29: 1282-1291
        • Golmard L.
        • Delnatte C.
        • Laugé A.
        • et al.
        Breast and ovarian cancer predisposition due to de novo BRCA1 and BRCA2 mutations.
        Oncogene. 2016; 35: 1324-1327
        • Jara L.
        • Morales S.
        • de Mayo T.
        • et al.
        Mutations in BRCA1, BRCA2 and other breast and ovarian cancer susceptibility genes in central and south american populations.
        Biol Res. 2017; 50: 35
        • Janavičius R.
        Founder BRCA1/2 mutations in the europe: implications for hereditary breast-ovarian cancer prevention and control.
        EPMA J. 2010; 1: 397-412
        • Dodova R.I.
        • Mitkova A.V.
        • Dacheva D.R.
        • et al.
        Spectrum and frequencies of BRCA1/2 mutations in bulgarian high risk breast cancer patients.
        BMC Cancer. 2015; 15: 523
        • Walsh E.R.
        • Pisitkun P.
        • Voynova E.
        • et al.
        Dual signaling by innate and adaptive immune receptors is required for TLR7-induced B-cell-mediated autoimmunity.
        in: Proceedings of the national academy of sciences of the United States of America. 109. 2012: 16276-16281
        • Weitzel J.N.
        • Blazer K.R.
        • MacDonald D.J.
        • et al.
        Genetics, genomics and cancer risk assessment: state of the art and future directions in the era of personalized medicine.
        CA Cancer J Clin. 2011; 61: 327-359
        • Vears D.F.
        • Niemiec E.
        • Howard H.C.
        • Borry P
        Analysis of vus reporting, variant reinterpretation and recontact policies in clinical genomic sequencing consent forms.
        Eur J Hum Genet. 2018; 26: 1743-1751
        • Plon S.E.
        • Eccles D.M.
        • Easton D.
        • et al.
        Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results.
        Hum Mutat. 2008; 29: 1282-1291
        • Calo V.
        • Bruno L.
        • La Paglia L.
        • et al.
        The clinical significance of unknown sequence variants in brca genes.
        Cancers. 2010; 2: 1644-1660
        • Plon S.E.
        • Eccles D.M.
        • Easton D.
        • et al.
        Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results.
        Hum Mutat. 2008; 29: 1282-1291
        • Yang S.
        • Cline M.
        • Zhang C.
        • et al.
        Data sharing and reproducible clinical genetic testing: Successes and challenges.
        Pac Symp Biocomput. 2016; 22: 166-176
        • Palmero E.I.
        • Alemar B.
        • Schüler-Faccini L.
        • et al.
        Screening for germline BRCA1, BRCA2, TP53 and CHEK2 mutations in families at-risk for hereditary breast cancer identified in a population-based study from southern brazil.
        Genet Mol Biol. 2017; 40: 552
        • Manguoğlu E.
        • Güran S.
        • Yamaç D.
        • et al.
        Germline mutations of BRCA1 and BRCA2 genes in turkish breast, ovarian, and prostate cancer patients.
        Cancer Genet Cytogenet. 2010; 203: 230-237
        • Aydin F.
        • Akagun T.
        • Yildiz B.
        • Fidan E.
        • Ozdemir F.
        • Kavgaci H
        Clinicopathologic characteristics and BRCA-1/BRCA-2 mutations of Turkish patients with breast cancer.
        Bratisl Lek Listy. 2011; 112: 521-523
        • Cecener G.
        • Egeli U.
        • Tunca B.
        • et al.
        BRCA1/2 germline mutations and their clinical importance in turkish breast cancer patients.
        Cancer Invest. 2014; 32: 375-387
        • Yazıcı H.
        • Kılıc S.
        • Akdeniz D.
        • et al.
        Frequency of rearrangements versus small indels mutations in BRCA1 and BRCA2 genes in turkish patients with high risk breast and ovarian cancer.
        Eur J Breast Health. 2018; 14: 93-99
        • Geredeli C.
        • Yasar N.
        • Sakin A
        Germline mutations in BRCA1 and BRCA2 in breast cancer patients with high genetic risk in turkish population.
        Int J Breast Cancer. 2019; 20199645147
        • Friedenson B.
        The BRCA1/2 pathway prevents hematologic cancers in addition to breast and ovarian cancers.
        BMC Cancer. 2007; 7: 152
        • Kang E.
        • Seong M.W.
        • Park S.K.
        • et al.
        Korean hereditary breast cancer study group. the prevalence and spectrum of BRCA1 and BRCA2 mutations in korean population: recent update of the korean hereditary breast cancer (KOHBRA) study.
        Breast Cancer Res Treat. 2015; 151: 157-168
        • Lalloo F.
        • Varley J.
        • Ellis D.
        • et al.
        Early onset breast cancer study group. prediction of pathogenic mutations in patients with early-onset breast cancer by family history.
        Lancet. 2003; 361: 1101-1102
        • Malone K.E.
        • Daling J.R.
        • Neal C.
        • Suter N.M.
        • et al.
        Frequency of BRCA1/BRCA2 mutations in a population-based sample of young breast carcinoma cases.
        Cancer. 2000; 88: 1393-1402
        • Young S.R.
        • Pilarski R.T.
        • Donenberg T.
        • et al.
        The prevalence of BRCA1 mutations among young women with triple-negative breast cancer.
        BMC Cancer. 2009; 9: 86
        • Schwartz M.D.
        • Lerman C.
        • Brogan B.
        • et al.
        Impact of BRCA1/BRCA2 counseling and testing on newly diagnosed breast cancer patients.
        J Clin Oncol. 2004; 22: 1823-1829
        • Torres D.
        • Lorenzo Bermejo J.
        • Rashid M.U.
        • et al.
        Prevalence and penetrance of BRCA1 and BRCA2 germline mutations in colombian breast cancer patients.
        Sci Rep. 2017; 7: 4713
        • Elizabeth Gilbert B.A.
        • Emily Zabor M.S.
        • Michelle Stempel M.P.H.
        • et al.
        Differences among a modern cohort of brca mutation carriers choosing bilateral prophylactic mastectomies compared to breast surveillance.
        Ann Surg Oncol. 2017; 24: 3048-3054
        • Sambiasi D
        • Lambo R.
        • Pilato B.
        • et al.
        BRCA1/2 and clinical outcome in a monoinstitutional cohort of women with hereditary breast cancer.
        Oncol Rep. 2017; 31: 365-369
        • Kirova Y.M.
        • Stoppa-Lyonnet D.
        • Savignoni A.
        • et al.
        Institut curie breast cancer study group. risk of breast cancer recurrence and contralateral breast cancer in relation to BRCA1 and BRCA2 mutation status following breast-conserving surgery and radiotherapy.
        Eur J Cancer. 2005; 41: 2304-2311
        • Brekelmans C.T.
        • Tilanus-Linthorst M.M.
        • Seynaeve C.
        • et al.
        Tumor characteristics, survival and prognostic factors of hereditary breast cancer from BRCA2-, BRCA1- and non-BRCA1/2 families as compared to sporadic breast cancer cases.
        Eur J Cancer. 2007; 43: 867-876
        • Young S.R.
        • Pilarski R.T.
        • Donenberg T.
        • et al.
        The prevalence of BRCA1 mutations among young women with triple-negative breast cancer.
        BMC Cancer. 2009; 9: 86
        • Krammer J.
        • Pinker-Domenig K.
        • Robson M.E.
        • et al.
        Breast cancer detection and tumor characteristics in BRCA1 and BRCA2 mutation carriers.
        Breast Cancer Res Treat. 2017; 163: 565-571
        • Gevensleben H.
        • Bossung V.
        • Meindl A.
        • Wappenschmidt B.
        • et al.
        Pathological features of breast and ovarian cancers in rad51c germline mutation carriers.
        Virchows Arch. 2014; 465: 365-369
        • Lagos-Jaramillo V.I.
        • Press M.F.
        • Ricker C.N.
        • et al.
        Pathological characteristics of BRCA-associated breast cancers in hispanics.
        Breast Cancer Res Treat. 2011; 130: 281-289