Abstract
Purpose
Testing for BRCA1 and BRCA2 mutations in breast cancer patients is used to identify the risk of second primary cancers and the risk of cancer in the patients’ family. Women with triple-negative breast cancer (TNBC) are thought to be more likely to be BRCA1/2 mutation carriers, but most national guidelines for genetic testing, including those used in Germany and Austria, do not consider receptor triple negativity.
Methods
We determined the prevalence of BRCA1 and BRCA2 mutations within a cohort of 100 unselected TNBC cases, including patients from Germany and Austria to identify those BRCA-positive patients with a masked family history and who would have been missed due to respective current national guidelines. Double-stranded Sanger sequencing of all exons of BRCA1 and BRCA2, respectively, was performed.
Results
We identified a total of 13 deleterious mutations in BRCA1 and a total of four deleterious mutations in BRCA2. The total rate of deleterious BRCA1/2 mutation carriers was 21 % in our cohort. Six novel mutations, including two deleterious mutations, have been identified, which have not been described in public mutation databases so far. According to current German and Austrian national guidelines for genetic testing, 38.1 and 52.4 %, respectively, of BRCA1/2 mutation carriers would have been overlooked.
Conclusions
We conclude that the prevalence of BRCA1 and BRCA2 mutations is high in TNBC patients and that BRCA1/2 mutations are not restricted to young women or patients with a positive family history. Receptor triple negativity should therefore be considered in BRCA1/2 genetic testing guidelines.
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References
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249
Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, Loman N, Olsson H, Johannsson O, Borg A, Pasini B, Radice P, Manoukian S, Eccles DM, Tang N, Olah E, Anton-Culver H, Warner E, Lubinski J, Gronwald J, Gorski B, Tulinius H, Thorlacius S, Eerola H, Nevanlinna H, Syrjakoski K, Kallioniemi OP, Thompson D, Evans C, Peto J, Lalloo F, Evans DG, Easton DF (2003) 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 72:1117–1130
Atchley DP, Albarracin CT, Lopez A, Valero V, Amos CI, Gonzalez-Angulo AM, Hortobagyi GN, Arun BK (2008) Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol 26:4282–4288
Balmana J, Diez O, Rubio IT, Cardoso F (2011) BRCA in breast cancer: ESMO clinical practice guidelines. Ann Oncol 22(Suppl 6):vi31–vi34
Comen E, Davids M, Kirchhoff T, Hudis C, Offit K, Robson M (2011) Relative contributions of BRCA1 and BRCA2 mutations to “triple-negative” breast cancer in Ashkenazi Women. Breast Cancer Res Treat 129:185–190
Couch FJ, Hart SN, Sharma P, Toland AE, Wang X, Miron P, Olson JE, Godwin AK, Pankratz VS, Olswold C, Slettedahl S, Hallberg E, Guidugli L, Davila JI, Beckmann MW, Janni W, Rack B, Ekici AB, Slamon DJ, Konstantopoulou I, Fostira F, Vratimos A, Fountzilas G, Pelttari LM, Tapper WJ, Durcan L, Cross SS, Pilarski R, Shapiro CL, Klemp J, Yao S, Garber J, Cox A, Brauch H, Ambrosone C, Nevanlinna H, Yannoukakos D, Slager SL, Vachon CM, Eccles DM, Fasching PA (2014) Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol 33:304–311
Daly MB, Pilarski R, Axilbund JE, Buys SS, Crawford B, Friedman S, Garber JE, Horton C, Kaklamani V, Klein C, Kohlmann W, Kurian A, Litton J, Madlensky L, Marcom PK, Merajver SD, Offit K, Pal T, Pasche B, Reiser G, Shannon KM, Swisher E, Voian NC, Weitzel JN, Whelan A, Wiesner GL, Dwyer MA, Kumar R (2014) Genetic/familial high-risk assessment: breast and ovarian, version 1. 2014. J Natl Compr Cancer Netw 12:1326–1338
Desmet FO, Hamroun D, Lalande M, Collod-Beroud G, Claustres M, Beroud C (2009) Human splicing finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 37:e67
Edge SB, Byrd DR, Compton CC (2009) AJCC cancer staging manual, 7th edn. Springer, Chicago
Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O’Connor MJ, Ashworth A, Carmichael J, Kaye SB, Schellens JH, de Bono JS (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361:123–134
Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE (1994) Risks of cancer in BRCA1-mutation carriers. Breast cancer linkage consortium. Lancet 343:692–695
Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop DT, Weber B, Lenoir G, Chang-Claude J, Sobol H, Teare MD, Struewing J, Arason A, Scherneck S, Peto J, Rebbeck TR, Tonin P, Neuhausen S, Barkardottir R, Eyfjord J, Lynch H, Ponder BA, Gayther SA, Zelada-Hedman M (1998) Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The breast cancer linkage consortium. Am J Hum Genet 62:676–689
Foulkes WD, Shuen AY (2013) In brief: BRCA1 and BRCA2. J Pathol 230:347–349
Foulkes WD, Smith IE, Reis-Filho JS (2010) Triple-negative breast cancer. N Engl J Med 363:1938–1948
Gadzicki D, Evans DG, Harris H, Julian-Reynier C, Nippert I, Schmidtke J, Tibben A, van Asperen CJ, Schlegelberger B (2011) Genetic testing for familial/hereditary breast cancer—comparison of guidelines and recommendations from the UK, France, the Netherlands and Germany. J Community Genet 2:53–69
Gonzalez-Angulo AM, Timms KM, Liu S, Chen H, Litton JK, Potter J, Lanchbury JS, Stemke-Hale K, Hennessy BT, Arun BK, Hortobagyi GN, Do KA, Mills GB, Meric-Bernstam F (2011) Incidence and outcome of BRCA mutations in unselected patients with triple receptor-negative breast cancer. Clin Cancer Res 17:1082–1089
Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, Miller K, Osborne CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FC, Taube S, Torlakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams RB, Wittliff JL, Wolff AC (2010) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 28:2784–2795
Hartman AR, Kaldate RR, Sailer LM, Painter L, Grier CE, Endsley RR, Griffin M, Hamilton SA, Frye CA, Silberman MA, Wenstrup RJ, Sandbach JF (2012) Prevalence of BRCA mutations in an unselected population of triple-negative breast cancer. Cancer 118:2787–2795
Irvin WJ Jr, Carey LA (2008) What is triple-negative breast cancer? Eur J Cancer 44:2799–2805
Karchin R, Agarwal M, Sali A, Couch F, Beattie MS (2008) Classifying variants of undetermined significance in BRCA2 with protein likelihood ratios. Cancer Inform 6:203–216
King MC, Marks JH, Mandell JB (2003) Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302:643–646
Knies K, Schuster B, Ameziane N, Rooimans M, Bettecken T, de Winter J, Schindler D (2012) Genotyping of fanconi anemia patients by whole exome sequencing: advantages and challenges. PLoS One 7:e52648
Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073–1081
Mayer IA, Abramson VG, Lehmann BD, Pietenpol JA (2014) New strategies for triple-negative breast cancer–deciphering the heterogeneity. Clin Cancer Res 20:782–790
Meindl A (2002) Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population. Int J Cancer 97:472–480
Mersch J, Jackson MA, Park M, Nebgen D, Peterson SK, Singletary C, Arun BK, Litton JK (2015) Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian. Cancer 121:269–275
Meyer P, Landgraf K, Hogel B, Eiermann W, Ataseven B (2012) BRCA2 mutations and triple-negative breast cancer. PLoS One 7:e38361
Pal SK, Childs BH, Pegram M (2011) Triple negative breast cancer: unmet medical needs. Breast Cancer Res Treat 125:627–636
Pern F, Bogdanova N, Schurmann P, Lin M, Ay A, Langer F, Hillemanns P, Christiansen H, Park-Simon TW, Dork T (2012) Mutation analysis of BRCA1, BRCA2, PALB2 and BRD7 in a hospital-based series of German patients with triple-negative breast cancer. PLoS One 7:e47993
Reese MG, Eeckman FH, Kulp D, Haussler D (1997) Improved splice site detection in Genie. J Comput Biol 4:311–323
Rummel S, Varner E, Shriver CD, Ellsworth RE (2013) Evaluation of BRCA1 mutations in an unselected patient population with triple-negative breast cancer. Breast Cancer Res Treat 137:119–125
Singer CF, Tea MK, Pristauz G, Hubalek M, Rappaport C, Riedl C, Helbich T (2012) Guideline for the prevention and early detection of breast and ovarian cancer in high risk patients, particularly in women from HBOC (hereditary breast and ovarian cancer) families. Wien Klin Wochenschr 124:334–339
Stegel V, Krajc M, Zgajnar J, Teugels E, De Greve J, Hocevar M, Novakovic S (2011) The occurrence of germline BRCA1 and BRCA2 sequence alterations in Slovenian population. BMC Med Genet 12:9
Telli M (2014) Optimizing chemotherapy in triple-negative breast cancer: the role of platinum. Am Soc Clin Oncol Educ Book. e37–e42
Tun NM, Villani G, Ong K, Yoe L, Bo ZM (2014) Risk of having BRCA1 mutation in high-risk women with triple-negative breast cancer: a meta-analysis. Clin Genet 85:43–48
Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, McShane LM, Paik S, Pegram MD, Perez EA, Press MF, Rhodes A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M, Wheeler TM, Hayes DF (2007) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25:118–145
Wong-Brown MW, Meldrum CJ, Carpenter JE, Clarke CL, Narod SA, Jakubowska A, Rudnicka H, Lubinski J, Scott RJ (2015) Prevalence of BRCA1 and BRCA2 germline mutations in patients with triple-negative breast cancer. Breast Cancer Res Treat 150:71–80
Acknowledgments
We are grateful to Mag. Gabriela Dür and the Vorarlberger Landesregierung (Bregenz, Austria), to Franz Rauch and the Vorarlberger Industriellenvereinigung (Bregenz, Austria), to Dr. Peter Woess and the Vorarlberger Aerztekammer (Dornbirn, Austria), as well as to Dr. Peter Fraunberger and the Institute for Clinical Chemistry at the Academic Teaching Hospital Feldkirch (Feldkirch, Austria) for continuously supporting our research institute. The present study was partly financed by the European Union’s European Regional Development Fund through the INTERREG IV Programme “Alpenrhein-Bodensee-Hochrhein,” Project Number: 179.
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The authors declare that they have no conflicts of interest.
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All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.
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Informed consent was obtained from all individual participants included in the study.
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Axel Muendlein and Bettina H. Rohde are first authors and have contributed equally to this article.
Thomas Decker and Alois H. Lang are senior authors and have contributed equally to this article.
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Muendlein, A., Rohde, B.H., Gasser, K. et al. Evaluation of BRCA1/2 mutational status among German and Austrian women with triple-negative breast cancer. J Cancer Res Clin Oncol 141, 2005–2012 (2015). https://doi.org/10.1007/s00432-015-1986-2
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DOI: https://doi.org/10.1007/s00432-015-1986-2