Abstract
Double heterozygosity for disease-causing BRCA1 and BRCA2 mutations is a very rare condition in most populations. Here we describe genetic and clinical data of eight female double heterozygotes (DH) for BRCA1 and BRCA2 mutations found in a cohort of 8162 German breast/ovarian cancer families and compare it with the data of their single heterozygous relatives and of the index patients of the German Consortium for Hereditary Breast and Ovarian Cancer. Furthermore, we analyze the phenotypic features of these patients with respect to age at onset of first cancer, first breast/ovarian cancer and the number of disease manifestations and compare them to that of published Caucasian female DHs and their single heterozygous female relatives. German DHs were not significantly younger at diagnosis of first breast cancer than the single heterozygous index patients of the German Consortium. However, if the data of our study were pooled with that of the literature, DHs were substantially younger at onset of first cancer (mean age 40.4 years, 95 % CI = 36.6–44.1) than their single heterozygous female relatives (mean age 51.9 years, 95 % CI = 46.8–57.0). The two groups also differed concerning the onset of first breast cancer (mean age 40.6 years, 95 % CI = 36.6–44.5 vs. 52.6, 95 % CI = 47.5–57.6). In addition, DHs had a more severe disease than their female relatives carrying a single BRCA mutation (1.4 vs. 0.6 manifestations per person). In contrast to Ashkenazi Jewish females, Caucasian DH females might develop breast cancer at an earlier age and have a more severe disease than single heterozygous BRCA mutation carriers. Therefore, DHs may benefit from more intensive surveillance programs/follow-up care and prophylactic surgery.
Similar content being viewed by others
Abbreviations
- GCHBOC:
-
German Consortium for Hereditary Breast and Ovarian Cancer
- BRCA:
-
Breast cancer gene
- CI:
-
Confidence interval (95 %)
- DH:
-
Double heterozygotes
- dh:
-
Double heterozygosity
- DHPLC:
-
High performance liquid chromatography
- MLPA:
-
Multiplex ligation-dependent probe amplification
- HGVS:
-
Human Genome Variation Society
- BIC:
-
Breast cancer information core
- LOH:
-
Loss of heterozygosity
References
Miki Y, Swensen J, Shattuck-Eidens P et al (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266:66–71
Wooster R, Bignel G, Lancaster J, Swift S, Seal S, Mangion J, Collins N (1995) Identification of the breast cancer susceptibility gene BRCA2. Nature 378:789–792
Ford D, Easton DF, Peto J (1995) Estimates of the gene frequency of BRCA1 and its contribution to breast and ovarian cancer incidence. Am J Hum Genet 57:1457–1462
Antoniou AC, Pharoah PDP, McMullan G, Day NE, Stratton MR, Peto J, Ponder BJ, Easton DF (2002) A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes. Br J Cancer 86:76–83
Hartge P, Struewing JP, Wacholder S, Brody LC, Tucker MA (1999) The prevalence of common BRCA1 and BRCA2 mutations among Ashkenazi Jews. Am J Hum Genet 64:963–970
Rennert G, Bisland-Naggan S, Bar-Joseph N (2007) Outcome of breast cancer in BRCA mutation carriers in Israel. N Engl J Med 357:115–123
Lavie O, Narod S, Lejbkowicz F, Dishon S, Goldberg Y, Gemer O, Rennert G (2011) Double heterozygosity in the BRCA1 and BRCA2 genes in the Jewish population. Ann Oncol 22:964–966
Liede A, Rehal P, Vesprini D, Jack E, Abrahamson J, Narod SA (1998) A breast cancer patient of Scottish descent with germline mutations in BRCA1 and BRCA2. Am J Hum Genet 62:1543–1544
Loader S, Rowley PT (1998) Deleterious mutations of both BRCA1 and BRCA2 in three siblings. Genet Test 2:75–77
Tsongalis GJ, Linfert DR, Johnson RC, Ackroyd R, Berman MM, Ricci A Jr (1998) Double heterozygosity for mutations in the BRCA1 and BRCA2 genes in a breast cancer patient. Arch Pathol Lab Med 122:548–550
Tesoriero A, Andersen C, Southey M, Somers G, McKay M, Armes J, McCredie M, Giles G, Hopper JL, Venter D (1999) De novo BRCA1 mutation in a patient with breast cancer and an inherited BRCA2 mutation. Am J Hum Genet 65:567–569
Caldes T, de la Hoya M, Tosar A, Sulleiro S, Godino J, Ibañez D, Martin M, Perez-Segura P, Diaz-Rubio E (2002) A breast cancer family from Spain with germline mutations in both the BRCA1 and BRCA2 genes. J Med Genet 39:e44
Cortesi L, Turchetti D, Bertoni C, Zanocco-Marani T, Vinceti M, Silvestri C, Federico M, Silingardi V, Ferrari S (2003) Italian Breast Cancer Res Treat 123 family with two independent mutations: 3358t/a in brca1 and 8756dela in brca2 genes. Eur J Hum Genet 11:210–214
Choi DH, Lee MH, Bale AE, Carter D, Haffty BG (2004) Incidence of BRCA1 and BRCA2 mutations in young Korean breast cancer patients. J Clin Oncol 22:1638–1645
Choi DH, Lee MH, Haffty BC (2006) Double heterizygotes for non-Caucasian families with mutations in BRCA1 and BRCA2 genes. Breast J 12:216–220
Claus EB, Petruzella S, Matloff E, Carter D (2005) Prevalence of BRCA1 and BRCA2 mutations in women diagnosed with ductal carcinoma in situ. JAMA 293:964–969
Leegte B, van der Hout AH, Deffenbaugh AM, Bakker MK, Mulder IM, ten Berge A, Leenders EP, Wesseling J, de Hullu J, Hoogerbrugge N, Ligtenberg MJ, Ardern-Jones A, Bancroft E, Salmon A, Barwell J, Eeles R, Oosterwijk JC (2005) Phenotypic expression of double heterozygosity for BRCA1 and BRCA2 germline mutations. J Med Genet 42:e20
Musolino A, Naldi N, Michiara M, Bella MA, Zanelli P, Bortesi B, Cappelletti M, Savi M, Neri TM, Ardizzoni A (2005) A breast cancer patient from Italy with germline mutations in both the BRCA1 and BRCA2 genes. Breast Cancer Res Treat 91:203–205
Smith M, Fawcett S, Sigalas E, Bell R, Devery S, Andrieska N, Winship I (2008) Familial breast cancer: double heterozygosity for BRCA1 and BRCA2 mutations with differing phenotypes. Fam Cancer 7:119–124
Pilato B, De Summa S, Danza K, Lambo R, Paradiso A, Tommasi S (2010) Maternal and paternal lineage double heterozygosity alteration in familial breast cancer: a first case report. Breast Cancer Res Treat 124:875–878
Zuradelli M, Peissel B, Manoukian S, Zaffaroni D, Barile M, Pensotti V, Cavallari U, Masci G, Mariette F, Benski AC, Santoro A, Radice P (2010) Four new cases of double heterozygosity for BRCA1 and BRCA2 gene mutations: clinical, pathological, and family characteristics. Breast Cancer Res Treat 124:251–258
Augustyn AM, Agostino NM, Namey TL, Nair S, Martino MA (2011) Two patients with germlline mutations in both BRCA1 and BRCA2 discovered unintentionally, a case series and discussion of BRCA testing modalities. Breast Cancer Res Treat 129:629–634
Interdisziplinare S3-Leitlinie für die Diagnostik, Therapie und Nachsorge des Mammakarzinoms (2008) http://www.awmf.org/uploads/tx_szleitlinien/032-045_01.pdf
Meindl A for the German Consortium for Hereditary Breast and Ovarian Cancer (2002) Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BCRA2 mutation profiles and frequencies for the German population. Int J Cancer 97(97):472–480
Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G (2002) Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucl Acids Res 30:e57
Neuhausen SL, Mazoyer S, Friedman L, Stratton M, Offit K, Caligo A, Tomlinson G, Cannon-Albright L, Bishop T, Kelsell D, Solomon E, Weber B, Couch F, Struewing J, Tonin P, Durocher F, Narod S, Skolnick MH, Lenoir G, Serova O, Ponder B, Stoppa-Lyonnet D, Easton D, King MC, Goldgar DE (1996) Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study. Am J Hum Genet 58:271–280
HGVS guidelines. http://www.hgvs.org/mutnomen
Craddock JM, Flood CR (1970) The distribution of Chi-squared statistic in small contingency tables. Appl Stat 19:173–181
Chen J, Silver DP, Walpita D, Cantor SB, Gazdar AF, Tomlinson G, Couch FJ, Weber BL, Ashley T, Livingston DM, Scully R (1998) Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells. Mol Cell 3:317–328
Liu Y, West SC (2002) Distinct functions of BRCA1 and BRCA2 in double-strand break repair. Breast Cancer Res 4:9–13
Gershoni-Baruch R, Dagan E, Kepten I, Freid G (1997) Cosegregation of BRCA1 185delAG mutation and BRCA2 6174delT in one single family. Eur J Cancer 33:2283–2284
Myriad Genetics Laboratories, Inc. Services and Price List. April 2010
Acknowledgments
We thank the German Consortium for Hereditary Breast and Ovarian Cancer (GCHBOC) for providing genetic data of the German index patients. The establishment of the German Consortium for Hereditary Breast and Ovarian Cancer (GCHBOC) was made possible by various grants of the German Cancer Aid (Grants no. 70-2006; 70-3268; 70-3277). We thank Meike Kreikemeier, Birgit Teegen, and Doris Karow for excellent technical assistance, Renate Hamann and Elke Janne for excellent patient’s care and Manuela Arnold for careful data documentation. Most of all we thank the patients and their families for their cooperation.
Declaration
This study complies with the current laws of the Federal Republic of Germany.
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Additional information
This study is conducted on behalf of the German Consortium for Hereditary Breast and Ovarian Cancer (GCHBOC).
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Heidemann, S., Fischer, C., Engel, C. et al. Double heterozygosity for mutations in BRCA1 and BRCA2 in German breast cancer patients: implications on test strategies and clinical management. Breast Cancer Res Treat 134, 1229–1239 (2012). https://doi.org/10.1007/s10549-012-2050-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-012-2050-4