Breast Cancer Research and Treatment

, Volume 131, Issue 1, pp 217–222 | Cite as

Characteristics of double heterozygosity for BRCA1 and BRCA2 germline mutations in Korean breast cancer patients

  • Jae Myoung Noh
  • Doo Ho Choi
  • Seok Jin Nam
  • Jeong Eon Lee
  • Jong Won Kim
  • Sung-Won Kim
  • Eunyoung Kang
  • Min Hyuk Lee
  • Sei Hyun Ahn
  • Ku Sang Kim
  • Sue K. Park
  • Bruce G. Haffty
  • Korea Breast Cancer Study Group


To investigate clinical, pathological, and familial characteristics of Korean patients with double heterozygosity for BRCA1 and BRCA2 mutations, six breast tumors of five patients who carried deleterious mutations in both of the genes were included. Medical records of the patients were reviewed and genetic testing by direct sequencing was undertaken to detect mutations in BRCA1 and BRCA2. Seven frameshift and three nonsense mutations were identified, and four mutations are novel in the Breast Cancer Information Core. There were no Ashkenazi founder mutations detected. The mean age at diagnosis for breast cancer was 33 years. All six tumors were infiltrating ductal carcinoma and poorly differentiated. Pathologic stage was I or II, and immunohistochemistry showed negative immunoreactivity for estrogen receptor and Her-2/neu in all tumors. Positive immunoreactivity for progesterone receptor was found only in one tumor. Three patients had familial history of breast, ovarian or other cancers. One patient who was diagnosed for breast cancer at the age of 26 had two maternal family members of metachronous bilateral breast cancer. Another patient who experienced metachronous bilateral breast cancer had maternal history of ovarian and esophageal cancer. In summary, Korean patients with double heterozygosity for BRCA1 and BRCA2 were young at diagnosis of breast cancer. Tumors were early stage, high grade, and almost triple-negative phenotype. All familial history of breast, ovary or other cancer was maternal. Close surveillance and accurate risk assessment should be provided for the patients with mutations in the both of the genes.


Breast cancer BRCA1 gene BRCA2 gene Heterozygote 



This study was partly supported by a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare, and Family Affairs, Republic of Korea (#1020350).

Conflict of interest



  1. 1.
    Ahn SH, Yoo KY (2006) Chronological changes of clinical characteristics in 31, 115 new breast cancer patients among Koreans during 1996–2004. Breast Cancer Res Treat 99:209–214. doi: 10.1007/s10549-006-9188-x PubMedCrossRefGoogle Scholar
  2. 2.
    Ko SS (2008) Chronological changing patterns of clinical characteristics of Korean breast cancer patients during 10 years (1996–2006) using nationwide breast cancer registration on-line program: biannual update. J Surg Oncol 98:318–323. doi: 10.1002/jso.21110 PubMedCrossRefGoogle Scholar
  3. 3.
    Son BH, Kwak BS, Kim JK, Kim HJ, Hong SJ, Lee JS, Hwang UK, Yoon HS, Ahn SH (2006) Changing patterns in the clinical characteristics of Korean patients with breast cancer during the last 15 years. Arch Surg 141:155–160. doi: 10.1001/archsurg.141.2.155 PubMedCrossRefGoogle Scholar
  4. 4.
    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 57:1457–1462PubMedGoogle Scholar
  5. 5.
    Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W et al (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266:66–71PubMedCrossRefGoogle Scholar
  6. 6.
    Robson M, Gilewski T, Haas B, Levin D, Borgen P, Rajan P, Hirschaut Y, Pressman P, Rosen PP, Lesser ML, Norton L, Offit K (1998) BRCA-associated breast cancer in young women. J Clin Oncol 16:1642–1649PubMedGoogle Scholar
  7. 7.
    Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, Collins N, Gregory S, Gumbs C, Micklem G (1995) Identification of the breast cancer susceptibility gene BRCA2. Nature 378:789–792. doi: 10.1038/378789a0 PubMedCrossRefGoogle Scholar
  8. 8.
    Oh JH, Noh DY, Choe KJ, Kang SB, Kim LS, Ro MS (1995) Germline mutation of BRCA1 gene in Korean breast and ovarian cancer patients. J Korean Cancer Ass 27:1061–1069Google Scholar
  9. 9.
    Kang HC, Kim IJ, Park JH, Kwon HJ, Won YJ, Heo SC, Lee SY, Kim KH, Shin Y, Noh DY, Yang DH, Choe KJ, Lee BH, King SB, Park JG (2002) Germline mutations of BRCA1 and BRCA2 in Korean breast and/or ovarian cancer families. Hum Mutat 20:235. doi: 10.1002/humu.9059 PubMedCrossRefGoogle Scholar
  10. 10.
    Ahn SH, Hwang UK, Kwak BS, Yoon HS, Ku BK, Kang HJ, Kim JS, Ko BK, Ko CD, Yoon KS, Cho DY, Son BH (2004) Prevalence of BRCA1 and BRCA2 mutations in Korean breast cancer patients. J Korean Med Sci 19:269–274PubMedCrossRefGoogle Scholar
  11. 11.
    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. doi: 10.1200/JCO.2004.04.179 PubMedCrossRefGoogle Scholar
  12. 12.
    Seo JH, Cho DY, Ahn SH, Yoon KS, Kang CS, Cho HM, Lee HS, Choe JJ, Choi CW, Kim BS, Shin SW, Kim YH, Kim JS, Son GS, Lee JB, Koo BH (2004) BRCA1 and BRCA2 germline mutations in Korean patients with sporadic breast cancer. Hum Mutat 24:350. doi: 10.1002/humu.9275 PubMedCrossRefGoogle Scholar
  13. 13.
    Han SH, Lee KR, Lee DG, Kim BY, Lee KE, Chung WS (2006) Mutation analysis of BRCA1 and BRCA2 from 793 Korean patients with sporadic breast cancer. Clin Genet 70:496–501. doi: 10.1111/j.1399-0004.2006.00717.x PubMedCrossRefGoogle Scholar
  14. 14.
    Ahn SH, Son BH, Yoon KS, Noh DY, Han W, Kim SW, Lee ES, Park HL, Hong YJ, Choi JJ, Moon SY, Kim MJ, Kim KH, Kwak BS, Cho DY (2007) BRCA1 and BRCA2 germline mutations in Korean breast cancer patients at high risk of carrying mutations. Cancer Lett 245:90–95. doi: 10.1016/j.canlet.2005.12.031 PubMedCrossRefGoogle Scholar
  15. 15.
    Haffty BG, Choi DH, Goyal S, Silber A, Ranieri K, Matloff E, Lee MH, Nissenblatt M, Toppmeyer D, Moran MS (2009) Breast cancer in young women (YBC): prevalence of BRCA1/2 mutations and risk of secondary malignancies across diverse racial groups. Ann Oncol 20:1653–1659. doi: 10.1093/annonc/mdp051 PubMedCrossRefGoogle Scholar
  16. 16.
    Choi DH, Lee MH, Haffty BG (2006) Double heterozygotes for non-Caucasian families with mutations in BRCA-1 and BRCA-2 genes. Breast J 12:216–220. doi: 10.1111/j.1075-122X.2006.00245.x PubMedCrossRefGoogle Scholar
  17. 17.
    Friedman E, Bar-Sade Bruchim R, Kruglikova A, Risel S, Levy-Lahad E, Halle D, Bar-On E, Gershoni-Baruch R, Dagan E, Kepten I, Peretz T, Lerer I, Wienberg N, Shushan A, Abeliovich AD (1998) Double heterozygotes for the Ashkenazi founder mutations in BRCA1 and BRCA2 genes. Am J Hum Genet 63:1224–1227PubMedCrossRefGoogle Scholar
  18. 18.
    Frank TS, Deffenbaugh AM, Reid JE, Hulick M, Ward BE, Lingenfelter B, Gumpper KL, Scholl T, Tavtigian SV, Pruss DR, Critchfield GC (2002) Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10, 000 individuals. J Clin Oncol 20:1480–1490PubMedCrossRefGoogle Scholar
  19. 19.
    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. doi: 10.1136/jmg.2004.027243 PubMedCrossRefGoogle Scholar
  20. 20.
    Spannuth WA, Thaker PH, Sood AK (2007) Concomitant BRCA1 and BRCA2 gene mutations in an Ashkenazi Jewish woman with primary breast and ovarian cancer. Am J Obstet Gynecol 196:e6–e9. doi: 10.1016/j.ajog.2007.01.026 PubMedCrossRefGoogle Scholar
  21. 21.
    Lavie O, Narod S, Lejbkowicz F, Dishon S, Goldberg Y, Gemer O, Rennert G (2010) Double heterozygosity in the BRCA1 and BRCA2 genes in the Jewish population. Ann Oncol 22:964–966. doi: 10.1093/annonc/mdq460 PubMedCrossRefGoogle Scholar
  22. 22.
    Kim EK, Kim KS, Park SK, Ahn SH, Lee MH, Kim SW (2007) The Korean Hereditary Breast Cancer (KOHBRA) study: protocol review. J Breast Cancer 10:241–247CrossRefGoogle Scholar
  23. 23.
    Han SA, Park SK, Hyun Ahn S, Hyuk Lee M, Noh DY, Kim LS, Noh WC, Jung Y, Sang Kim K, Kim SW, Korean Breast Cancer Study Group (2011) The Korean Hereditary Breast Cancer (KOHBRA) Study: protocols and interim report. Clin Oncol (R Coll Radiol) 23:434–441. doi: 10.1016/j.clon.2010.11.007 CrossRefGoogle Scholar
  24. 24.
    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. doi: 10.1007/s10549-010-0853-8 PubMedCrossRefGoogle Scholar
  25. 25.
    Phillips KA (2000) Immunophenotypic and pathologic differences between BRCA1 and BRCA2 hereditary breast cancers. J Clin Oncol 18:107S–112SPubMedGoogle Scholar
  26. 26.
    Levine DA, Argenta PA, Yee CJ, Marshall DS, Olvera N, Bogomolniy F, Rahaman JA, Robson ME, Offit K, Barakat RR, Soslow RA, Boyd J (2003) Fallopian tube and primary peritoneal carcinomas associated with BRCA mutations. J Clin Oncol 21:4222–4227. doi: 10.1200/JCO.2003.04.131 PubMedCrossRefGoogle Scholar
  27. 27.
    The Breast Cancer Linkage Consortium (1999) Cancer risks in BRCA2 mutation carriers. The Breast Cancer Linkage Consortium. J Natl Cancer Inst 91:1310–1316CrossRefGoogle Scholar
  28. 28.
    Thompson D, Easton DF (2002) Cancer Incidence in BRCA1 mutation carriers. J Natl Cancer Inst 94:1358–1365PubMedGoogle Scholar
  29. 29.
    Augustyn AM, Agostino NM, Namey TL, Nair S, Martino MA (2011) Two patients with germline mutations in both BRCA1 and BRCA2 discovered unintentionally: a case series and discussion of BRCA testing modalities. Breast Cancer Res Treat. doi: 10.1007/s10549-011-1597-9
  30. 30.
    Metcalfe K, Gershman S, Lynch HT, Ghadirian P, Tung N, Kim-Sing C, Olopade OI, Domchek S, McLennan J, Eisen A, Foulkes WD, Rosen B, Sun P, Narod SA (2011) Predictors of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. Br J Cancer 104:1384–1392. doi: 10.1038/bjc.2011.120 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Jae Myoung Noh
    • 1
  • Doo Ho Choi
    • 1
  • Seok Jin Nam
    • 2
  • Jeong Eon Lee
    • 2
  • Jong Won Kim
    • 3
  • Sung-Won Kim
    • 4
  • Eunyoung Kang
    • 4
  • Min Hyuk Lee
    • 5
  • Sei Hyun Ahn
    • 6
  • Ku Sang Kim
    • 7
  • Sue K. Park
    • 8
    • 9
    • 10
  • Bruce G. Haffty
    • 11
  • Korea Breast Cancer Study Group
    • 12
  1. 1.Department of Radiation Oncology, Samsung Medical CenterSungkyunkwan University School of MedicineGangnam-gu, SeoulKorea
  2. 2.Department of Surgery, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulKorea
  3. 3.Department of Laboratory Medicine and Genetics, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulKorea
  4. 4.Department of SurgerySeoul National University College of MedicineSeoulKorea
  5. 5.Department of SurgerySoonchunhyang University HospitalSeoulKorea
  6. 6.Department of Surgery, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulKorea
  7. 7.Department of SurgeryAjou University School of MedicineSuwonKorea
  8. 8.Department of Preventive MedicineSeoul National University College of MedicineSeoulKorea
  9. 9.Department of Biomedical ScienceSeoul National University Graduate SchoolSeoulKorea
  10. 10.Cancer Research InstituteSeoul National UniversitySeoulKorea
  11. 11.Department of Radiation OncologyRobert Wood Johnson Medical School, Cancer Institute of New JerseyNew BrunswickUSA
  12. 12.Korea Breast Cancer SocietySeoulKorea

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