Abstract
Hereditary breast carcinomas associated with BRCA1/2 mutations have unique clinicopathological and epidemiological characteristics. The objective of this study is to outline the prevalence, founder effect and clinicopathological characteristics of BRCA1/2 mutations for hereditary breast cancers from an analysis of reports recently published regarding Korean subjects.
The prevalence of BRCA1 and/or BRCA2 mutations is 2.5-3.1% for sporadic breast cancers, 19.4-42.9% for familiar breast cancer patients with two or more affected first- and second- degree relatives with breast or ovarian cancers and 9.6-18.3% for early breast cancers. Common mutations for the Korean subjects were 2552delC, 3476insA, 4184del4, 5589del8, and 5615del111insA for BRCA1; and 7708C>T for BRCA2. These mutations were not found in Ashkenazi Jewish or Icelandic subjects. The proportion of estrogen or progesterone receptor (ER/PR) or ER/PR/HER2 triple negative status, basal-like phenotype as detected by immunohistochemical staining, and undifferentiated histological grade in Korean BRCA mutation subjects were higher than in subjects lacking BRCA1/2 mutations.
Our review found that previous studies describing BRCA mutations among Korean subjects were limited. Since the clinicopathological, phenotypic and epidemiological characteristics of the BRCA1/2 mutations among Korean subjects are different from those among subjects from the Americas and Europe, more studies of hereditary or familial breast cancer including BRCA mutations must be conducted. A largescale prospective study called Korean Hereditary Breast Cancer Study (KOHBRA) was started from May 2007, and future information provided by the KOHBRA study will make a substantial contribution to solving the basic questions in etiology, individual susceptibility and clinicopathological characteristics for hereditary breast cancer among Korean subjects.
Figures and Tables
References
1. Daly PA. Hereditary cancer: guidelines in clinical practice-general overview. Ann Oncol. 2004. 15:(Suppl). iv121–iv125.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
2. Clinical Practice Guidelines in Oncology. Genetic/Familial High Risk Assessment: Breast and Ovarian Cancer. 2007. accessed March 13, 2008. National Comprehensive Cancer Network;http://www.nccn.org/professionals/physician_gls/PDF/genetics_screening.pdf.
3. American Society of Clinical Oncology. American Society of Clinical Oncology Policy Statement Update: Genetic Testing for Cancer Susceptibility. J Clin Oncol. 2003. 21:2397–2406.
4. U.S. Preventive Services Task Force. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility recommendation statement. Ann Intern Med. 2005. 143:355–361.
5. Clinical Practice Guidelines in Oncology. Genetic Susceptibility to Breast and Ovarian Cancer: Assessment, Counseling and Testing Guidelines. 1999. accessed March 13, 2008. American College of Medical Genetics Foundation;http://www.health.state.ny.us/nysdoh/cancer/obcancer/contents.htm.
6. Kim EK, Kim KS, Park SK, Ahn SH, Lee MH, Kim SW, et al. The Korean Hereditary Breast Cancer (KOHBRA) Study: Protocol review. J Breast Cancer. 2007. 10:241–247.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
7. Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994. 266:66–71.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
8. Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995. 378:789–792.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
9. National Human Genome Research Institute. Breast Cancer Information Core Database. 1999. accessed Feb 23, 2008. National Institutes of Health;http://www.nhgri.nih.gov/projects/bic/.
10. Brose MS, Rebbeck TR, Calzone KA, Stopfer JE, Nathanson KL, Weber BL. Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst. 2002. 94:1365–1372.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
11. Thompson D, Easton DF. Breast Cancer Linkage Consortium. Cancer Incidence in BRCA1 mutation carriers. J Natl Cancer Inst. 2002. 94:1358–1365.
12. Easton DF, Ford D, Bishop DT. Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet. 1995. 56:265–271.
13. Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE. Breast Cancer Linkage Consortium. Risks of cancer in BRCA1-mutation carriers. Lancet. 1994. 343:692–695.
15. Easton DF, Bishop DT, Ford D, Crockford GP. The Breast Cancer Linkage Consortium. Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. Am J Hum Genet. 1993. 52:678–701.
16. Liede A, Karlan BY, Narod SA. Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J Clin Oncol. 2004. 22:735–742.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
17. Nagy R, Sweet K, Eng C. Highly penetrant hereditary cancer syndromes. Oncogene. 2004. 23:6445–6470.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
18. Liede A, Narod SA. Hereditary breast and ovarian cancer in Asia: genetic epidemiology of BRCA1 and BRCA2. Hum Mutat. 2002. 20:413–424.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
19. Neuhausen SL. Founder populations and their uses for breast cancer genetics. Breast Cancer Res. 2000. 2:77–81.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
20. Neuhausen S, Gilewski T, Norton L, Tran T, McGuire P, Swensen J, et al. Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer. Nat Genet. 1996. 13:126–128.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
21. Struewing JP, Abeliovich D, Peretz T, Avishai N, Kaback MM, Collins FS, et al. The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. Nat Genet. 1995. 11:198–200.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
22. Tonin P, Weber B, Offit K, Couch F, Rebbeck TR, Neuhausen S, et al. Frequency of recurrent BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer families. Nat Med. 1996. 2:1179–1183.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
23. Phelan CM, Kwan E, Jack E, Li S, Morgan C, Aubé J, et al. A low frequency of non-founder BRCA1 mutations in Ashkenazi Jewish breastovarian cancer families. Hum Mutat. 2002. 20:352–357.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
24. Warner E, Foulkes W, Goodwin P, Meschino W, Blondal J, Paterson C, 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.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
25. Thorlacius S, Struewing JP, Hartge P, Olafsdottir GH, Sigvaldason H, Tryggvadottir L, et al. Population-based study of risk of breast cancer in carriers of BRCA2 mutation. Lancet. 1998. 352:1337–1339.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
26. Oh JH, Noh DY, Choe KJ, Kang SB, Kim LS, Ro MS, et al. Germline mutation of BRCA1 gene in Korean breast and ovarian cancer patients. J Korean Cancer Ass. 1995. 27:1061–1069.
27. Kang HC, Kim IJ, Park JH, Kwon HJ, Won YJ, Heo SC, et al. Germline mutations of BRCA1 and BRCA2 in Korean breast and/or ovarian cancer families. Hum Mutat. 2002. 20:235–239.
28. Choi DH, Lee MH, Bale AE, Carter D, Haffty BG. Incidence of BRCA1 and BRCA2 mutations in young Korean breast cancer patients. J Clin Oncol. 2004. 22:1638–1645.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
29. Seo JH, Cho DY, Ahn SH, Yoon KS, Kang CS, Cho HM, et al. BRCA1 and BRCA2 germline mutations in Korean patients with sporadic breast cancer. Hum Mutat. 2004. 24:350.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
30. Ahn SH, Hwang UK, Kwak BS, Yoon HS, Ku BK, Kang HJ, et al. Prevalence of BRCA1 and BRCA2 mutations in Korean breast cancer patients. J Korean Med Sci. 2004. 19:269–274.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
31. Ahn SH, Son BH, Yoon KS, Noh DY, Han W, Kim SW, et al. BRCA1 and BRCA2 germline mutations in Korean breast cancer patients at high risk of carrying mutations. Cancer Lett. 2007. 245:90–95.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
32. Han SH, Lee KR, Lee DG, Kim BY, Lee KE, Chung WS. Mutation analysis of BRCA1 and BRCA2 from 793 Korean patients with sporadic breast cancer. Clin Genet. 2006. 70:496–501.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
33. Kim BY, Lee DG, Lee KR, Han SH, Surendran S, Han CW, et al. Identification of BRCA1 and BRCA2 mutations from Korean breast cancer patients using denaturing HPLC. Biochem Biophys Res Commun. 2006. 349:604–610.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
34. Kim TJ, Lee KM, Choi CH, Lee JW, Lee JH, Bae DS, et al. Germline mutations of BRCA1 in two Korean hereditary breast/ovarian cancer families. Oncol Rep. 2006. 15:565–569.
35. Cho J, Kim SW, Kim S, Choi YS, Ko E, Lee JW, et al. Analysis of BRCA1 and BRCA2 germline mutations in high-risk Korean breast cancer patients. Global Breast Cancer Conference 2007. Proceeding. Abstract #01-013.
36. Son BH, Ahn SH, Kim HJ, Lee JS, Park EH, Choi SL, et al. Basla-like cytokeratin expression profiles of Korean hereditary breast cancers having BRCA gene mutation. Global Breast Cancer Conference 2007. Proceeding. Abstract #01-012.
37. Son B, Ahn S, Kim H, Hong S, Lee J, Jung M, et al. BRCA1/2 associated Korean breast cancer has more often ER/c-erbB2 negative phenotype. 25th Congress of the International Association for Breast Cancer Research. Proceeding. Abstract #46.
38. Newman B, Mu H, Butler LM, Millikan RC, Moorman PG, King MC. Frequency of breast cancer attributable to BRCA1 in a population-based series of American women. JAMA. 1998. 279:915–921.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
39. Kim SW, Lee CS, Fey JV, Borgen PI, Boyd J. Prevalence of BRCA2 mutations in a hospital based series of unselected breast cancer cases. J Med Genet. 2005. 42:e5.
40. Clinical Practice Guidelines in Oncology. BRCA mutation prevalence tables. Data last updated: spring 2006. accessed March 13, 2008. Myriad Genetic Laborctories;http://www.myriadtests.com/provider/brca-mutation-prevalence.htm.
41. Szabo CS, King MC. Population genetics of BRCA1 and BRCA2. Am J Hum Genet. 1997. 60:1013–1020.
42. Son BH, Kwak BS, Kim JK, Kim HJ, Hong SJ, Lee JS, et al. Changing patterns in the clinical characteristics of Korean breast cancer patients over the last 15 years. Arch Surg. 2006. 141:155–160.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
43. Ahn SH, Yoo KY, Korean Breast. Chronological changes of clinical characteristics in 31,115 new breast cancer patients among Koreans during 1996-2000. Breast Cancer Res Treat. 2006. 99:209–214.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
44. Golshan M, Miron A, Nixon AJ, Garber JE, Cash EP, Iglehart JD, et al. The prevalence of germline BRCA1 and BRCA2 mutations in young women with breast cancer undergoing breast-conservation therapy. Am J Surg. 2006. 192:58–62.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
45. Kim SW, Ahn SH, Son BH, Lee MH, Choi DH, Noh DY, et al. Cancer risk estimates for Korean BRCA1 and BRCA2 mutation carriers. Global Breast Cancer Conference 2007. Proceeding. Abstract #01-011.
46. Unger MA, Nathanson KL, Calzone K, Antin-Ozerkis D, Shih HA, Martin AM, et al. Screening for genomic rearrangements in families with breast and ovarian cancer identifies BRCA1 mutations previously missed by conformation-sensitive gel electrophoresis or sequencing. Am J Hum Genet. 2000. 67:841–850.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
47. Iau PT, Macmillan RD, Blamey RW. Germ line mutations associated with breast cancer susceptibility. Eur J Cancer. 2001. 37:300–321.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
48. Nathanson KL, Weber BL. "Other" breast cancer susceptibility genes: searching for more holy grail. Hum Mol Genet. 2001. 10:715–720.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
49. Lacroix M, Leclercq G, on behalf. The "portrait" of hereditary breast cancer. Breast Cancer Res Treat. 2005. 89:297–304.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
50. Weber BL, Nathanson KL. Low penetrance genes associated with increased risk for breast cancer. Eur J Cancer. 2000. 36:1193–1199.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
51. Bonadona V, Lasset C. Inherited predisposition to breast cancer: after the BRCA1 and BRCA2 genes, what next. Bull Cancer. 2003. 90:587–594.
52. Hartmann LC, Schaid DJ, Woods JE, Crotty TP, Myers JL, Arnold PG, et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med. 1999. 340:77–84.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
53. Wainberg S, Husted J. Utilization of screening and preventive surgery among unaffected carriers of a BRCA1 or BRCA2 gene mutation. Cancer Epidemiol Biomarkers Prev. 2004. 13:1989–1995.
37. Kim KS, Kim S, Han SA, Jeon YT, Ha TH, Heo CY, et al. Prophylactic mastectomy and oophorectomy in a BRCA1-positive patient. Global Breast Cancer Conference 2007. Proceeding. Abstract #01-010.
55. Kim KS, Kim SW, Lee MH, Ahn SH, Park SK. Korean Breast Cancer Society. 'Surgeons' practice patterns for management of Hereditary Breast Cancer in Korea. J Breast Cancer. 2008. (In press).
56. Jernström H, Lubinski J, Lynch HT, Ghadirian P, Neuhausen S, Isaacs C, et al. Breast-feeding and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst. 2004. 96:1094–1098.
57. Narod SA, Dubé MP, Klijn J, Lubinski J, Lynch HT, Ghadirian P, et al. Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst. 2002. 94:1773–1779.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
58. King MC, Wieand S, Hale K, Lee M, Walsh T, Owens K, et al. Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: national Surgical Adjuvant Breast and Bowel Project NSABP-P1) Breast Cancer Prevention Trial. JAMA. 2001. 286:2251–2256.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
59. Narod SA, Brunet JS, Ghadirian P, Robson M, Heimdal K, Neuhausen SL, et al. Hereditary Breast Cancer Clinical Study Group. Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case-control study. Lancet. 2000. 356:1876–1881.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
60. Scheuer L, Kauff N, Robson M, Kelly B, Barakat R, Satagopan J, et al. Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers. J Clin Oncol. 2002. 20:1260–1268.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
61. Kriege M, Brekelmans CT, Boetes C, Besnard PE, Zonderland HM, Obdeijn IM, et al. Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. N Engl J Med. 2004. 351:427–437.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)