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Br J Cancer. 2000 November; 83(10): 1301–1308.
Published online 2000 October 26. doi:  10.1054/bjoc.2000.1407
PMCID: PMC2408797

Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases

Anglian Breast Cancer Study Group

Abstract

Estimates of the contribution of BRCA1 and BRCA2 to breast cancer incidence in outbred populations have been based on studies that are either small or have selected for cases diagnosed at an early age. Only one of these has reported an estimate of the breast cancer risk associated with a mutation in these genes, and there is no published ovarian cancer risk estimate derived from a population-based case series. We screened a population-based series of breast cancer cases diagnosed before the age of 55 for mutations in BRCA1 and BRCA2. Pedigree information from the mutation carriers was used to estimate penetrance and the proportion of familial risk of breast cancer due to BRCA1 and BRCA2. We identified eight (0.7%)BRCA1 and 16 (1.3%)BRCA2 mutation carriers in 1220 breast cancer cases (actual sample size 1435 adjusted for 15% polymerase chain reaction failure rate). Mutation prevalence was substantially higher in cases diagnosed before 35 years-of-age and with increasing number of relatives affected with breast or ovarian cancer. However, most mutation carriers were diagnosed in the older age groups, and a minority reported a first-degree relative with breast cancer. Breast cancer penetrance by age 80 was estimated to be 48% (95% CI 7–82%) for BRCA1 mutation carriers and 74% (7–94%) for BRCA2 mutation carriers. Ovarian cancer penetrance for BRCA1 and BRCA2 combined was 22% (6–65%) by age 80. 17% of the familial risk of breast cancer was attributable to BRCA1 and BRCA2. At birth, the estimated prevalence of BRCA1 mutation carriers was 0.07% or 0.09% depending on the penetrance function used for the calculation. For BRCA2 the birth prevalence estimates were 0.14% and 0.22%. Mutations in the genes BRCA1 and BRCA2 are rare in the population and account for a small fraction of all breast cancer in the UK. They account for less than one fifth of the familial risk of breast cancer. Eligibility criteria for BRCA1 and BRCA2 mutation testing based on family history and age of onset will identify only a small proportion of mutation carriers. © 2000 CancerResearch Campaign

Keywords: breast, ovarian, cancer, BRCA1, BRCA2, prevalence, penetrance

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Selected References

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  • Ansquer Y, Gautier C, Fourquet A, Asselain B, Stoppa-Lyonnet D. Survival in early-onset BRCA1 breast-cancer patients. Institut Curie Breast Cancer Group. Lancet. 1998 Aug 15;352(9127):541–541. [PubMed]
  • Antoniou AC, Gayther SA, Stratton JF, Ponder BA, Easton DF. Risk models for familial ovarian and breast cancer. Genet Epidemiol. 2000 Feb;18(2):173–190. [PubMed]
  • Coleman M, Douglas A, Hermon C, Peto J. Cohort study analysis with a FORTRAN computer program. Int J Epidemiol. 1986 Mar;15(1):134–137. [PubMed]
  • Couch FJ, DeShano ML, Blackwood MA, Calzone K, Stopfer J, Campeau L, Ganguly A, Rebbeck T, Weber BL. BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. N Engl J Med. 1997 May 15;336(20):1409–1415. [PubMed]
  • Easton DF, Ford D, Bishop DT. Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet. 1995 Jan;56(1):265–271. [PubMed]
  • Easton DF, Steele L, Fields P, Ormiston W, Averill D, Daly PA, McManus R, Neuhausen SL, Ford D, Wooster R, et al. Cancer risks in two large breast cancer families linked to BRCA2 on chromosome 13q12-13. Am J Hum Genet. 1997 Jul;61(1):120–128. [PubMed]
  • Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE. Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet. 1994 Mar 19;343(8899):692–695. [PubMed]
  • Ford D, Easton DF, Peto J. Estimates of the gene frequency of BRCA1 and its contribution to breast and ovarian cancer incidence. Am J Hum Genet. 1995 Dec;57(6):1457–1462. [PubMed]
  • Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop DT, Weber B, Lenoir G, Chang-Claude J, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1998 Mar;62(3):676–689. [PubMed]
  • Gayther SA, Mangion J, Russell P, Seal S, Barfoot R, Ponder BA, Stratton MR, Easton D. Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat Genet. 1997 Jan;15(1):103–105. [PubMed]
  • Gayther SA, Pharoah PD, Ponder BA. The genetics of inherited breast cancer. J Mammary Gland Biol Neoplasia. 1998 Oct;3(4):365–376. [PubMed]
  • Gayther SA, Warren W, Mazoyer S, Russell PA, Harrington PA, Chiano M, Seal S, Hamoudi R, van Rensburg EJ, Dunning AM, et al. Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation. Nat Genet. 1995 Dec;11(4):428–433. [PubMed]
  • Hopper JL, Southey MC, Dite GS, Jolley DJ, Giles GG, McCredie MR, Easton DF, Venter DJ. Population-based estimate of the average age-specific cumulative risk of breast cancer for a defined set of protein-truncating mutations in BRCA1 and BRCA2. Australian Breast Cancer Family Study. Cancer Epidemiol Biomarkers Prev. 1999 Sep;8(9):741–747. [PubMed]
  • Johannesdottir G, Gudmundsson J, Bergthorsson JT, Arason A, Agnarsson BA, Eiriksdottir G, Johannsson OT, Borg A, Ingvarsson S, Easton DF, et al. High prevalence of the 999del5 mutation in icelandic breast and ovarian cancer patients. Cancer Res. 1996 Aug 15;56(16):3663–3665. [PubMed]
  • Krainer M, Silva-Arrieta S, FitzGerald MG, Shimada A, Ishioka C, Kanamaru R, MacDonald DJ, Unsal H, Finkelstein DM, Bowcock A, et al. Differential contributions of BRCA1 and BRCA2 to early-onset breast cancer. N Engl J Med. 1997 May 15;336(20):1416–1421. [PubMed]
  • Langston AA, Malone KE, Thompson JD, Daling JR, Ostrander EA. BRCA1 mutations in a population-based sample of young women with breast cancer. N Engl J Med. 1996 Jan 18;334(3):137–142. [PubMed]
  • Malone KE, Daling JR, Thompson JD, O'Brien CA, Francisco LV, Ostrander EA. BRCA1 mutations and breast cancer in the general population: analyses in women before age 35 years and in women before age 45 years with first-degree family history. JAMA. 1998 Mar 25;279(12):922–929. [PubMed]
  • Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994 Oct 7;266(5182):66–71. [PubMed]
  • Neuhausen S, Gilewski T, Norton L, Tran T, McGuire P, Swensen J, Hampel H, Borgen P, Brown K, Skolnick M, et al. Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer. Nat Genet. 1996 May;13(1):126–128. [PubMed]
  • 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 Mar 25;279(12):915–921. [PubMed]
  • Nordling M, Karlsson P, Wahlström J, Engwall Y, Wallgren A, Martinsson T. A large deletion disrupts the exon 3 transcription activation domain of the BRCA2 gene in a breast/ovarian cancer family. Cancer Res. 1998 Apr 1;58(7):1372–1375. [PubMed]
  • Offit K, Gilewski T, McGuire P, Schluger A, Hampel H, Brown K, Swensen J, Neuhausen S, Skolnick M, Norton L, et al. Germline BRCA1 185delAG mutations in Jewish women with breast cancer. Lancet. 1996 Jun 15;347(9016):1643–1645. [PubMed]
  • Peto J, Collins N, Barfoot R, Seal S, Warren W, Rahman N, Easton DF, Evans C, Deacon J, Stratton MR. Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst. 1999 Jun 2;91(11):943–949. [PubMed]
  • Petrij-Bosch A, Peelen T, van Vliet M, van Eijk R, Olmer R, Drüsedau M, Hogervorst FB, Hageman S, Arts PJ, Ligtenberg MJ, et al. BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients. Nat Genet. 1997 Nov;17(3):341–345. [PubMed]
  • Smith TM, Lee MK, Szabo CI, Jerome N, McEuen M, Taylor M, Hood L, King MC. Complete genomic sequence and analysis of 117 kb of human DNA containing the gene BRCA1. Genome Res. 1996 Nov;6(11):1029–1049. [PubMed]
  • Struewing JP, Abeliovich D, Peretz T, Avishai N, Kaback MM, Collins FS, Brody LC. The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. Nat Genet. 1995 Oct;11(2):198–200. [PubMed]
  • Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M, McAdams M, Timmerman MM, Brody LC, Tucker MA. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med. 1997 May 15;336(20):1401–1408. [PubMed]
  • Thorlacius S, Sigurdsson S, Bjarnadottir H, Olafsdottir G, Jonasson JG, Tryggvadottir L, Tulinius H, Eyfjörd JE. Study of a single BRCA2 mutation with high carrier frequency in a small population. Am J Hum Genet. 1997 May;60(5):1079–1084. [PubMed]
  • Thorlacius S, Struewing JP, Hartge P, Olafsdottir GH, Sigvaldason H, Tryggvadottir L, Wacholder S, Tulinius H, Eyfjörd JE. Population-based study of risk of breast cancer in carriers of BRCA2 mutation. Lancet. 1998 Oct 24;352(9137):1337–1339. [PubMed]
  • Verhoog LC, Brekelmans CT, Seynaeve C, van den Bosch LM, Dahmen G, van Geel AN, Tilanus-Linthorst MM, Bartels CC, Wagner A, van den Ouweland A, et al. Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1. Lancet. 1998 Jan 31;351(9099):316–321. [PubMed]
  • Watson P, Marcus JN, Lynch HT. Prognosis of BRCA1 hereditary breast cancer. Lancet. 1998 Jan 31;351(9099):304–305. [PubMed]
  • Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, Collins N, Gregory S, Gumbs C, Micklem G. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995 Dec 21;378(6559):789–792. [PubMed]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK