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 Cancer Research Campaign
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References
Ansquer Y, Gautier C, Fourquet A, Asselain B and Stoppa-Lyonnet D (1998) Survival in early-onset BRCA1 breast cancer patients. Lancet 352: 541
Antoniou AC, Gayther SA, Stratton JF, Ponder BAJ and Easton DF (2000) Risk models for familial breast and ovarian cancer. Genet Epidemiol 18: 173–190
Breast Cancer Linkage Consortium (1997) Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Lancet 349: 1505–1510
Coleman M, Douglas A, Hermon C and Peto J (1986) Cohort study analysis with a FORTRAN computer program. Int J Epidemiol 15: 134–137
Couch FJ, Deshano ML, Blackwood MA, Calzone K, Stopfer J, Campeau L, Ganguly A, Rebbeck T and Weber BL (1997) BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. N Engl J Med 336: 1409–1415
Easton DF, Ford D and Bishop DT Breast Cancer Linkage Consortium (1995) Breast and ovarian cancer incidence in BRCA1-mutation carriers. Am J Hum Genet 56: 265–271
Easton DF, Steele L, Fields P, Ormiston W, Averill D, Daly PA, McManus R, Neuhausen SL, Ford D, Wooster R, Cannon Albright LA, Stratton MR and Goldgar DE (1997) Cancer risks in two large breast cancer families linked to BRCA2 on chromosome 13q 12–13. Am J Hum Genet 61: 120–128
Ford D, Easton DF, Bishop DT, Narod SA and Goldgar DE Breast Cancer Linkage Consortium (1994) Risks of cancer in BRCA1 mutation carriers. Lancet 343: 692–695
Ford D, Easton DF and 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
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, Barkadottir R, Eyfjord J, Lynch H, Ponder BAJ, Gayhter SA, Birch JM, Lindblom A, Stoppa-Lyonnet D, Bignon Y, Borg A, Hamann U, Haites N, Scott RJ, Maugard CM, Vasen H, Seitz S, Cannon-Albright LA, Schofield A and Hedman MZ Breast Cancer Linkage Consortium (1998) Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet 62: 676–689
Ganguly A, Rock MJ and Prockop DJ (1993) Conformation-sensitive gel electrophoresis for rapid detection of single-base difference in double stranded PCR products and DNA fragments: evidence for solvent-induced bends in DNA heteroduplexes. Proc Natl Acad Sci USA 90: 10325–10329
Gayther SA, Mangion J, Russell P, Seal S, Barfoot R, Ponder BA, Stratton MR and Easton D (1997) Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2gene. Nat Genet 15: 103–105
Gayther SA, Pharoah PDP and Ponder BAJ (1998) The genetics of inherited breast cancer. J Mamm Gland Biol Neoplasia 3: 365–376
Gayther SA, Warren W, Mazoyer S, Russell PA, Harrington PA, Chiano M, Seal S, Hamoudi R, van Rensburg EJ, Dunning AM, Love R, Evans G, Easton D, Clayton C, Stratton MR and Ponder BAJ (1995) Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype–phenotype correlation. Nat Genet 11: 428–433
Hopper JL, Southey MC, Dite GS, Jolley DJ, Giles GG, McCredie MR, Easton DF and Venter DJ Australian Breast Cancer Family Study (1999) 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. Cancer Epidemiol Biomarkers Prev 8: 741–747
Johannesdottir G, Gudmundsson J, Bergthorsson JT, Arason A, Agnarsson BA, Eiriksdottir G, Johannsson OT, Borg A, Ingvarsson S, Easton DF, Egilsson V and Barkardottir RB (1996) High prevalence of the 999del5 mutation in Icelandic breast and ovarian cancer patients. Cancer Res 56: 3663–3665
Krainer M, Silva Arrieta S, Fitzgerald MG, Shimada A, Ishioka C, Kanamaru R, MacDonald DJ, Unsal H, Finkelstein DM, Bowcock A, Isselbacher KJ and Haber DA (1997) Differential contributions of BRCA1 and BRCA2 to early-onset breast cancer. N Engl J Med 336: 1416–1421
Langston A, Malone KE, Thompson JD, Daling, JR and Ostrander EA (1996) BRCA1 mutations in a population-based sample of young women with breast cancer. N Engl J Med 334: 137–142
Malone KE, Daling, JR, Thompson JD, O'Brien CA, Francisco LV and Ostrander EA (1998) BRCA1 mutations and breast cancer in the general population. JAMA 279: 922–929
Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harsham K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W, Bell R, Rosenthal J, Hussey C, Tran T, McClure M, Frye C, Hattier T, Phelps R, Haugenstrano A, Katcher H, Yakumo K, Gholami Z, Shaffer D, Stone S, Bayer S, Wray C, Bogden R, Dayananth P, Ward J, Tonin P, Narod S, Bristow PK, Norris FH, Helvering L, Morrison P, Rosteck P, Lai M, Barrett JC, Lewis C, Neuhausen S, Cannon-Albright L, Goldgar D, Wiseman R, Kamb A and Skolnick MH (1994) A strong candidate for the 17-linked breast and ovarian cancer susceptibility gene BRCA1. Science 266: 66–71
Neuhausen S, Gilewski T, Norton L, Tran T, McGuire P, Swensen J, Hampel H, Borgen P, Brown K, Skolnick M, Shattuck Eidens D, Jhanwar S, Goldgar D and Offit K (1996) RecurrentBRCA26174delT mutations in Ashkenazi Jewish women affected by breast cancer. Nat Genet 13: 126–128
Newman B, Mu H, Butler LM, Millikan RC, Moorman PG and King M-C (1998) Frequency of breast cancer attributable to BRCA1 in a population-based series of American women. JAMA 279: 915–921
Nordling M, Karlsson P, Wahlstrom J, Engwall Y, Wallgren A and Martinsson T (1998) A large deletion disrupts the exon 3 transcription activation domain of theBRCA2gene in a breast/ovarian cancer family. Cancer Res 58: 1372–1375
Offit K, Gilewski T, McGuire P, Schluger A, Hampel H, Brown K, Swensen J, Neuhausen S, Skolnick M, Norton L and Goldgar D (1996) Germline BRCA1 185delAG mutations in Jewish women with breast cancer. Lancet 347: 1643–1645
Peto J, Collins N, Barfoot R, Seal S, Warren W, Rahman N, Easton DF, Evans C, Deacon J and Stratton MR (1999) Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst 91: 943–949
Petrij Bosch A, Peelen T, van Vliet M, van Eijk R, Olmer R, Drusedau M, Hogervorst FB, Hageman S, Arts PJ, Ligtenberg MJ, Meijers Heijboer H, Klijn JG, Vasen HF, Cornelisse CJ, van't Veer LJ, Bakker E, van Ommen GJ and Devilee P (1997) BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients. Nat Genet 17: 341–345
Smith TM, Lee MK, Szabo CI, Jerome N, McEuen M, Taylor M, Hood L and King M-C (1996) Complete genomic sequence and analysis of 117kb of human DNA containing the gene BRCA1. Genome Res 6: 1029–1049
Struewing JP, Abeliovich D, Peretz T, Avishai N, Kaback MM, Collins FS and Brody LC (1995) The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. Nat Genet 11: 198–200
Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M, McAdams M, Timmerman MM, Brody LC and Tucker MA (1997) The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336: 1401–1408
Thorlacius S, Sigurdsson S, Bjarnadottir H, Olafsdottir G, Jonasson JG, Tryggvadottir L, Tulinius H and Eyfjord JE (1997) Study of a singleBRCA2mutation with high carrier frequency in a small population. Am J Hum Genet 60: 1079–1084
Thorlacius S, Struewing JP, Hartge P, Olafsdottir GH, Sigvaldason H, Tryggvadottir L, Wacholder S, Tulinius H and Eyfjord JE (1998) Population-based study of risk of breast cancer in carriers ofBRCA2mutation. Lancet 352: 1337–1339
Verhoog LC, Brekelmans CTM, Seynaeve C, van den Bosch LMC, Dahmen G, van Geel AN, Tilanus-Linthorst MMA, Bartels CCM, Wagner A, van den Ouweland A, Devilee P, Meijers-Heijboer EJ and Klijn JGM (1998) Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1. Lancet 351: 316–321
Watson P, Marcus JN and Lynch HT (1998) Prognosis of BRCA1 hereditary breast cancer. Lancet 351: 304–305
Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, Collins N, Gregory S, Gumbs C, Micklem G, Barfoot R, Hamoudi R, Patel S, Rice C, Biggs P, Hashim Y, Smith A, Connor F, Arason A, Gudmundsson J, Ficenec D, Kelsell D, Ford D, Tonin P, Bishop DT, Spurr NK, Ponder BAJ, Eeles R, Peto J, Devilee P, Cornelisse C, Lynch H, Narod S, Lenoir G, Egilsson V, Barkadottir RB, Easton DF, Bentley DR, Futreal PA, Ashworth A and Stratton MR (1995) Identification of the breast cancer susceptibility geneBRCA2. Nature 378: 789–792
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Anglian Breast Cancer Study Group. Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Br J Cancer 83, 1301–1308 (2000). https://doi.org/10.1054/bjoc.2000.1407
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DOI: https://doi.org/10.1054/bjoc.2000.1407
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