Variation of Breast Cancer Risk Among BRCA1/2 Carriers | Breast Cancer | JAMA | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 35.175.212.130. Please contact the publisher to request reinstatement.
1.
Struewing JP, Hartge P, Wacholder S.  et al.   The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews.   N Engl J Med. 1997;336(20):1401-14089145676Google ScholarCrossref
2.
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. 2000;83(10):1301-130811044354Google ScholarCrossref
3.
Antoniou AC, Gayther SA, Stratton JF, Ponder BA, Easton DF. Risk models for familial ovarian and breast cancer.  Genet Epidemiol. 2000;18(2):173-19010642429Google ScholarCrossref
4.
Hopper JL, Southey MC, Dite GS.  et al.   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. 1999;8(9):741-74710498392Google Scholar
5.
Risch HA, McLaughlin JR, Cole DE.  et al.   Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer.   Am J Hum Genet. 2001;68(3):700-71011179017Google ScholarCrossref
6.
Risch HA, McLaughlin JR, Cole DE.  et al.   Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada.   J Natl Cancer Inst. 2006;98(23):1694-170617148771Google ScholarCrossref
7.
Thorlacius S, Struewing JP, Hartge P.  et al.   Population-based study of risk of breast cancer in carriers of BRCA2 mutation.   Lancet. 1998;352(9137):1337-13399802270Google ScholarCrossref
8.
Warner E, Foulkes W, Goodwin P.  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(14):1241-124710413426Google ScholarCrossref
9.
Begg CB. On the use of familial aggregation in population-based case probands for calculating penetrance.  J Natl Cancer Inst. 2002;94(16):1221-122612189225Google ScholarCrossref
10.
Gong G, Whittemore AS. Optimal designs for estimating penetrance of rare mutations of disease-susceptibility genes.  Genet Epidemiol. 2003;24(3):173-18012652521Google ScholarCrossref
11.
Whittemore AS, Gong G. On the use of familial aggregation in population-based case probands for calculating penetrance.  J Natl Cancer Inst. 2003;95(1):76-7712509408Google ScholarCrossref
12.
Ponder BA, Antoniou A, Dunning A, Easton DF, Pharoah PD. Polygenic inherited predisposition to breast cancer.  Cold Spring Harb Symp Quant Biol. 2005;70:35-4116869736Google ScholarCrossref
13.
Antoniou AC, Pharoah PD, McMullan G.  et al.   A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes.   Br J Cancer. 2002;86(1):76-8311857015Google ScholarCrossref
14.
Pharoah PD, Antoniou A, Bobrow M, Zimmern RL, Easton DF, Ponder BAJ. Polygenic susceptibility to breast cancer and implications for prevention.  Nat Genet. 2002;31(1):33-3611984562Google ScholarCrossref
15.
Garber JE, Goldstein AM, Kantor AF, Dreyfus MG, Fraumeni JF, Li FP. Follow-up study of twenty-four families with Li-Fraumeni syndrome.  Cancer Res. 1991;51(22):6094-60971933872Google Scholar
16.
Meijers-Heijboer H, van den Ouweland A, Klijn J.  et al.   Low penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in non-carriers of BRCA1 and BRCA2 mutations.   Nat Genet. 2002;31(1):55-5911967536Google ScholarCrossref
17.
Ahmed M, Rahman N. ATM and breast cancer susceptibility.   Oncogene. 2006;25(43):5906-591116998505Google ScholarCrossref
18.
Bernstein JL, Langholz B, Haile RW.  et al.  Study design: evaluating gene-environment interactions in the etiology of breast cancer: the WECARE study.  Breast Cancer Res. 2004;6(3):R199-R21415084244Google ScholarCrossref
19.
Langholz B, Goldstein L. Risk set sampling in epidemiologic cohort studies.  Stat Sci. 1996;11(1):35-53Google ScholarCrossref
20.
Ziogas A, Anton-Culver H. Validation of family history data in cancer family registries.  Am J Prev Med. 2003;24(2):190-19812568826Google ScholarCrossref
21.
Bondy ML, Strom SS, Colopy MW, Brown BW, Strong LC. Accuracy of family history of cancer obtained through interview with relatives of patients with childhood sarcoma.  J Clin Epidemiol. 1994;47(1):89-968283198Google ScholarCrossref
22.
Bernstein JL, Teraoka S, Haile RW.  et al.   Designing and implementing quality control for multi-center screening of mutations in the ATM gene among women with breast cancer.   Hum Mutat. 2003;21(5):542-55012673797Google ScholarCrossref
23.
Antoniou A, Pharoah PD, Narod S.  et al.   Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies.   Am J Hum Genet. 2003;72(5):1117-113012677558Google ScholarCrossref
24.
Chatterjee N, Wacholder S. A marginal likelihood approach for estimating penetrance from kin-cohort designs.  Biometrics. 2001;57(1):245-25211252606Google ScholarCrossref
25.
Andrieu N, Goldgar DE, Easton DF.  et al.   Pregnancies, breast feeding, and breast cancer risk in the International BRCA1/2 Carrier Cohort Study.   J Natl Cancer Inst. 2006;98(8):535-54416622123Google ScholarCrossref
26.
Antoniou AC, Shenton A, Maher ER.  et al.   Parity and breast cancer risk among BRCA1 And BRCA2 mutation carriers.   Breast Cancer Res. 2006;8(6):R7217187672Google ScholarCrossref
27.
Cullinane CA, Lubinski J, Neuhausen SL.  et al.   Effect of pregnancy as a risk factor for breast cancer in BRCA1/BRCA2 mutation carriers.   Int J Cancer. 2005;117(6):988-99115986445Google ScholarCrossref
28.
Mitchell G, Antoniou AC, Warren R.  et al.   Mammographic density and breast cancer risk in BRCA1 and BRCA2 mutation carriers.   Cancer Res. 2006;66(3):1866-187216452249Google ScholarCrossref
29.
Chen S, Parmigiani G.  Meta-analysis of BRCA1 and BRCA2 penetrance.   J Clin Oncol. 2007;25(11):1329-133317416853Google ScholarCrossref
30.
Thompson D, Easton DF.  Variation in BRCA1 cancer risks by mutation position.   Cancer Epidemiol Biomarkers Prev. 2002;11(4):329-33711927492Google Scholar
31.
Antoniou AC, Easton DF. Models of genetic susceptibility to breast cancer.  Oncogene. 2006;25(43):5898-590616998504Google ScholarCrossref
32.
Hunter DJ, Kraft P, Jacobs KB.  et al.   A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic post-menopausal breast cancer.   Nat Genet. 2007;39(7):870-87417529973Google ScholarCrossref
33.
Easton DF, Pooley KA, Dunning AM.  et al.  Genome-wide association study identifies novel breast cancer susceptibility loci.  Nature. 2007;447(7148):1087-109317529967Google ScholarCrossref
34.
Cui J, Hopper JL. Why are the majority of hereditary cases of early-onset breast cancer sporadic? a simulation study.  Cancer Epidemiol Biomarkers Prev. 2000;9(8):805-81210952097Google Scholar
35.
Khoury MJ, Beaty TH, Liang KY. Can familial aggregation of disease be explained by familial aggregation of environmental risk factors?  Am J Epidemiol. 1988;127(3):674-6833341366Google Scholar
36.
Thomas DC. Statistical Methods in Genetic Epidemiology. New York, NY: Oxford University Press; 2004:137-138
37.
Langholz B, Ziogas A, Thomas DC, Faucett C, Huberman M, Goldstein L. Ascertainment bias in rate ratio estimation from case-sibling control studies of variable age-at-onset diseases.  Biometrics. 1999;55(4):1129-113611315058Google ScholarCrossref
38.
Pharoah PDP, Day NE, Duffy S, Easton DF, Ponder BAJ. Family history and the risk of breast cancer: a systematic review and meta-analysis.  Int J Cancer. 1997;71(5):800-8099180149Google ScholarCrossref
Original Contribution
January 9/16, 2008

Variation of Breast Cancer Risk Among BRCA1/2 Carriers

Author Affiliations
 

Author Affiliations: Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York (Drs Begg, Capanu, Liang, Sima, and J. Bernstein and Ms Hummer); Department of Preventive Medicine, University of Southern California, Los Angeles (Drs Haile, Thomas, Langholz, and L. Bernstein); Department of Oncology, University Hospital, Lund, Sweden (Dr Borg); Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington (Dr Malone); Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville (Dr Concannon); Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark (Dr Olsen); Department of Epidemiology, University of Iowa, Iowa City (Dr Lynch); and Department of Medicine, University of California, Irvine (Dr Anton-Culver).

JAMA. 2008;299(2):194-201. doi:10.1001/jama.2007.55-a
Abstract

Context  The risk of breast cancer in BRCA1 and BRCA2 mutation carriers has been examined in many studies, but relatively little attention has been paid to the degree to which the risk may vary among carriers.

Objectives  To determine the extent to which risks for BRCA1 and BRCA2 carriers vary with respect to observable and unobservable characteristics.

Design, Setting, and Participants  Probands were identified from a population-based, case-control study (Women’s Environmental Cancer and Radiation Epidemiology [WECARE]) of asynchronous contralateral breast cancer conducted during the period of January 2000 to July 2004. Participants previously diagnosed with contralateral breast cancer or unilateral breast cancer were genotyped for mutations in BRCA1 and BRCA2. All participants had their initial breast cancer diagnosed during the period of January 1985 to December 2000, before the age of 55 years.

Main Outcome Measure Incidence of breast cancer in first-degree female relatives of the probands was examined and compared on the basis of proband characteristics and on the basis of variation between families.

Results  Among the 1394 participants with unilateral breast cancer, 73 (5.2%) were identified as carriers of deleterious mutations (42 with BRCA1 and 31 with BRCA2). Among the 704 participants with contralateral breast cancer, 108 (15.3%) were identified as carriers of deleterious mutations (67 with BRCA1 and 41 with BRCA2). Among relatives of carriers, risk was significantly associated with younger age at diagnosis in the proband (P = .04), and there was a trend toward higher risk for relatives of contralateral breast cancer vs unilateral breast cancer participants (odds ratio, 1.4 [95% confidence interval, 0.8-2.4]; P = .28). In addition, there were significant differences in risk between carrier families after adjusting for these observed characteristics.

Conclusion  There exists broad variation in breast cancer risk among carriers of BRCA1 and BRCA2 mutations.

×