This Article  • Full text  • PDF  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on Web of Science (201)  • Contact me when this article is cited  Related Content  • Related letter  • Related articles  • Similar articles in JAMA  Topic Collections  • Oncology  • Breast Cancer  • Genetics  • Genetic Counseling/ Testing/ Therapy  • Genetic Disorders  • Alert me on articles by topic  Social Bookmarking   What's this?

Beth Newman, PhD; Hua Mu, MD, PhD; Lesley M. Butler; Robert C. Millikan, DVM, PhD; Patricia G. Moorman, PhD; Mary-Claire King, PhD

JAMA. 1998;279:915-921.

Context.— Previous studies of BRCA1 mutation prevalence have been based on high-risk groups, yielding estimates that do not reflect the experience of the general population of US patients with breast cancer.

Objective.— To determine prevalence of known disease-related mutations and other variants in BRCA1 and how it differs by race, age at diagnosis, and family history status in a population-based sample of white and black patients with breast cancer unselected for family history.

Design.— Case-control study.

Setting.— A 24-county area of central and eastern North Carolina.

Participants.— Cases were women aged 20 to 74 years diagnosed as having a first invasive breast cancer between May 1993 and June 1996. Controls were frequency matched to cases by 5-year age range and race. The first 211 cases and 188 controls regardless of race and the subsequent 99 cases and 108 controls of African American ancestry are included in this report.

Main Outcome Measure.— Germline variants at any site in the coding sequence, splice junctions, 5' untranslated region, or 3' untranslated region of the BRCA1 gene were analyzed in cases, and selected variants were analyzed in controls. Screening was performed using multiplex single-strand conformation analysis, with all potential variants confirmed using genomic sequencing.

Results.— Three of 211 patients with breast cancer had disease-related variants at BRCA1, all of which were protein-truncating mutations. After adjustment for sampling probabilities, the proportion of patients with breast cancer with disease-related variants was 3.3% (95% confidence interval, 0%-7.2%) in white women and 0% in black women. Young age at diagnosis alone did not predict BRCA1 carrier status in this population. In white women, prevalence of inherited mutation was 23% for cases with family history of ovarian cancer, 13% for cases from families with at least 4 cases of breast cancer with or without ovarian cancer, and 33% for cases from families with both breast and ovarian cancer and at least 4 affected relatives. Because these results are based on few families at the highest levels of risk, confidence intervals around these estimates are wide. An additional 5 patients had rare missense mutations or a single amino acid deletion, the biological significance of which is unknown. In black women, a variant in the 3' untranslated region was statistically significantly more common in cases than in controls.

Conclusions.— These data suggest that in the general US population, widespread screening of BRCA1 is not warranted. In contrast, BRCA1 mutations are sufficiently frequent in families with both breast and ovarian cancer, or at least 4 cases of breast cancer (at any age), that genotyping might be considered. The emerging picture of BRCA1 population genetics involves complex interactions of family history, age, and genetic ancestry, all of which should be taken into account when considering testing or interpreting results.

From the Department of Epidemiology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill (Drs Newman, Millikan, and Moorman and Ms Butler); and the Department of Genetics and Division of Medical Genetics, Department of Medicine, University of Washington, Seattle (Drs Mu and King and Ms Butler); and the Department of Epidemiology and Public Health, Yale University, New Haven, Conn (Dr Moorman).

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter     What's this?

RELATED LETTER

BRCA1 and Medullary Breast Cancer
François Eisinger, Catherine Noguès, Daniel Birnbaum, Jocelyne Jacquemier, Hagay Sobol, Kathleen E. Malone, Janet R. Daling, and Elaine A. Ostrander
JAMA. 1998;280(14):1227-1228.
EXTRACT | FULL TEXT  

RELATED ARTICLES

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
Kathleen E. Malone, Janet R. Daling, Jennifer D. Thompson, Cecilia A. O'Brien, Leigh V. Francisco, and Elaine A. Ostrander
JAMA. 1998;279(12):922-929.
ABSTRACT | FULL TEXT  

BRCA1 Testing—Advances and Retreats
Fergus J. Couch and Lynn C. Hartmann
JAMA. 1998;279(12):955-957.
EXTRACT | FULL TEXT  

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Hormone Therapy and the Risk of Breast Cancer in BRCA1 Mutation Carriers
Eisen et al.
JNCI J Natl Cancer Inst 2008;100:1361-1367.
ABSTRACT | FULL TEXT  

Allelic imbalance in BRCA1 and BRCA2 gene expression is associated with an increased breast cancer risk
Chen et al.
Hum Mol Genet 2008;17:1336-1348.
ABSTRACT | FULL TEXT  

Prevalence of Pathogenic BRCA1 Mutation Carriers in 5 US Racial/Ethnic Groups
John et al.
JAMA 2007;298:2869-2876.
ABSTRACT | FULL TEXT  

Genetic Mapping in Mice Identifies DMBT1 as a Candidate Modifier of Mammary Tumors and Breast Cancer Risk
Blackburn et al.
Am. J. Pathol. 2007;170:2030-2041.
ABSTRACT | FULL TEXT  

Prevalence and Predictors of BRCA1 and BRCA2 Mutations in a Population-Based Study of Breast Cancer in White and Black American Women Ages 35 to 64 Years
Malone et al.
Cancer Res. 2006;66:8297-8308.
ABSTRACT | FULL TEXT  

Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study.
Carey et al.
JAMA 2006;295:2492-2502.
ABSTRACT | FULL TEXT  

Estimating the effect of human base excision repair protein variants on the repair of oxidative DNA base damage.
Sokhansanj and Wilson
Cancer Epidemiol. Biomarkers Prev. 2006;15:1000-1008.
ABSTRACT | FULL TEXT  

Spectrum of Mutations in BRCA1, BRCA2, CHEK2, and TP53 in Families at High Risk of Breast Cancer
Walsh et al.
JAMA 2006;295:1379-1388.
ABSTRACT | FULL TEXT  

Androgen Receptor and Prostate-Specific Antigen Gene Polymorphisms and Breast Cancer in African-American Women
Wang et al.
Cancer Epidemiol. Biomarkers Prev. 2005;14:2990-2994.
ABSTRACT | FULL TEXT  

Genetic Testing in an Ethnically Diverse Cohort of High-Risk Women: A Comparative Analysis of BRCA1 and BRCA2 Mutations in American Families of European and African Ancestry
Nanda et al.
JAMA 2005;294:1925-1933.
ABSTRACT | FULL TEXT  

Marketing Genetic Tests: Empowerment or Snake Oil?
Bowen et al.
Health Educ Behav 2005;32:676-685.
ABSTRACT  

Complete allelic analysis of BRCA1 and BRCA2 variants in young Nigerian breast cancer patients
Fackenthal et al.
J. Med. Genet. 2005;42:276-281.
FULL TEXT  

Prevalence of BRCA1 and BRCA2 Mutations in Women Diagnosed With Ductal Carcinoma In Situ
Claus et al.
JAMA 2005;293:964-969.
ABSTRACT | FULL TEXT  

Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population
Shaag et al.
Hum Mol Genet 2005;14:555-563.
ABSTRACT | FULL TEXT  

Prevalence of BRCA2 mutations in a hospital based series of unselected breast cancer cases
Kim et al.
J. Med. Genet. 2005;42:e5-e5.
FULL TEXT  

Breast Cancer in African-American Women
Newman
The Oncologist 2005;10:1-14.
ABSTRACT | FULL TEXT  

Estrogen Receptor Genotypes and Haplotypes Associated with Breast Cancer Risk
Gold et al.
Cancer Res. 2004;64:8891-8900.
ABSTRACT | FULL TEXT  

Prevalence of BRCA1 Mutation Carriers among U.S. Non-Hispanic Whites
Whittemore et al.
Cancer Epidemiol. Biomarkers Prev. 2004;13:2078-2083.
ABSTRACT | FULL TEXT  

BRCA1 and BRCA2 Mutations in a Study of African American Breast Cancer Patients
Pal et al.
Cancer Epidemiol. Biomarkers Prev. 2004;13:1794-1799.
ABSTRACT | FULL TEXT  

Minority Recruitment in Hereditary Breast Cancer Research
Hughes et al.
Cancer Epidemiol. Biomarkers Prev. 2004;13:1146-1155.
ABSTRACT | FULL TEXT  

Structure-Based Assessment of Missense Mutations in Human BRCA1: Implications for Breast and Ovarian Cancer Predisposition
Mirkovic et al.
Cancer Res. 2004;64:3790-3797.
ABSTRACT | FULL TEXT  

Fertility preservation in female patients
Sonmezer and Oktay
Hum Reprod Update 2004;10:251-266.
ABSTRACT | FULL TEXT  

BRCA1 and BRCA2 Mutations in Women from Shanghai China
Suter et al.
Cancer Epidemiol. Biomarkers Prev. 2004;13:181-189.
ABSTRACT | FULL TEXT  

Racial Meanings and Scientific Methods: Changing Policies for NIH-Sponsored Publications Reporting Human Variation
Stevens
Journal of Health Politics, Policy and Law 2003;28:1033-1088.
ABSTRACT  

Prognostic significance of the allelic loss of the BRCA1 gene in colorectal cancer
Garcia et al.
Gut 2003;52:1756-1763.
ABSTRACT | FULL TEXT  

Individual and family characteristics associated with protein truncating BRCA1 and BRCA2 mutations in an Ontario population based series from the Cooperative Family Registry for Breast Cancer Studies
Ozcelik et al.
J. Med. Genet. 2003;40:e91-91.
FULL TEXT  

Application of Breast Cancer Risk Prediction Models in Clinical Practice
Domchek et al.
JCO 2003;21:593-601.
ABSTRACT | FULL TEXT  

Understanding missense mutations in the BRCA1 gene: An evolutionary approach
Fleming et al.
Proc. Natl. Acad. Sci. USA 2003;100:1151-1156.
ABSTRACT | FULL TEXT  

BRCA1/2 Genetic Testing in the Community Setting
Chen et al.
JCO 2002;20:4485-4492.
ABSTRACT | FULL TEXT  

Heritability of Mammographic Density, a Risk Factor for Breast Cancer
Boyd et al.
NEJM 2002;347:886-894.
ABSTRACT | FULL TEXT  

Clinical Characteristics of Individuals With Germline Mutations in BRCA1 and BRCA2: Analysis of 10,000 Individuals
Frank et al.
JCO 2002;20:1480-1490.
ABSTRACT | FULL TEXT  

BRCA1 and BRCA2 Mutation Frequency in Women Evaluated in a Breast Cancer Risk Evaluation Clinic
Shih et al.
JCO 2002;20:994-999.
ABSTRACT | FULL TEXT  

Unique de novo mutation of BRCA2 in a woman with early onset breast cancer
Robson et al.
J. Med. Genet. 2002;39:126-128.
FULL TEXT  

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
King et al.
JAMA 2001;286:2251-2256.
ABSTRACT | FULL TEXT  

Family History of Breast and Ovarian Cancers and BRCA1 and BRCA2 Mutations in a Population-Based Series of Early-Onset Breast Cancer
Loman et al.
JNCI J Natl Cancer Inst 2001;93:1215-1223.
ABSTRACT | FULL TEXT  

Association Between the T29->C Polymorphism in the Transforming Growth Factor {beta}1 Gene and Breast Cancer Among Elderly White Women: The Study of Osteoporotic Fractures
Ziv et al.
JAMA 2001;285:2859-2863.
ABSTRACT | FULL TEXT  

The Lifetime Risks of Breast Cancer in Ashkenazi Jewish Carriers of BRCA1 and BRCA2 Mutations
Satagopan et al.
Cancer Epidemiol. Biomarkers Prev. 2001;10:467-473.
ABSTRACT | FULL TEXT  

Cost of Genetic Counseling and Testing for BRCA1 and BRCA2 Breast Cancer Susceptibility Mutations
Lawrence et al.
Cancer Epidemiol. Biomarkers Prev. 2001;10:475-481.
ABSTRACT | FULL TEXT  

'Other' breast cancer susceptibility genes: searching for more holy grail
Nathanson and Weber
Hum Mol Genet 2001;10:715-720.
ABSTRACT | FULL TEXT  

Towards a molecular epidemiology of alcohol dependence: analysing the interplay of genetic and environmental risk factors
HEATH et al.
Br. J. Psychiatry 2001;178 :s33-s40.
ABSTRACT | FULL TEXT  

Genetically Engineered Rodent Models of Mammary Gland Carcinogenesis: An Overview
Blackshear
Toxicol Pathol 2001;29:105-116.
ABSTRACT  

Are BRCA1- and BRCA2-Associated Breast Cancers Different? Prognosis of BRCA1-Associated Breast Cancer
Robson
JCO 2000;18:113s-118.
ABSTRACT | FULL TEXT  

Prognostic Significance of Germline BRCA2 Mutations in Hereditary Breast Cancer Patients
Verhoog et al.
JCO 2000;18:119s-124.
ABSTRACT | FULL TEXT  

Population-Based Study of BRCA1 and BRCA2 Mutations in 1035 Unselected Finnish Breast Cancer Patients
Syrjakoski et al.
JNCI J Natl Cancer Inst 2000;92:1529-1531.
FULL TEXT  

BRCA2 germline mutations among early onset breast cancer patients unselected for family history of the disease
PLASCHKE et al.
J. Med. Genet. 2000;37:17e-17.
FULL TEXT  

Glutathione S-Transferases M1, T1, and P1 and Breast Cancer
Millikan et al.
Cancer Epidemiol. Biomarkers Prev. 2000;9:567-573.
ABSTRACT | FULL TEXT  

Major Improvement in the Efficacy of BRCA1 Mutation Screening Using Morphoclinical Features of Breast Cancer
Lidereau et al.
Cancer Res. 2000;60:1206-1210.
ABSTRACT | FULL TEXT  

Breast Conservation Therapy for Invasive Breast Cancer in Ashkenazi Women With BRCA Gene Founder Mutations
Robson et al.
JNCI J Natl Cancer Inst 1999;91:2112-2117.
ABSTRACT | FULL TEXT  

Study Design in Genetic Epidemiology: Theoretical and Practical Considerations
Whittemore and Nelson
J Natl Cancer Inst Monogr 1999;1999:61-69.
ABSTRACT | FULL TEXT  

A 40-Year-Old Woman With a Strong Family History of Breast Cancer
Garber
JAMA 1999;282:1953-1960.
FULL TEXT  

Weighing the Risks and Benefits of Tamoxifen Treatment for Preventing Breast Cancer
Gail et al.
JNCI J Natl Cancer Inst 1999;91:1829-1846.
ABSTRACT | FULL TEXT  

Genetic Polymorphisms and Risk of Breast Cancer
Coughlin and Piper
Cancer Epidemiol. Biomarkers Prev. 1999;8:1023-1032.
FULL TEXT  

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
Hopper et al.
Cancer Epidemiol. Biomarkers Prev. 1999;8:741-747.
ABSTRACT | FULL TEXT  

Prevalence and Penetrance of BRCA1 and BRCA2 Gene Mutations in Unselected Ashkenazi Jewish Women With Breast Cancer
Warner et al.
JNCI J Natl Cancer Inst 1999;91:1241-1247.
ABSTRACT | FULL TEXT  

BRCA1 and BRCA2: a Small Part of the Puzzle
Burke et al.
JNCI J Natl Cancer Inst 1999;91:904-905.
FULL TEXT  

Prevalence of BRCA1 and BRCA2 Gene Mutations in Patients With Early-Onset Breast Cancer
Peto et al.
JNCI J Natl Cancer Inst 1999;91:943-949.
ABSTRACT | FULL TEXT  

Attitudes and Interest in Genetic Testing for Breast and Ovarian Cancer Susceptibility in Diverse Groups of Women in Western Washington
Durfy et al.
Cancer Epidemiol. Biomarkers Prev. 1999;8:369-375.
ABSTRACT | FULL TEXT  

BRCA1 is associated with the centrosome during mitosis
Hsu and White
Proc. Natl. Acad. Sci. USA 1998;95:12983-12988.
ABSTRACT | FULL TEXT  

BRCA1 and Medullary Breast Cancer
Eisinger et al.
JAMA 1998;280:1227-1228.
FULL TEXT  

More on BRCA1 and Breast Cancer
JWatch Women's Health 1998;1998:4-4.
FULL TEXT  

Limitations of BRCA1 as Marker for Breast Cancer Risk
JWatch General 1998;1998:6-6.
FULL TEXT  

BRCA1 Testing--Advances and Retreats
Couch and Hartmann
JAMA 1998;279:955-957.
FULL TEXT