This Article  • References  • Full text PDF  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Contact me when this article is cited  Related Content  • Similar articles in JAMA  Social Bookmarking   What's this?

Risk Factor Analysis and Implications for Genetic Testing

Donna Shattuck-Eidens, PhD; Arnold Oliphant, PhD; Melody McClure; Celeste McBride; Jamila Gupte, MPhil; Todd Rubano, ME; Dmitry Pruss, PhD; Sean V. Tavtigian, PhD; David H.-F. Teng, PhD; Nils Adey, PhD; Mark Staebell, MS; Kathryn Gumpper; Ron Lundstrom, PhD; Mark Hulick; Mark Kelly; John Holmen, PhD; Beth Lingenfelter, MS; Susan Manley, MS; Frank Fujimura, PhD; Michael Luce, PhD; Brian Ward, PhD; Lisa Cannon-Albright, PhD; Linda Steele; Kenneth Offit, MD; Teresa Gilewski, MD; Larry Norton, MD; Karen Brown, MS; Charlene Schulz, MS; Heather Hampel, MS; Alice Schluger, MS; Elena Giulotto, PhD; Wainer Zoli, PhD; Alberto Ravaioli, MD; Heli Nevanlinna, PhD; Seppo Pyrhonen, MD, PhD; Peter Rowley, MD; Starlene Loader; Michael P. Osborne, MD; Mary Daly, MD; Isidore Tepler, MD; Paul L. Weinstein, MD; Jennifer L. Scalia, MS; Richard Michaelson, MD; Rodney J. Scott, PhD; Paolo Radice, PhD; Marco A. Pierotti, PhD; Judy E. Garber, MD; Claudine Isaacs, MD; Beth Peshkin, MS; Marc E. Lippman, MD; Michael H. Dosik, MD; Maria A. Caligo, MD; Robert M. Greenstein, MD; Robert Pilarski; Barbara Weber, MD; Renate Burgemeister, MD; Thomas S. Frank, MD; Mark H. Skolnick, PhD; Alun Thomas, PhD

JAMA. 1997;278(15):1242-1250.

Abstract
Octext.
—A mutation in the BRCA1 gene may confer substantial risk for breast and/or ovarian cancer. However, knowledge regarding all possible mutations and the relationship between risk factors and mutations is incomplete.

Objectives.
—To identify BRCA1 mutations and to determine factors that best predict presence of a deleterious BRCA1 mutation in patients with breast and/or ovarian cancer.

Design.
—A complete sequence analysis of the BRCA1 coding sequence and flanking intronic regions was performed in 798 women in a collaborative effort involving institutions from the United States, Italy, Germany, Finland, and Switzerland.

Participanta.
—Institutions selected 798 persons representing families (1 person for each family) thought to be at elevated a priori risk of BRCA1 mutation due to potential risk factors, such as multiple cases of breast cancer, early age of breast cancer diagnosis, and cases of ovarian cancer. No participant was from a family in which genetic markers showed linkage to the BRCA1 locus.

Major Outcome Measures.
—Sequence variants detected in this sample are presented along with analyses designed to determine predictive characteristics of those testing positive for BRCA1 mutations.

Results.
—In 102 women (12.8%), clearly deleterious mutations were detected. Fifty new genetic alterations were found including 24 deleterious mutations, 24 variants of unknown significance, and 2 rare polymorphisms. In a subset of 71 Ashkenazi Jewish women, only 2 distinct deleterious mutations were found: 185delAG in 17 cases and 5382insC in 7 cases. A bias in prior reports for mutations in exon 11 was revealed. Characteristics of a patient's specific diagnosis (unilateral or bilateral breast cancer, with or without ovarian cancer), early age at diagnosis, Ashkenazi Jewish ethnicity, and family history of cancer were positively associated with the probability of her carrying a deleterious BRCA1 mutation.

Conclusions.
—Using logistic regression analysis, we provide a method for evaluating the probability of a woman's carrying a deleterious BRCA1 mutation for a wide range of cases, which can be an important tool for clinicians as they incorporate genetic susceptibility testing into their medical practice.

Footnotes
A complete list of authors' affiliations and financial disclosures appears at the end of this article.

Reprints: Alun Thomas, PhD, Myriad Genetics, Inc, 390 Wakara Way, Salt Lake City, UT 84108.

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

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Oral Contraceptive Use and BRCA Penetrance: A Case-Only Study
Pasanisi et al.
Cancer Epidemiol. Biomarkers Prev. 2009;18:2107-2113.
ABSTRACT | FULL TEXT  

Diffusion of Breast Cancer Risk Assessment in Primary Care
Guerra et al.
J Am Board Fam Med 2009;22:272-279.
ABSTRACT | FULL TEXT  

High Prevalence of Preinvasive Lesions Adjacent to BRCA1/2-Associated Breast Cancers
Arun et al.
Cancer Prevention Research 2009;2:122-127.
ABSTRACT | FULL TEXT  

BRCA Germline Mutations in Jewish Patients With Pancreatic Adenocarcinoma
Ferrone et al.
JCO 2009;27:433-438.
ABSTRACT | FULL TEXT  

Genetic Counseling and Testing for Common Hereditary Breast Cancer Syndromes: A Paper from the 2007 William Beaumont Hospital Symposium on Molecular Pathology
Allain
J. Mol. Diagn. 2008;10:383-395.
ABSTRACT | FULL TEXT  

BRCA1 and BRCA2 Genetic Testing in Hispanic Patients: Mutation Prevalence and Evaluation of the BRCAPRO Risk Assessment Model
Vogel et al.
JCO 2007;25:4635-4641.
ABSTRACT | FULL TEXT  

Validity of Models for Predicting BRCA1 and BRCA2 Mutations
Parmigiani et al.
ANN INTERN MED 2007;147:441-450.
ABSTRACT | FULL TEXT  

Counting potentially functional variants in BRCA1, BRCA2 and ATM predicts breast cancer susceptibility
Johnson et al.
Hum Mol Genet 2007;16:1051-1057.
ABSTRACT | FULL TEXT  

Effect of raloxifene on salivary sex steroid concentrations in premenopausal women
Chatterton et al.
J Endocrinol 2006;191:599-604.
ABSTRACT | FULL TEXT  

Effect of Raloxifene on Bone Mineral Density in Premenopausal Women at Increased Risk of Breast Cancer
Eng-Wong et al.
J. Clin. Endocrinol. Metab. 2006;91:3941-3946.
ABSTRACT | FULL TEXT  

Assessing BRCA Carrier Probabilities in Extended Families
Barcenas et al.
JCO 2006;24:354-360.
ABSTRACT | FULL TEXT  

Application of Embryonic Lethal or Other Obvious Phenotypes to Characterize the Clinical Significance of Genetic Variants Found in Trans with Known Deleterious Mutations
Judkins et al.
Cancer Res. 2005;65:10096-10103.
ABSTRACT | FULL TEXT  

Genetic Risk Assessment and BRCA Mutation Testing for Breast and Ovarian Cancer Susceptibility: Recommendation Statement
U.S. Preventive Services Task Force*
ANN INTERN MED 2005;143:355-361.
ABSTRACT | FULL TEXT  

Genetic Risk Assessment and BRCA Mutation Testing for Breast and Ovarian Cancer Susceptibility: Systematic Evidence Review for the U.S. Preventive Services Task Force
Nelson et al.
ANN INTERN MED 2005;143:362-379.
ABSTRACT | FULL TEXT  

Cancer Risk Prediction Models: A Workshop on Development, Evaluation, and Application
Freedman et al.
JNCI J Natl Cancer Inst 2005;97:715-723.
ABSTRACT | 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  

A Multi-Exonic BRCA1 Deletion Identified in Multiple Families through Single Nucleotide Polymorphism Haplotype Pair Analysis and Gene Amplification with Widely Dispersed Primer Sets
Ward et al.
J. Mol. Diagn. 2005;7:139-142.
ABSTRACT | FULL TEXT  

Identifying and Testing for Hereditary Susceptibility to Common Cancers
Sifri et al.
CA Cancer J Clin 2004;54:309-326.
ABSTRACT | FULL TEXT  

Does This Patient Have a Family History of Cancer?: An Evidence-Based Analysis of the Accuracy of Family Cancer History
Murff et al.
JAMA 2004;292:1480-1489.
ABSTRACT | FULL TEXT  

BRCA1 and BRCA2 mutations as prognostic factors in bilateral breast cancer patients
Rogozinska-Szczepka et al.
Ann Oncol 2004;15:1373-1376.
ABSTRACT | FULL TEXT  

Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation
Abkevich et al.
J. Med. Genet. 2004;41:492-507.
ABSTRACT | FULL TEXT  

A new scoring system for the chances of identifying a BRCA1/2 mutation outperforms existing models including BRCAPRO
Evans et al.
J. Med. Genet. 2004;41:474-480.
ABSTRACT | FULL TEXT  

Evaluation of widely used models for predicting BRCA1 and BRCA2 mutations
Marroni et al.
J. Med. Genet. 2004;41:278-285.
FULL TEXT  

Referral for cancer genetics consultation: a review and compilation of risk assessment criteria
Hampel et al.
J. Med. Genet. 2004;41:81-91.
ABSTRACT | FULL TEXT  

Recognition and Management of Hereditary Breast Cancer Syndromes
Thull and Vogel
The Oncologist 2004;9:13-24.
ABSTRACT | FULL TEXT  

Risk Estimation for Healthy Women from Breast Cancer Families: New Insights and New Strategies
van Asperen et al.
Cancer Epidemiol. Biomarkers Prev. 2004;13:87-93.
ABSTRACT | FULL TEXT  

Effect of Raloxifene on Insulin-Like Growth Factor-I, Insulin-Like Growth Factor Binding Protein-3, and Leptin in Premenopausal Women at High Risk for Developing Breast Cancer
Eng-Wong et al.
Cancer Epidemiol. Biomarkers Prev. 2003;12:1468-1473.
ABSTRACT | FULL TEXT  

Segregation Analysis of 231 Ashkenazi Jewish Families for Evidence of Additional Breast Cancer Susceptibility Genes
Kaufman et al.
Cancer Epidemiol. Biomarkers Prev. 2003;12:1045-1052.
ABSTRACT | FULL TEXT  

BRCA1 c.2845insA is a recurring mutation with a founder effect in Singapore Malay women with early onset breast/ovarian cancer
Sng et al.
J. Med. Genet. 2003;40:e117-117.
FULL TEXT  

Genetics and the Management of Women at High Risk for Breast Cancer
Mincey
The Oncologist 2003;8:466-473.
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  

Pre-test prediction models of BRCA1 or BRCA2 mutation in breast/ovarian families attending familial cancer clinics
de la Hoya et al.
J. Med. Genet. 2003;40:503-510.
ABSTRACT | FULL TEXT  

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

Incidence of non-founder BRCA1 and BRCA2 mutations in high risk Ashkenazi breast and ovarian cancer families
Kauff et al.
J. Med. Genet. 2002;39:611-614.
FULL TEXT  

Pretest Prediction of BRCA1 or BRCA2 Mutation by Risk Counselors and the Computer Model BRCAPRO
Euhus et al.
JNCI J Natl Cancer Inst 2002;94:844-851.
ABSTRACT | FULL TEXT  

BRCAPRO Validation, Sensitivity of Genetic Testing of BRCA1/BRCA2, and Prevalence of Other Breast Cancer Susceptibility Genes
Berry et al.
JCO 2002;20:2701-2712.
ABSTRACT | FULL TEXT  

Identification and Referral of Families at High Risk for Cancer Susceptibility
Sweet et al.
JCO 2002;20:528-537.
ABSTRACT | FULL TEXT  

Combined SSCP/duplex analysis by capillary electrophoresis for more efficient mutation detection
Kozlowski and Krzyzosiak
Nucleic Acids Res 2001;29:e71-e71.
ABSTRACT | FULL TEXT  

Diagnostic Strategy for Analytical Scanning of BRCA1 Gene by Fluorescence-assisted Mismatch Analysis Using Large, Bifluorescently Labeled Amplicons
Ricevuto et al.
Clin. Cancer Res. 2001;7:1638-1646.
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  

BRCA1/2 Testing: Complex Themes in Result Interpretation
Peshkin et al.
JCO 2001;19:2555-2565.
ABSTRACT | FULL TEXT  

Germline Mutations in BRCA1 and BRCA2 in Breast-Ovarian Families From a Breast Cancer Risk Evaluation Clinic
Martin et al.
JCO 2001;19:2247-2253.
ABSTRACT | FULL TEXT  

Chemoprevention Options for BRCA1 and BRCA2 Mutation Carriers
Eeles and Powles
JCO 2000;18:93s-99.
ABSTRACT | FULL TEXT  

BRCA1 and BRCA2 Mutations in Breast Cancer Families with Multiple Primary Cancers
Shih et al.
Clin. Cancer Res. 2000;6:4259-4264.
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  

Intention to Undergo Prophylactic Bilateral Mastectomy in Women at Increased Risk of Developing Hereditary Breast Cancer
Meiser et al.
JCO 2000;18:2250-2257.
ABSTRACT | FULL TEXT  

Clinicopathologic Features of BRCA-Linked and Sporadic Ovarian Cancer
Boyd et al.
JAMA 2000;283:2260-2265.
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  

Assessing the Risk of Breast Cancer
Armstrong et al.
NEJM 2000;342:564-571.
FULL TEXT  

Elevated Frequency and Functional Activity of a Specific Germ-Line p53 Intron Mutation in Familial Breast Cancer
Lehman et al.
Cancer Res. 2000;60:1062-1069.
ABSTRACT | FULL TEXT  

BRCA1/BRCA2 Germline Mutations in Locally Recurrent Breast Cancer Patients After Lumpectomy and Radiation Therapy: Implications for Breast-Conserving Management in Patients With BRCA1/BRCA2 Mutations
Turner et al.
JCO 1999;17:3017-3024.
ABSTRACT | FULL TEXT  

Underreporting of Family History of Colon Cancer: Correlates and Implications
Glanz et al.
Cancer Epidemiol. Biomarkers Prev. 1999;8:635-639.
ABSTRACT | FULL TEXT  

Biochemical and genetic characterisation shows that the BRCA1 IVS20 insertion is a polymorphism
SCHOLL et al.
J. Med. Genet. 1999;36:571-572.
FULL TEXT  

Prevalence of Mutations in the BRCA1 Gene Among Chinese Patients With Breast Cancer
Tang et al.
JNCI J Natl Cancer Inst 1999;91:882-885.
FULL TEXT  

Risk factors for detecting germline BRCA1 and BRCA2 founder mutations in Ashkenazi Jewish women with breast or ovarian cancer
Hodgson et al.
J. Med. Genet. 1999;36:369-373.
ABSTRACT | FULL TEXT  

High frequency of BRCA1/2 germline mutations in 42 Belgian families with a small number of symptomatic subjects
Goelen et al.
J. Med. Genet. 1999;36:304-308.
ABSTRACT | FULL TEXT  

Re: Multifactorial Analysis of Differences Between Sporadic Breast Cancers and Cancers Involving BRCA1 and BRCA2 Mutations
Brown et al.
JNCI J Natl Cancer Inst 1999;91:90a-91a.
FULL TEXT  

Screening for Germ-Line Rearrangements and Regulatory Mutations in BRCA1 Led to the Identification of Four New Deletions
Puget et al.
Cancer Res. 1999;59:455-461.
ABSTRACT | FULL TEXT  

Hereditary Risk of Breast and Ovarian Carcinoma: The Role of the Oncologist
Frank
The Oncologist 1998;3:403-412.
ABSTRACT | FULL TEXT  

Testing for the BRCA1 and BRCA2 Breast-Ovarian Cancer Susceptibility Genes: A Decision Analysis
Tengs et al.
Med Decis Making 1998;18:365-375.
ABSTRACT  

Frequency of Breast Cancer Attributable to BRCA1 in a Population-Based Series of American Women
Newman et al.
JAMA 1998;279:915-921.
ABSTRACT | FULL TEXT  

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
Malone et al.
JAMA 1998;279:922-929.
ABSTRACT | FULL TEXT  

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

Special JAMA Highlights Genetic Revolution
Journal Watch Dermatology 1997;1997:16-16.
FULL TEXT  

BRCA1: From the Bench to the Office
JWatch Women's Health 1997;1997:8-8.
FULL TEXT  

SPECIAL JAMA ISSUE HIGHLIGHTS GENETIC MEDICINE REVOLUTION
JWatch General 1997;1997:7-7.
FULL TEXT  

Family History and Genetic Risk Factors: Forward to the Future
Pyeritz
JAMA 1997;278:1284-1285.
ABSTRACT