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Journal of Clinical Oncology, Vol 20, Issue 11 (June), 2002: 2701-2712
© 2002 American Society for Clinical Oncology

BRCAPRO Validation, Sensitivity of Genetic Testing of BRCA1/BRCA2, and Prevalence of Other Breast Cancer Susceptibility Genes

By Donald A. Berry, Edwin S. Iversen, Jr, Daniel F. Gudbjartsson, Elaine H. Hiller, Judy E. Garber, Beth N. Peshkin, Caryn Lerman, Patrice Watson, Henry T. Lynch, Susan G. Hilsenbeck, Wendy S. Rubinstein, Kevin S. Hughes, Giovanni Parmigiani

From the Department of Biostatistics, University of Texas M.D. Anderson Cancer Center, and Breast Center, Baylor College of Medicine, Houston, TX; Institute of Statistics and Decision Sciences, Duke University, Durham, NC; Dana-Farber Cancer Institute, Harvard University, and Division of Surgical Oncology, Massachusetts General Hospital, Boston, and Lahey Clinic, Burlington, MA; Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC; University of Pennsylvania Cancer Center, Philadelphia, PA; Creighton University, Omaha, NE; Center for Medical Genetics, Evanston Northwestern Healthcare, Evanston, IL; and Departments of Oncology and Biostatistics, Johns Hopkins University, Baltimore, MD.

Address reprint requests to Donald A. Berry, PhD, Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 447, Houston, TX 77030-4009; email: dberry{at}mdanderson.org

PURPOSE: To compare genetic test results for deleterious mutations of BRCA1 and BRCA2 with estimated probabilities of carrying such mutations; to assess sensitivity of genetic testing; and to assess the relevance of other susceptibility genes in familial breast and ovarian cancer.

PATIENTS AND METHODS: Data analyzed were from six high-risk genetic counseling clinics and concern individuals from families for which at least one member was tested for mutations at BRCA1 and BRCA2. Predictions of genetic predisposition to breast and ovarian cancer for 301 individuals were made using BRCAPRO, a statistical model and software using Mendelian genetics and Bayesian updating. Model predictions were compared with the results of genetic testing.

RESULTS: Among the test individuals, 126 were Ashkenazi Jewish, three were male subjects, 243 had breast cancer, 49 had ovarian cancer, 34 were unaffected, and 139 tested positive for BRCA1 mutations and 29 for BRCA2 mutations. BRCAPRO performed well: for the 150 probands with the smallest BRCAPRO carrier probabilities (average, 29.0%), the proportion testing positive was 32.7%; for the 151 probands with the largest carrier probabilities (average, 95.2%), 78.8% tested positive. Genetic testing sensitivity was estimated to be at least 85%, with false-negatives including mutations of susceptibility genes heretofore unknown.

CONCLUSION: BRCAPRO is an accurate counseling tool for determining the probability of carrying mutations of BRCA1 and BRCA2. Genetic testing for BRCA1 and BRCA2 is highly sensitive, missing an estimated 15% of mutations. In the populations studied, breast cancer susceptibility genes other than BRCA1 and BRCA2 either do not exist, are rare, or are associated with low disease penetrance.




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