Affiliations of authors: V. Bonadona, C. Lasset, Unit of Prevention and Genetic Epidemiology, Department of Public Health, Cancer Centre Léon Bérard, Lyon, France; O. M. Sinilnikova, Hospices Civils de Lyon and the International Agency for Research on Cancer, Lyon; G. M. Lenoir, Institut Gustave Roussy Villejuif and the International Agency for Research on Cancer, Lyon.
Correspondence to: V. Bonadona, M.D., Unit of Prevention and Genetic Epidemiology, Department of Public Health, Cancer Centre Léon Bérard, 28 rue Laénnec, Lyon 69 008, France (e-mail: bonadona{at}lyon.fnclcc.fr).
Euhus and colleagues (1) have assessed the performance of the computer model BRCAPRO (2) at identifying families likely to carry a deleterious germline mutation in the BRCA1/2 breast/ ovarian cancer predisposing genes in a series of 148 high-risk pedigrees. Compared with subjective assessment by cancer risk counselors, BRCAPRO estimation of BRCA1/2 gene mutation-carrier probabilities showed superior specificity (15.7% versus 31.7%, respectively).
Because the study by Euhus et al. (1) was limited to a highly selected sample of women with strong family histories of cancer, it is important to assess the validity of BRCAPRO probability estimates in a more general context of breast cancer susceptibility. We recently reported data from a French prospective series of early-onset breast cancer patients ascertained through a population-based cancer registry (3). Pedigree information and blood samples were available for 232 women diagnosed with breast cancer before age 46 years. The BRCA1 and BRCA2 genes were analyzed by heteroduplex analysis and denaturing high performance liquid chromatography. The cancer family history of each patient was assessed by two cancer geneticists and classified by consensus into one of the following hereditary breast cancer risk categories: 1) unknown risk (28 patients), 2) isolated breast cancer (103 patients), (3) low risk (38 patients), and 4) high risk (63 patients) (Table 1). BRCA gene mutation-carrier probability estimates were calculated using the BRCAPRO model.
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The lower predictive value of the BRCAPRO model in our population-based study may be explained by the limitations of the model, which uses pedigree information from first- and second-degree relatives only and breast/ovarian cancer penetrance estimates based on selected high-risk families from the Breast Cancer Linkage Consortium (4). Population-based penetrance estimates have been shown to be lower than those derived from high-risk families (5,6). In addition, Berry et al. (7) have shown that assuming smaller penetrance increases BRCAPRO sensitivity. Thus, the use of inaccurate, overestimated penetrance estimates may partly explain the low performance of BRCAPRO at identifying families with deleterious BRCA mutations in our study.
In summary, although BRCAPRO is an accurate counseling tool for estimating the probability of gene mutations in high-risk cancer families, cancer risk counselors should be aware that BRCAPRO may not be suitable for families of probands ascertained through a population-based approach or for families presenting with small family size or male predominance. Our findings suggest that selection of an individual for BRCA gene mutation testing based on calculated BRCAPRO probabilities in young breast cancer patients could lead to a substantial number of gene mutations being missed.
REFERENCES
1 Euhus DM, Smith KC, Robinson L, Stucky A, Olopade OI, Cummings S, et al. Pretest prediction of BRCA1 or BRCA2 mutation by risk counselors and the computer model BRCAPRO. J Natl Cancer Inst 2002;94:84451.
2 Parmigiani G, Berry D, Aguilar O. Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2. Am J Hum Genet 1998;62:14558.[Medline]
3 Lasset C, Bonadona V, Bremond A, Mignotte H, Mathevet P, Martin A, et al. Prevalence of BRCA1 and BRCA2 germline mutations in young women diagnosed with breast cancer. Results from a population-based study in France [abstract 1677]. Proc ASCO 2001;20.
4 Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet 1998;62:67689.[Medline]
5 Hopper JL, Southey MC, Dite GS, Jolley DJ, Giles GG, McCredie MR, 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;8:7417.
6 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;83:13018.[Medline]
7 Berry D, Iversen ES, Gudbjartsson DF, Hiller EH, Garber JE, Peshkin BN, et al. BRCAPRO validation, sensitivity of genetic testing of BRCA1/2, and prevalence of other breast cancer susceptibility genes. J Clin Oncol 2002;20:270112.
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