1. ¹Department of Oncology, Transplants and New Technologies in Medicine, Section of Pathology, University of Pisa, Pisa, Italy
2. ²Center of Statistical Genetics, University of Pisa, Pisa, Italy
3. ³Department of Oncology and Surgical Sciences, Section of Oncology, Section of Viral and Molecular Oncology, University of Padua, Padua, Italy
4. ⁴Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy
5. ⁵Experimental Oncology 1, Oncology Referral Center, IRCCS, Aviano, Italy
6. ⁶Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy
7. ⁷IST, Section of Viral and Molecular Oncology, University of Padua, Padua, Italy
8. ⁸Modena's Oncology Center; University of Modena and Reggio Emilia, Modena, Italy
9. ⁹Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD, USA
10. ¹⁰Departments of Oncology and Biostatistics, Johns Hopkins University, Baltimore, MD, USA

Correspondence: Professor Silvano Presciuttini, Department of Experimental Pathology, Center of Statistical Genetics, SS Abetone e Brennero 2, 56127 Pisa, Italy. Tel: +39 050 2213797; Fax: +39 050 2213524; E-mail: sprex@biomed.unipi.it

Received 16 January 2004; Revised 10 June 2004; Accepted 20 June 2004; Published online 1 September 2004.

Abstract

Accurate estimates of breast and ovarian cancer penetrance in BRCA1/2 mutation carriers are crucial in genetic counseling. Estimation is difficult because of the low frequency of mutated alleles and the often-uncertain mechanisms of family ascertainment. We estimated the penetrances of breast and ovarian cancers in carriers of BRCA1/2 mutations by maximizing the retrospective likelihood of the genetic model, given the observed test results, in 568 Italian families screened for germline mutations. The software BRCAPRO was used as a probability calculation tool in a Markov Chain Monte Carlo approach. Breast cancer penetrances were 27% (95% CI 20–34%) at age 50 years and 39% (27–52%) at age 70 in BRCA1 carriers, and 26% (0.18–0.34%) at age 50 and 44% (29–58%) at age 70 in BRCA2 carriers, and ovarian cancer penetrances were 14% (7–22%) at age 50 and 43% (21–66%) at age 70 in BRCA1 carriers and 3% (0–7%) at age 50 and 15% (4–26%) at age 70 in BRCA2 carriers. The new model gave a better fit than the current default in BRCAPRO, the likelihood being 70 log units greater; in addition, the observed numbers of mutations in families stratified by gene and by cancer profile were not significantly different from those expected. Our new penetrance functions are appropriate for predicting breast cancer risk, and for determining the probability of carrying BRCA1/2 mutations, in people who are presently referred to genetic counseling in Italy. Our approach could lead to country-customized versions of the BRCAPRO software by providing appropriate population-specific estimates.