title: Penetrances of breast and ovarian cancer in a large series of families tested for BRCA1/2 mutations.
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.
authors.affiliation: Department of Oncology, Transplants and New Technologies in Medicine, Section of Pathology, University of Pisa, Pisa, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Marroni
authors.forename: Paolo
authors.initials: P
authors.lastname: Aretini
authors.forename: Emma
authors.initials: E
authors.lastname: D'Andrea
authors.forename: Maria Adelaide
authors.initials: MA
authors.lastname: Caligo
authors.forename: Laura
authors.initials: L
authors.lastname: Cortesi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Viel
authors.forename: Enrico
authors.initials: E
authors.lastname: Ricevuto
authors.forename: Marco
authors.initials: M
authors.lastname: Montagna
authors.forename: Giovanna
authors.initials: G
authors.lastname: Cipollini
authors.forename: Massimo
authors.initials: M
authors.lastname: Federico
authors.forename: Manuela
authors.initials: M
authors.lastname: Santarosa
authors.forename: Paolo
authors.initials: P
authors.lastname: Marchetti
authors.forename: Joan E
authors.initials: JE
authors.lastname: Bailey-Wilson
authors.forename: Generoso
authors.initials: G
authors.lastname: Bevilacqua
authors.forename: Giovanni
authors.initials: G
authors.lastname: Parmigiani
authors.forename: Silvano
authors.initials: S
authors.lastname: Presciuttini
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D002874:Chromosome Mapping; D003198:Computer Simulation; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D016013:Likelihood Functions; D008875:Middle Aged; D009154:Mutation; D010051:Ovarian Neoplasms / Q000453:epidemiology / Q000235:genetics*; D019683:Penetrance; D012306:Risk