Estimate of the penetrance of BRCA mutation and the COS software for the assessment of BRCA mutation probability.
We have designed the user-friendly COS software with the intent to improve estimation of the probability of a family carrying a deleterious BRCA gene mutation. The COS software is similar to the widely-used Bayesian-based BRCAPRO software, but it incorporates improved assumptions on cancer incidence in women with and without a deleterious mutation, takes into account relatives up to the fourth degree and allows researchers to consider an hypothetical third gene or a polygenic model of inheritance. Since breast cancer incidence and penetrance increase over generations, we estimated birth-cohort-specific incidence and penetrance curves. We estimated breast and ovarian cancer penetrance in 384 BRCA1 and 229 BRCA2 mutated families. We tested the COS performance in 436 Italian breast/ovarian cancer families including 79 with BRCA1 and 27 with BRCA2 mutations. The area under receiver operator curve (AUROC) was 84.4 %. The best probability threshold for offering the test was 22.9 %, with sensitivity 80.2 % and specificity 80.3 %. Notwithstanding very different assumptions, COS results were similar to BRCAPRO v6.0.
Department of Preventive and Predictive Medicine, Fondazione IRCSS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy.
Jacopo
J
Berrino
Franco
F
Berrino
Silvia
S
Francisci
Bernard
B
Peissel
Jacopo
J
Azzollini
Valeria
V
Pensotti
Paolo
P
Radice
Patrizia
P
Pasanisi
Siranoush
S
Manoukian
D019540:Area Under Curve; D001499:Bayes Theorem; D001943:Breast Neoplasms / Q000235:genetics; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics*; D019683:Penetrance; D012372:ROC Curve; D012984:Software