title: Improving the accuracy of BRCA1/2 mutation prediction: validation of the novel country-customized IC software.
abstract: Inherited mutations of the BRCA1/2 genes confer a significantly increased risk for breast and/or ovarian cancer development. Several models were elaborated to help genetic counsellors in selecting individuals with high probability of being mutation carriers. The IC software, a country-customized version of the Brcapro model, was recently shown to be particularly accurate in the prediction of carrier probability status in the Italian population. Here, we used our independent series of 70 breast/ovarian cancer families to analyze the performances of the IC software and compare it to widely used models, such as Brcapro and the Myriad mutation prevalence tables. Analysis of the areas under the receiver operator characteristics (ROC) curves indicated that overall the models performed well. However, the IC software and Myriad tables were more efficient in predicting mutated cases, showing a higher sensitivity (94 and 88%, respectively) and negative predictive value (NPV, 94 and 92%, respectively) compared to Brcapro (sensitivity 71 and NPV 83%). IC software also appeared particularly accurate in the identification of families belonging the low mutation risk group (<10%). Finally, most Brcapro failures occurred in the hereditary breast cancer (HBC) family subset, and in 75% of the cases, the IC software corrected them. Our data suggest that the country-customized implementation operated on the Brcapro software generated a more accurate tool for the prediction of BRCA1/2 gene mutation. Whether the IC or other country-customized models might improve BRCA1/2 mutation prediction also in non-Italian families needs to be further explored.
authors.affiliation: Department of Experimental Medicine and Pathology, University La Sapienza, Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Capalbo
authors.forename: Enrico
authors.initials: E
authors.lastname: Ricevuto
authors.forename: Annarita
authors.initials: A
authors.lastname: Vestri
authors.forename: Tina
authors.initials: T
authors.lastname: Sidoni
authors.forename: Amelia
authors.initials: A
authors.lastname: Buffone
authors.forename: Enrico
authors.initials: E
authors.lastname: Cortesi
authors.forename: Paolo
authors.initials: P
authors.lastname: Marchetti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Scambia
authors.forename: Silverio
authors.initials: S
authors.lastname: Tomao
authors.forename: Christian
authors.initials: C
authors.lastname: Rinaldi
authors.forename: Massimo
authors.initials: M
authors.lastname: Zani
authors.forename: Sergio
authors.initials: S
authors.lastname: Ferraro
authors.forename: Luigi
authors.initials: L
authors.lastname: Frati
authors.forename: Isabella
authors.initials: I
authors.lastname: Screpanti
authors.forename: Alberto
authors.initials: A
authors.lastname: Gulino
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannini
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D007558:Italy; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics*; D012372:ROC Curve; D012680:Sensitivity and Specificity; D012984:Software
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein