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Purpose: To evaluate in current practice the performance of BOADICEA and BRCAPRO risk models and empirical criteria based on cancer family history for the selection of individuals for BRCA genetic testing., Patients and Methods: The probability of BRCA mutation according to the three tools was retrospectively estimated in 918 index cases consecutively undergone BRCA testing at 15 Italian cancer genetics clinics between 2006 and 2008., Results: 179 of 918 cases (19.5%) carried BRCA mutations. With the strict use of the criteria based on cancer family history 173 BRCA (21.9%) mutations would have been detected in 789 individuals. At the commonly used 10% threshold of BRCA mutation carrier probability, the genetic models showed a similar performance [PPV (38% and 37%), sensitivity (76% and 77%) and specificity (70% and 69%)]. Their strict use would have avoided around 60% of the tests but would have missed approximately 1 every 4 carriers., Conclusion: Our data highlight the complexity of BRCA testing referral in routine practice and question the strict use of genetic models for BRCA risk assessment., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

An increasing body of evidence points to a possible role of microRNAs (miRNAs) in hereditary cancer syndromes. To evaluate the role of miRNA allelic variants in the susceptibility to familial breast and ovarian cancers in BRCA1/BRCA2-negative patients, we focused our attention on three miRNAs, miR-146a, miR-17 and miR-369, based on their affinity to either BRCA1 or BRCA2 messenger RNA and their localization on chromosome regions commonly deleted in those tumors. The analysis was performed on 101 Italian probands with ascertained familiarity for breast/ovarian cancer and tested negative for both BRCA1 and BRCA2 gene mutations. No allelic variant was detected for hsa-mir-17 and hsa-mir-369, and allelic and genotype frequencies for miR-146a rs2910164 single-nucleotide polymorphism (SNP) were comparable with that of 155 controls from the same population, ruling out a role for genetic variations in these three miRNAs as major determinants in cancer predisposition of BRCA1/BRCA2-negative patients. Instead, our study suggests that mir-146a rs2910164 SNP may impact on the age of cancer onset. In fact, subjects with mir-146a a GC or CC genotypes developed tumors at younger age compared with individuals with the GG genotype Thus, in contrast to a recent report, our data support the hypothesis by Shen and coworkers of an association between the C allele of hsa-mir-146a and early cancer onset and prompt further investigations on the relevance of this polymorphism in early familial breast/ovarian tumor development.

The presence of genomic rearrangements of the BRCA1 gene in breast and/or ovarian cancer families has been intensively investigated in patients from various countries over the last years. A number of different rearrangements have been reported by several studies that clearly document the involvement of this mutation type in genetic predisposition to breast and ovarian cancer. Population-specific studies are now needed to evaluate the prevalence of genomic rearrangements before deciding whether to include ad hoc screening procedures into standard diagnostic mutation detection approaches. Indeed, the vast majority of the studies have been performed on small, highly selected, sample sets because of the limitations imposed by the laborious technical approaches. Moreover, prevalence figures are likely to differ across different countries according to the ethnic origin of each specific population. Here we analyze a large cohort of 653 Italian probands, negative for BRCA1 and BRCA2 point mutations, gathered from four National Institutions. We report the identification of BRCA1 genomic rearrangements in 12 independent families. Noteworthy, half of the probands carry mutations that recur in more than one Italian family. Considering the whole spectrum of Italian BRCA1 gene rearrangements identified thus far in consecutive patients, we estimate that alterations of this type account for 19% (95% CI: 0.11 < 0.19 < 0.28) of the BRCA1 mutation positive families. We conclude that the search for major genomic rearrangements is essential for an accurate and comprehensive BRCA1 mutation detection strategy in Italy., ((c) 2006 Wiley-Liss, Inc.)

Mutations in BRCA1 and BRCA2 show different expressivity with respect to cancer risk, and allelic heterogeneity may be present in both genes. We collected 179 pedigrees with identified germline mutation (104 BRCA1 and 75 BRCA2), ascertained in six collaborating centers of the Italian Consortium for Hereditary Breast and Ovarian Cancer. Significant heterogeneity was detected for several variables, and a logistic regression model including age of diagnosis in the proband, presence of ovarian cancer in the family, presence of prostate or pancreatic cancer in the family, and presence of male breast cancer in the family proved to be effective in predicting the presence of a mutation in a gene rather than the other. Excess of familial aggregation of both breast and ovarian cancer was observed in both genes. Proportion of ovarian cancer was increased in the 5' portion of BRCA1, and presence of prostate or pancreatic cancer in a family was correlated with presence of ovarian cancer in BRCA2.