Recent advances in the detection of germline pathogenic variants (PVs) in BRCA1/2 genes have allowed a deeper understanding of the BRCA-related cancer risk. Several studies showed a significant heterogeneity in the prevalence of PVs across different populations. Because little is known about this in the Sicilian population, our study was aimed at investigating the prevalence and geographic distribution of inherited BRCA1/2 PVs in families from this specific geographical area of Southern Italy. We retrospectively collected and analyzed all clinical information of 1346 hereditary breast and/or ovarian cancer patients genetically tested for germline BRCA1/2 PVs at University Hospital Policlinico “P. Giaccone” of Palermo from January 1999 to October 2019. Thirty PVs were more frequently observed in the Sicilian population but only some of these showed a specific territorial prevalence, unlike other Italian and European regions. This difference could be attributed to the genetic heterogeneity of the Sicilian people and its historical background. Therefore hereditary breast and ovarian cancers could be predominantly due to BRCA1/2 PVs different from those usually detected in other geographical areas of Italy and Europe. Our investigation led us to hypothesize that a higher prevalence of some germline BRCA PVs in Sicily could be a population-specific genetic feature of BRCA-positive carriers.

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Background: Several available data suggest the association between specific molecular subtypes and BRCA1/2 mutational status. Previous investigations showed the association between BRCA1/2 pathogenic variants (PVs) in specific genomic regions and phenotypic variations of cancer relative risk, while the role of PV type and location in determining the breast cancer (BC) phenotypic features remains still unclear. The aim of this research was to describe the germline BRCA1/2 PVs in triple-negative breast cancer (TNBC) versus luminal-like BC and their potential leverage on BC phenotype. Patients & methods: We retrospectively collected and analyzed all clinical information of 531 patients with BC genetically tested for germline BRCA1/2 PVs by Next-Generation Sequencing analysis at University Hospital Policlinico “P. Giaccone” of Palermo (Sicily) from January 2016 to February 2020. Results: Our results corroborate the evidence that BRCA1-related tumors often have a profile which resembles the TNBC subtype, whereas BRCA2-associated tumors have a profile that resembles luminal-like BC, especially the Luminal B subtype. Interestingly, our findings suggest that the PVs identified in TNBC were not largely overlapping with those in luminal-like tumors. Differences in the frequency of two PVs potentially associated with different molecular tumor subtypes were observed. BRCA1-633delC was detected with relatively higher prevalence in patients with TNBC, whereas BRCA2-1466delT was found mainly in Luminal B tumors, but in no TNBC patient. Conclusion: Future studies examining the type and location of BRCA1/2 PVs within different molecular subtypes are required to verify our hypothesis and could provide an interesting insight into the complex topic of genotype–phenotype correlations. Additionally, a more in-depth understanding of the potential correlations between BRCA PVs and clinical and phenotypic features of hereditary BC syndrome patients could be the key to develop better strategies of prevention and surveillance in BRCA-positive carriers without disease.

Highlights Hormonal receptors positive breast tumor and prostate cancer are managed with endocrine therapies. Endocrine therapies designed for breast and prostate cancer are often associated to serious adverse skeletal related events, such fractures. Denosumab is a monoclonal anti-body binding RANKL which acts as inhibitor of osteoclasts activity, thus increasing bone mass. Denosumab was showed to strongly prevent hormonal therapies-related skeletal issues. Denosumab administration results safe in bone mass increase and reduction of fractures risk.

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