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.

IntroductionGalectin-3 (Gal-3) is an independent predictor of poor outcomes and mortality in patients with heart failure (HF). Thus, it has been proposed as a reliable prognostic biomarker for HF. The definition of reference intervals is mandatory for interpreting the findings of experimental studies and encouraging the routine use of biomarkers in clinical practice. To date, no study assessed the reference intervals of Gal-3 and identified the biological variables that affect its concentration in a well-defined healthy population. The aim of this study was to determine the upper reference limit (URL) of Gal-3 in a highly reliable population of healthy subjects.Materials and methodsWe recruited 714 blood donors. After measuring surrogate biomarkers to identify underlying diseases, 8 subjects were excluded. A final population of 706 individuals (385 men (54.5%); median age 39 (18-65) years) was included. The URL was calculated using the non-parametric percentile approach.ResultsThe 97.5th percentile URL of plasma Gal-3 in our study population (90% CI) was 26.1 (23.3–31.5) ng/mL. After stratifying subjects according to age, the URL of Gal-3 was found to be considerably higher in older (> 45 years) than in younger subjects (31.5 (26.2–51.4) vs 21.8 (21–26.1) ng/mL, respectively). No sex-related differences were found in Gal-3 plasma concentration.ConclusionsWe established the URL of Gal-3 in a highly selected healthy population. Our findings indicate that age is an important determinant of Gal-3 plasma concentration, so that multiple diagnostic cut-offs should be preferably used according to the different age classes.

Vascular calcification has been recently associated to an increased cardiovascular risk and mortality. In few studies, Fetuin-A showed an association to coronary artery calcification (CAC), although the physiopathological mechanism underlying this association has not been fully established yet. Seventy-four patients with one or more cardiovascular risk factor and asymptomatic for coronary vasculopathy were included in the study. CAC was evaluated by Agatston score. Serum Fetuin-A levels were determined by ELISA. Molecular analysis of AHSG T256S gene variant (rs4918) was performed by PCR-RFLP. Serum Fetuin-A was correlated to serum calcium (r = 0,321; P = 0,018), but not to serum phosphorous. Multivariate linear regression analysis confirmed this association and showed that calcium and AHSG genotype were independent predictors of Fetuin-A (P = 0.037, P = 0.014, respectively). In particular, subjects carrying the SS genotype had lower levels of Fetuin-A and calcium (P = 0.037 and P = 0.038, respectively). When we compare subjects with CAC 0-10 with subjects with CAC > 10, we found that only age and male gender (P < 0.001, P = 0.035, respectively), but not Fetuin-A, were associated to CAC. Fetuin-A is not associated to CAC in subjects with low cardiovascular risk profile and asymptomatic for coronary vasculopathy, suggesting that in this setting Fetuin-A, although correlated to serum levels of calcium, could be not involved in mineral deposition on coronary vessels.