Prevalence and Spectrum of BRCA Germline Variants in Central Italian High Risk or Familial Breast/Ovarian Cancer Patients: A Monocentric Study

Abstract

Hereditary breast and ovarian cancers are mainly linked to variants in BRCA1/2 genes. Recently, data has shown that identification of BRCA variants has an immediate impact not only in cancer prevention but also in targeted therapeutic approaches. This prospective observational study characterized the overall germline BRCA variant and variant of uncertain significance (VUS) frequency and spectrum in individuals affected by breast (BC) or ovarian cancer (OC) and in healthy individuals at risk by sequencing the entire BRCA genes. Of the 363 probands analyzed, 50 (13.8%) were BRCA1/2 mutated, 28 (7.7%) at BRCA1 and 23 (6.3%) at BRCA2 gene. The variant c.5266dupC p.(Gln1756Profs) was the most frequent alteration, representing 21.4% of the BRCA1 variants and 12.0% of all variants identified. The variant c.6313delA p.(Ile2105Tyrfs) of BRCA2 was the most frequent alteration observed in 6 patients. Interestingly, two new variants were identified in BRCA2. In addition, 25 different VUS were identified; two were reported for the first time in BRCA1 and two in BRCA2. The number of triple-negative BCs was significantly higher in patients with the pathogenic BRCA1/2-variant (36.4%) than in BRCA1/2 VUS (16.0%) and BRCA1/2 wild-type patients (10.7%) (p < 0.001). Our study reveals that the overall frequency of BRCA germline variants in the selected high-risk Italian population is about 13.8%. We believe that our results could have significant implications for preventive strategies for unaffected BRCA-carriers and effective targeted treatments such as PARP inhibitors for patients with BC or OC.

Spectrum of Germline Pathogenic Variants in BRCA1/2 Genes in the Apulian Southern Italy Population: Geographic Distribution and Evidence for Targeted Genetic Testing

“…The percentage of BRCA1 PVs found in our study was higher than that of the BRCA2 PVs (68.4% and 31.6, respectively). This distribution differs from that of other Italian regions [ 21 , 22 , 23 ] where the percentage of PVs observed in the 2 genes is generally the same, except for Sardinia where BRCA2 PVs are more frequent [ 26 ].…”

“…A pathogenic variant was identified in 24.5% probands. This figure is higher than the prevalence reported in other Italian regions: 10% in Sardinia [ 26 ], 14.8% in Sicily [ 21 ], 13.8% in Central Italy [ 22 ], and 18.9% in northeastern Italy [ 23 ]. While interesting, this finding is severely limited by the different genetic test access criteria used in the previous reports.…”

“…The strengths of the study include the large sample size and its homogeneity. Other similar Italian studies had been published previously but with a less homogeneous sample than ours, since they enrolled both probands and relatives [ 21 , 22 ] as well as patients from different Italian regions [ 23 , 24 , 25 ]. Therefore, our work depicts the actual prevalence, spectrum, and distribution of BRCA1/2 variants in the Apulia region.…”

The results of multigene panel sequencing in Slovak HBOC families

“…However, they indicate that:1./ This is additional evidence suggesting that the controversial CHEK2 variant c.599T>C (p.Ile200Thr) represents with high probability a low penetrance variant associated with lower susceptibility of cancer risk[62] mainly because it is known that CHEK2 protein affected by this missense variant has a lower activity[65].2./ The presence of pathogenic mutations in HBOC-associated genes relates to the notable decrease of the age of cancer diagnosis and this fact results in a significant increase of mutation frequency with decreasing age at diagnosis[69].Overall, the age at cancer diagnosis in our study is relatively low when comparing with other multigene based studies. For example, Foglietta et al[47] reported the mean age in the group of breast cancer cases to be 46 years and in the BRCA1/2 positive cases even higher at 48 years, while the mean age in our group of breast cancer patients was 43.7 and in positive cases at 43.5. Similar average age of breast cancer cases at 43.2 years was reported also in their study by Felicio et al[70].…”

“…In the French HBOC population, Velásquez et al[45] and Benusiglio et al[46] detected 8.3% and 12.1% in the group of 128 and 234 cases, respectively. Foglietta et al[47] reported a mutation detection rate of 13.8% in the group of 363 cases in the Italian population and Lerner-Ellis et al[40] detected a mutation detection rate at a level of 9.1% in 3,251 cases in the population of Ontario. Such discrepancies in the identified PV/LPV frequencies between the various studies may be explained by the number and composition of analysed samples and differences in the indication criteria between several countries.…”