Ana Blatnik

Genetic testing results in Slovenian male breast cancer cohort indicate the BRCA2 7806-2A > G founder variant could be associated with higher male breast cancer risk

Abstract Purpose To analyze the prevalence of pathogenic/likely pathogenic variants (P/LPVs) in BRCA1 and BRCA2 genes in the largest cohort of Slovenian male breast cancer (MBC) patients to date and to explore a possible correlation between the Slovenian founder variant BRCA2:c.7806-2A > G and predisposition to MBC. Methods We performed a retrospective analysis of 81 MBC cases who underwent genetic counseling and/or testing between January 1999 and May 2020. To explore a possible genotype–phenotype correlation, we performed additional analyses of 203 unrelated families with P/LPVs in BRCA2 and 177 cases of female breast cancer (FBC) in carriers of P/LPVs in BRCA2. Results Detection rate of P/LPVs in the BRCA1 and BRCA2 genes was 24.7% (20/81) with 95% of them in BRCA2 gene. The only two recurrent P/LPVs were BRCA2:c.7806-2A > G and BRCA2:c.3975_3978dupTGCT (9 and 5 MBC cases, respectively). In families with BRCA2:c.7806-2A > G, the incidence of MBC cases was higher compared to families with other P/LPVs in BRCA2; however, the difference did not reach statistical significance (17.8% vs. 8.9%, p = 0.105). BRCA2:c.7806-2A > G was detected in both families with multiple cases of MBC. This splice-site variant represented a significantly higher proportion of all BRCA2 P/LPVs detected in MBC carriers compared to FBC carriers (47.4% vs. 26%, p = 0.049). Conclusion We observed a high mutation detection rate and conclude this may be due to the prevalent BRCA2:c.7806-2A > G variant in Slovenia. Our results indicate a possible association between this variant and higher risk of breast cancer in males compared to other identified P/LPVs in BRCA2.

Trends and timing of risk-reducing mastectomy uptake in unaffected BRCA1 and BRCA2 carriers in Slovenia

Risk-reducing mastectomy (RRM) is one of key prevention strategies in female carriers of germline BRCA pathogenic/likely pathogenic variants (PV/LPV). We retrospectively investigated the rate, timing and longitudinal trends of bilateral RRM uptake and the incidence and types of cancers among unaffected BRCA carriers who underwent genetic counseling at the Institute of Oncology Ljubljana in Slovenia. Female BRCA carriers without personal history of cancer were included in the study. Clinical data on PV/LPV type, date of RRM, type of reconstructive procedure, occult carcinoma and histopathology results was collected and analyzed. Of the 346 unaffected BRCA carriers (median age 43 years, 70% BRCA1, 30% BRCA2, median follow-up 46 months) who underwent genetic testing between October 1999 and December 2019, 25.1% had a RRM (range 35-50 years, median age at surgery 38 years). A significant difference in time to prophylactic surgery between women undergoing RRM only vs. women undergoing RRM combined with risk-reducing salpingo-oophorectomy was observed (22.6 vs 8.7 months, p = 0.0009). We observed an upward trend in the annual uptake in line with the previously observed Angelina Jolie effect. In 5.7% of cases, occult breast cancer was detected. No women developed breast cancer after RRM. Women who did not opt for surgical prevention developed BRCA1/2-related cancers (9.3%). The uptake of RRM among unaffected BRCA carriers is 25.1% and is similar to our neighboring countries. No women developed breast cancer after RRM while women who did not opt for surgical prevention developed BRCA1/2 related cancers in 9.3% of cases. The reported data may provide meaningful aid for carriers when deciding on an optimal prevention strategy.