Maria Teresa Vietri

Prevalence of mutations in BRCA and MMR genes in patients affected with hereditary endometrial cancer

AbstractEndometrial cancer (EC) is the fifth most common cancer in women from developed countries, accounting for 4.8% of new cases and 2.1% of deaths. The genetic basis for the familial risk of endometrial cancer has not been completely defined. Mostly, hereditary EC is part of two syndromes as Lynch syndrome (LS) and Hereditary Breast and Ovarian Cancer syndrome (HBOC). LS is the prototypical hereditary cancer syndrome in EC and accounts for 2–6% of all endometrial cancers. This disease is caused by autosomal dominant mutations in DNA mismatch repair (MMR) genes. Patients carrying a germline mutation in one of the MMR genes have a cumulative lifetime risk to develop EC of 20–70%. HBOC is an autosomal dominantly inherited disease, which mostly predisposes to breast and ovarian cancers, but it can be also associated with other malignancies. HBOC results from germline mutations in BRCA1/2 genes. The aim of this study was to determine the mutational status of a cohort of 40 EC patients, 19 belonging to families with LS and 21 to HBOC. Mutation analysis of MLH1, MSH2, BRCA1 and BRCA2 genes showed pathogenic variants in 17/40 (42.5%) patients. Out of 19 patients belonging to LS families, 8 (42.1%) showed a pathogenic variant. Out of 21 patients belonging to HBOC families, 9 (42.8%) showed a pathogenic variant. 1/21 (4.8%) patient report 1 variant of unknown significance (UV), c.599 C > T (p.T200I), in BRCA2. Moreover, in 1/21 (4.8%) patient we identified a novel missense variant in BRCA2, c.9541A > T (p.Met3181Leu). Mutational analysis was extended to family members, both healthy and cancer affected, of mutated patients; all the tested relatives affected with cancer displayed the pathogenic variant. Our data suggest that patients with hereditary EC have a high percentage of mutations in the LS and HBOC main susceptibility genes; therefore, the surveillance for EC, already indicated in LS patients, should also be recommended for patients with HBOC.

Comparative analysis of a founder BRCA2 double mutation versus single mutation carriers reveals no additional clinical risk

Double mutations (DMs) in cis within the same BRCA gene are extremely rare, and their clinical significance remains uncertain, as it is unclear whether they confer an additive risk compared with single pathogenic variants (PVs). We retrospectively analyzed a cohort of 1722 patients referred for suspected Hereditary Breast and Ovarian Cancer (HBOC). Among them, 9 unrelated probands were found to carry the same BRCA2 DM: c.631G>A (p.Val211Ile) in exon 7 and c.7008-2A>T (IVS13-2A>T) at the acceptor splice site of intron 13. Both variants were confirmed to co-segregate in cis. A control group of 19 probands with a single BRCA2 PV located between exons 7 and 14 was selected for comparison. All DM families originated from the same geographic area in Southern Italy, suggesting a founder effect. The mean age at breast cancer onset was 50.7 years in the DM group and 51.4 years in the control group. Tumor spectrum and distribution among probands and relatives were comparable between groups, and BRCA2-related breast cancers were predominantly hormone receptor-positive in both cohorts. No statistically significant differences were observed regarding cancer types, stage, or receptor profile. These findings suggest that the BRCA2 double mutation c.631G>A/c.7008-2A>T may have a founder effect, and the coexistence of the two variants does not appear to confer an additive cancer risk or a more severe clinical phenotype compared with carriers of a single BRCA2 pathogenic mutation.