Study of the Genetic Variants in BRCA1/2 and Non-BRCA Genes in a Population-Based Cohort of 2155 Breast/Ovary Cancer Patients, Including 443 Triple-Negative Breast Cancer Patients, in Argentina.

Gene/s sequencing in hereditary breast/ovary cancer (HBOC) in routine diagnosis is challenged by the analysis of panels. We aim to report a retrospective analysis of BRCA1/2 and non-BRCA gene sequencing in patients with breast/ovary cancer (BOC), including triple-negative breast cancer (TNBC), in our population. In total 2155 BOC patients (1900 analyzed in BRCA1/2 and 255 by multigenic panels) gave 372 (17.2.6%) and 107 (24.1%) likely pathogenic/pathogenic variants (LPVs/PVs), including BRCA and non-BRCA genes, for the total and TNBC patients, respectively. When BOC was present in the same proband, a 51.3% rate was found for LPVs/PVs in BRCA1/2. Most of the LPVs/PVs in the panels were in BRCA1/2; non-BRCA gene LPVs/PVs were in CDH1, CHEK2, CDKN2A, MUTYH, NBN, RAD51D, and TP53. TNBC is associated with BRCA1/2 at a higher rate than the rest of the breast cancer types. The more prevalent PVs in BRCA1/2 genes (mostly in BRCA1) do not rule out the importance to panels of genes, although they are certainly far from shedding light on the gap of the 85% predicted linkage association of BOC with BRCA1/2 and are still not elucidated.

BRCA1 and BRCA2 Mutations Other Than the Founder Alleles Among Ashkenazi Jewish in the Population of Argentina.

In Ashkenazi Jewish (AJ) high risk families 3 mutations [2 in BRCA1 (c. 68_69del and c.5266dup) and 1 in BRCA2 (c.5946del)] account for the majority of high risk breast and ovarian cancer cases in that ethnic group. Few studies with limited number of genotyped individuals have expanded the spectrum of mutations in both BRCA genes beyond the 3 mutation panel. In this study, 279 high risk individual AJ were counseled at CEMIC (Centro de Educación Médica e Investigaciones Clínicas), and were genotyped first for the 3 recurrent mutation panel followed by Next Generation Sequencing (NGS) of BRCA1 BRCA2 in 76 individuals who tested negative for the first genotyping step. Of 279 probands (259 women), 55 (50 women) harbored one of the 3 mutations (19.7%); Of 76 fully sequenced cases (73 women), 6 (5 women) (7.9%) carried a pathogenic mutation: in BRCA1, c.2728C>T - p.(Gln910*); c.5407-?_(*1_?)del and c.5445G>A - p.(Trp1815*); in BRCA2, c.5351dup - p.(Asn1784Lysfs*3); c.7308del - p.(Asn2436Lysfs*33) and c.9026_9030del - p.(Tyr3009Serfs*7). Of 61 mutation carriers the distribution was as follows: 11 cancer free at the time of genotyping, 34 female breast cancer cases with age range 28-72 years (41.6 ± 9.3), 3 male breast cancer cases with age range 59-75 years (65 ± 7.3), 6 breast and ovarian cancer cases with age range 35-60 years (breast 40.4 ± 5.2; ovary 47.8 ± 7.2) and 7 ovarian cancer cases with age range 41-77 years (60.6 ± 13.3). This information proved highly useful for counseling, treatment, and prevention for the patient and the family. In conclusion comprehensive BRCA1/2 testing in AJ high risk breast ovarian cancer cases adds valuable clinically relevant information in a subset of cases estimated up to 7% and is therefore recommended.