Novel and Recurrent BRCA1/BRCA2 Germline Mutations in Patients with Breast /Ovarian Cancer: A Series from the South of Tunisia

Abstract

Background: The incidence of breast/ovarian cancer is increasing in Tunisia especially in young women and mostly those with family history. However, the spectrum of BRCA mutations remains little explored in Tunisian patients in particular in the southern region. Methods: We sequenced the entire coding regions of BRCA1and BRCA2 genes using Next Generation Sequencing (NGS) in 134 selected patients with breast/ovarian cancer. Results: Among the 134 patients, 19 (14.17%) carried pathogenic mutations (10 are BRCA1 mutation carriers and 9 are BRCA2 mutation carriers) that are mainly frameshisft indel (76.9%). Interestingly, 5 out of the 13 variants (38.46%) were found at least twice in unrelated patients, as the c.1310-1313 delAAGA in BRCA2 and the c.5030_5033 delCTAA that has been identified in 4/98 BC patients and in 3/15 OC patients from unrelated families with strong history of cancer. Besides recurrent mutations, 6 variant (4 in BRCA1 and 2 in BRCA2) were not reported previously. Furthermore, 3 unrelated patients carried the VUS c.9976A>T, (K3326*) in BRCA2 exon 27. BRCA carriers correlated significantly with tumor site (p=0.029) and TNBC cases (p=0.008). In the groups of patients (31-40 y and 41-50 y), BRCA1 mutations occurred more frequently in patients with OC than those with BC, and conversely BRCA2 carriers are mostly affected with BC (p=0.001 and p=0.044 respectively).Conclusions: The overall frequency of the BRCA germline mutations was 14.17% in patients with high risk of breast /ovarian cancer. We identified recurrent mutations as the c.1310_1313 delAAGA in BRCA2 gene and the c.5030_5033 delCTAA in BRCA1 gene that were found in 4% and 20% of familial BC and OC respectively. Our data will contribute in the implementation of genetic counseling and testing for families with high-risk of breast/ovarian cancer.

Prevalence of specific and recurrent/founder pathogenic variants in BRCA genes in breast and ovarian cancer in North Africa

“…The search of the databases yielded 25 relevant references which are closely related to de ning the inclusion criteria and was included in this review. The retrieved articles describe studies conducted in Morocco (n = 11) [9][10][11][12][13][14][15][16][17][18][19], Algeria (n = 5) [20][21][22][23][24], and Tunisia (n = 9) [25][26][27][28][29][30][31][32][33]. Overall, 15 studies investigated both BRCA1 and BRCA2 genes [9, 10, 13, 16-19, 21-23, 25, 28, 30-33], four studies examined the entire coding regions of the BRCA1 gene [11,20,26,27], and six studies in which the analysis was restricted to a few BRCA1 and/or BRCA2 exons [12,14,15,24,29].…”

“…A total of 18 of the 76 (23.7%) PVs [10/44 (22.7%) in BRCA1, 8/32 (25%) in BRCA2] were reported for the rst time and were considered to be novel PVs in the North African populations. Among them, four PVs were reported in Morocco (c.3453delT in BRCA1 [19], and c.3381delT, c.7110delA, c.7234_7235insG in BRCA2[10], three in Algeria (deletion of exon2 in BRCA1[21], c.2805delAand c.6450del in BRCA2[22], and eleven in Tunisia (c.211dupA[25, 26], c.296_297delTG[33], c.2418dupA[32], c.3254delG[33], c.3364_3370dupACAGATT[33], c.3751dup[29], c.4067_4071delAAGAA in BRCA1[33] and c.1313dupT [28], c.1976_1800delCTTAT [28], c.2095C > T [33], c.7654dupT [28] in BRCA2). The reported PVs in BRCA genes from North African studies are presented in Table…”

“…Furthermore, other PVs have been described worldwide and represented as common PVs in several populations (ex: BRCA1 c.1016dupA in Italy, Germany, Scandinavian countries and French-Canadians, BRCA1 c.2125_2126insA in French-Canadians, BRCA1 c.2338C > T and BRCA2 c.1813dupA in Germany, BRCA1 c.5030_5033delCTAA in France, BRCA2 c.3860delA in Austrian population, and BRCA2 c.3847_3848delGT in Denmark). The most well characterized ve PVs are four in BRCA1 gene including c.211dupA (19/129, 14.7%) [25, 26, 28, 29, 32], c.798_799detTT (18/129, 14%) [10, 11, 13, 16-18, 21, 26, 27, 30], c.5266dup (11/129, 8.5%) [25-29, 31], c.5309G > T (10/129, 7.8%) [14, 18], c.3279delC (6/129, 4.7%) [10, 12, 16] and one in BRCA2 including c.1310_1313detAAGA (26/67, 38.9%)[15, 19,21,29,33]. The BRCA1 c.798_799delTT was identi ed in 18 North African patients, accounting for 14% (18/129) of total identi ed BRCA1 PVs[10, 11, 13, 16- 18, 20, 21, 26, 27, 30].…”