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

Abstract

Background Elucidation of specific and recurrent/founder pathogenic variants (PVs) in BRCA (BRCA1 and BRCA2) genes can make the genetic testing, for breast cancer (BC) and/or ovarian cancer (OC), affordable for developing nations. Methods To establish the knowledge about BRCA PVs and to determine the prevalence of the specific and recurrent/founder variants in BRCA genes in BC and/or OC women in North Africa, a systematic review was conducted in Morocco, Algeria, and Tunisia. Results Search of the databases yielded 25 relevant references, including eleven studies in Morocco, five in Algeria, and nine in Tunisia. Overall, 15 studies investigated both BRCA1 and BRCA2 genes, four studies examined the entire coding region of the BRCA1 gene, and six studies in which the analysis was limited to a few BRCA1 and/or BRCA2 exons. Overall, 76 PVs (44 in BRCA1 and32 in BRCA2) were identified in 196 BC and/or OC patients (129 BRCA1 and 67 BRCA2 carriers). Eighteen of the 76 (23.7%) PVs [10/44 (22.7%) in BRCA1 and 8/32 (25%) in BRCA2] were reported for the first time and considered to be novel PVs. Among those identified as unlikely to be of North African origin, the BRCA1 c.68_69del and BRCA1 c.5266dupC Jewish founder alleles and PVs that have been reported as recurrent/founder variants in European populations (ex: BRCA1 c.181T>G, BRCA1 c1016dupA). The most well characterized PVs are four in BRCA1 gene [c.211dupA (14.7%), c.798_799detTT (14%), c.5266dup (8.5%), c.5309G>T (7.8%), c.3279delC (4.7%)] and one in BRCA2 [c.1310_1313detAAGA (38.9%)]. The c.211dupA and c.5309G>T PVs were identified as specific founder variants in Tunisia and Morocco, accounting for 35.2% (19/54) and 20.4% (10/49) of total established BRCA1 PVs, respectively. c.798_799delTT variant was identified in 14% (18/129) of all BRCA1 North African carriers, suggesting a founder allele. A broad spectrum of recurrent variants including BRCA1 3279delC, BRCA1 c.5266dup and BRCA2 c.1310_1313detAAGA was detected in 42 patients. BRCA1 founder variants explain around 36.4% (47/129) of BC and outnumber BRCA2 founder variants by a ratio of ≈3:1. Conclusions Testing BC and/or OC patients for the panel of specific and recurrent/founder PVs might be the most cost-effective molecular diagnosis strategy.

Frequency of Pathogenic Germline Mutations in Early and Late Onset Familial Breast Cancer Patients Using Multi-Gene Panel Sequencing: An Egyptian Study

“…Our findings revealed that familial BC Egyptian patients have high genetic variations, which reflect their different ethnic origins. Of note, mutations found in the BRCA2 gene (29.6%) in this cohort were almost two times higher than those found in the BRCA1 gene (14.8%), which is different from that reported in the literature [39,43,48,49]. Our findings suggest a higher BRCA2 mutation burden in Egyptian patients with familial BC.…”

“…This variant was also detected by Yang et al among Malaysian BC patients in two different cases: the first one had a family history and was diagnosed at a very early age (23 years), and the other one had no family history and was diagnosed at 42 years old [42]. Furthermore, we also identified the c.1961delA (p.Lys654fs) BRCA1 pathogenic variant in seven patients, and it was previously reported as a recurrent founder mutation in BC patients in different countries and worldwide [43][44][45][46]. On the other hand, we identified eight different deleterious mutations in the BRCA2 gene.…”

“…Another identified BRCA2 pathogenic variant (c.9097delA) in this study was previously identified in North African breast/ovarian cancer patients in Tunisia. One more c.4808delA (p.Asn1603fs) BRCA2 pathogenic variant (rs397507743) was also reported as a recurrent founder mutation in the Brazilian population [43].…”

Germline variants profiling of BRCA1 and BRCA2 in Chinese Hakka breast and ovarian cancer patients

“…There were different hotspot mutations among other populations. They are as follows: BRCA1 c.5251C > T and c.4997dup in the Vietnamese population [ 19 ]; BRCA1 c.4508C > A, c.4065_4068delTCAA, and BRCA2 c.3109C > T, c.4829_4830delTG in the Pakistani population [ 20 ]; BRCA1 c.390C > A, c.3627dupA, and BRCA2 c.7480C > T, c.1399A > T in the Korean population [ 21 ]; BRCA1 c.5123C > A, c.211A > G, and BRCA2 c.2806_2809delAAAC, c.6024dupG in the Spanish population [ 22 ]; BRCA1 c.5123C > A, and BRCA2 c.6174delT in the Latin American and the Caribbean populations [ 23 ]; and BRCA1 c.211dupA, c.798_799delTT, and BRCA2 c.1310_1313delAAGA in the North African population [ 24 ]. In a recent meta-analysis of BRCA1 and BRCA2 gene variations in Chinese individuals, c.5470_5477delATTGGGCA, c.2612C > T, and c.3548A > G in BRCA1 , and c.3109C > T, c.2806_2809delAAAC, and c.5164_5165delAG in BRCA2 were the most common variants [ 25 ].…”

Prevalence and clinical implications of germline mutations among Jordanian patients with ovarian cancer. The Jordanian exploratory cancer genetics (Jo‐ECAG) ovarian study

“…Only 5 patients with BRCA1 / BRCA2 somatic variants had germline testing, and 3 of them tested positive (Azribi et al, 2021 ). Other studies from north Africa including Morocco, Algeria and Tunisia, reported lower rates (Ben Ayed‐Guerfali et al, 2021 ; ElBiad et al, 2022 ; Fourati et al, 2014 ). In a small study from Tunisia that involved 134 patients with breast or ovarian cancers, 19 (14.2%) patients carried pathogenic mutations in BRCA1 or BRCA2 (Ben Ayed‐Guerfali et al, 2021 ).…”