Preliminary results of targeted sequencing of BRCA1 and BRCA2 in a cohort of breast cancer families: New insight into pathogenic variants in patients and at‑risk relatives

Abstract

Breast cancer (Bc) is the most commonly diagnosed cancer worldwide and a major health concern in egypt. There is a known association between pathogenic variants identified in breast cancer susceptibility gene (BRCA)1 and 2 and the risk of developing Bc. However, the number of studies investigating mutations in BRCA1 and BRCA2 in egypt remains limited. Thus, the aim of the present study was to investigate the frequency of BRCA1 and BRCA2 variants in patients with Bc and their relatives. For this purpose, 11 families (11 patients and 16 relatives) were included in the present study. BRCA1 and BRCA2 variants were investigated using the ion S5 next-generation sequencer. it was found that pathogenic variants were more frequent in patients with familial Bc (FBc) than in those with sporadic Bc, with 71% of variants in BRCA2, including the first reported identification of c.9089del, c.5583_5584dup, c.8243G>A and c.7976G>A pathogenic variants in Egyptian patients with BC. Pathogenic variants in relatives were confined to FBC c.1278delA, c.1960_1961del, and c.1224delT, with a higher incidence of variants of uncertain significance (VUS), such as BRCA2 intron 2 c.68-16delT. of note, two cold spot benign variants, c.3113A>G and c.4837A>G, were repeatedly found (67%) in patients and relatives. in conclusion, to the best of our knowledge, novel pathogenic variants and VUS in Egyptian patients with BC and their high-risk relatives were identified for the first time in the present study. These findings should be integrated with other genomic data concerning egyptian families and carefully interpreted during genetic counseling.

Deleterious and ethnic-related BRCA1/2 mutations in tissue and blood of Egyptian colorectal cancer patients and its correlation with human papillomavirus

“…This intriguing ethnic diversity indicates Egypt's unique genetic composition, situated as a transcontinental nation between the northeastern corner of Africa and the southwestern corner of Asia. Notably, previous research corroborates these findings, as the identified BRCA1 (c.4900A > G, c.2612C > T, c.3548A > G, 0.3113A > G) and BRCA2 (c.7397 T > C, c.1114A > C) clusters were observed in an earlier Egyptian study [ 67 ] as well as within Arab African populations like Algerian [ 68 ], Bahrainian [ 69 ], Moroccan [ 70 ] and Tunisian [ 71 ] groups, alongside Asian populations encompassing Chinese [ 72 ], Korean [ 73 ], Iranian [ 74 ] and Indian [ 75 ] cohorts, and even in American and European populations such as Brazilian [ 76 ], and Italian [ 77 ] ones, respectively. This reinforces the intricate interplay of various ethnic backgrounds shaping the genetic landscape of Egypt.…”

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

“…Few relevant studies have been conducted to address the frequency of germline mutations in familial Egyptian BC patients, and they were only to investigate BRCA1/2 germline profiling. For example, a recent study by Saied et al investigated the frequency of BRCA1/2 variants in patients with BC and their relatives [21]. Another study by , used whole exome sequencing to investigate genetic predisposition in five Egyptian families with BC.…”

“…Since the advent of next-generation sequencing (NGS), multi-gene testing panels have been increasingly applied to detect genetic mutations that may be associated with increased BC risk [20]. However, very limited studies have addressed the frequency of germline mutations in BC susceptibility genes among Egyptian patients with BC family history, such as Saied et al [21] and Kim et al [22]. Thus, in the current study and to the best of our knowledge, we were the first to assess the frequency of deleterious germline mutations in familial BC Egyptian patients using a multi-gene panel sequencing of 93 genes, to better understand the contribution of the inherited germline mutations in the predisposition of BC in an Egyptian BC cohort selected for BC family history.…”

The Identification by Exome Sequencing of Candidate Genes in BRCA-Negative Tunisian Patients at a High Risk of Hereditary Breast/Ovarian Cancer

“…In our recent study, using NGS, we found that among 113 patients, 18 (15.9%) harbored germline BRCA mutations [ 17 ]. Furthermore, recurrent mutations have been reported in the North African population, such as BRCA2 -c.1310_1313delAAGA [ 17 , 18 , 19 , 20 ]. However, some mutations are likely to be specific to the Tunisian population and more precisely to patients from the North-East, such as BRCA1 -c.211dupA [ 13 , 14 , 15 , 21 ], or from the South, such as the BRCA1 -c.5030_5033delCTAA and the BRCA2 -c.17_20 delAAGA mutations [ 17 ].…”