Identification of novel BRCA founder mutations in Middle Eastern breast cancer patients using capture and Sanger sequencing analysis

Abstract

Ethnic differences of breast cancer genomics have prompted us to investigate the spectra of BRCA1 and BRCA2 mutations in different populations. The prevalence and effect of BRCA 1 and BRCA 2 mutations in Middle Eastern population is not fully explored. To characterize the prevalence of BRCA mutations in Middle Eastern breast cancer patients, BRCA mutation screening was performed in 818 unselected breast cancer patients using Capture and/or Sanger sequencing. 19 short tandem repeat (STR) markers were used for founder mutation analysis. In our study, nine different types of deleterious mutation were identified in 28 (3.4%) cases, 25 (89.3%) cases in BRCA 1 and 3 (10.7%) cases in BRCA 2. Seven recurrent mutations identified accounted for 92.9% (26/28) of all the mutant cases. Haplotype analysis was performed to confirm c.1140 dupG and c.4136_4137delCT mutations as novel putative founder mutation, accounting for 46.4% (13/28) of all BRCA mutant cases and 1.6% (13/818) of all the breast cancer cases, respectively. Moreover, BRCA 1 mutation was significantly associated with BRCA 1 protein expression loss (p = 0.0005). Our finding revealed that a substantial number of BRCA mutations were identified in clinically high risk breast cancer from Middle East region. Identification of the mutation spectrum, prevalence and founder effect in Middle Eastern population facilitates genetic counseling, risk assessment and development of cost‐effective screening strategy.

Recurrent BRCA1 Mutation, but no BRCA2 Mutation, in Vietnamese Patients with Ovarian Carcinoma Detected with Next Generation Sequencing

“…Some founder mutations of BRCA1/2 have been recorded in many different races (Janavičius et al, 2010). Particularly, the p.Arg1751Ter mutation has been recognized as founder mutation of Greek, Hungarian, Middle Eastern, Italian and Polish patients (Bu et al, 2016;Kowalik et al, 2018).…”

Germline BRCA1/BRCA2 mutations among high risk breast cancer patients in Jordan

“…The small sample size of this pilot study and the fact that genetic analysis was performed at Myriad Genetics laboratories did not allow for haplotype and founder mutation analyses which will be sought in future studies. Most of the detected mutations were reported previously in the Breast Cancer Information Core (BIC) [ 25 ] among Caucasian and Western populations, possibly due to similarity of genetic makeup between Middle Eastern population and Western population [ 26 ]. Only one variant of uncertain significance (VUS) in BRCA1, E1478D (4553G > C), was reported by Myriad Genetics variant information sheet as the first observation for this variant (personal communication).…”

Prevalence and Spectrum of BRCA1/2 Germline Mutations in Women with Breast Cancer in China Based on Next-Generation Sequencing

“…In total, 595 breast cancer patients were recruited from Hospitals of Guangdong, Chongqing, and Shandong Province from 2014 to 2016, and 2 ml of peripheral blood was obtained from each patient. Among them, 203 were high-risk breast cancer cases who met 1 of the following criteria: 1) at least 1 first- and/or second-degree relative had breast and/or ovarian cancer; 2) younger than 35 years of age at breast cancer onset; 3) bilateral breast cancer; and 4) triple-negative breast cancer (TNBC; estrogen receptor-negative, progesterone receptor-negative, and HER2-negative) [ 13 – 15 ]. The remaining patients were low-risk in terms of family history, age at onset, bilateral breast cancer, and TNBC.…”