Identification of novelBRCAfounder mutations in Middle Eastern breast cancer patients using capture and Sanger sequencing analysis

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Ethnic differences of breast cancer genomics have prompted us to investigate the spectra ofBRCA1andBRCA2mutations in different populations. The prevalence and effect ofBRCA 1andBRCA 2mutations in Middle Eastern population is not fully explored. To characterize the prevalence ofBRCAmutations in Middle Eastern breast cancer patients,BRCAmutation 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 inBRCA 1and 3 (10.7%) cases inBRCA 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 allBRCAmutant cases and 1.6% (13/818) of all the breast cancer cases, respectively. Moreover,BRCA 1mutation was significantly associated withBRCA 1protein expression loss (p= 0.0005). Our finding revealed that a substantial number ofBRCAmutations 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.

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