Abstract
Abstract
Epithelial ovarian cancer (EOC) remains the most fatal gynecological malignancies. Germline mutations in Breast Cancer susceptibility gene 1 and 2 (BRCA1 and BRCA2) have previously been estimated to contribute to 13-18% of all EOC. The prevalence and influence of BRCA1 and BRCA2 mutations in EOC in Middle Eastern population is not fully explored. Ethnic differences of ovarian cancer genomics have prompted us to investigate the spectrum of BRCA1 and BRCA2 mutations among our Middle Eastern EOC patients. To characterize the prevalence of BRCA mutations in our patients, BRCA mutation screening was performed in over 400 unselected ovarian cancer patients using Capture and/or Sanger sequencing. Seventeen short tandem repeat (STR) markers were used for founder mutation analysis. A total of 19 different types of pathogenic mutations were identified in 50 cases (40 mutant cases in BRCA1 and 10 in BRCA2). Nine mutations were recurrent accounting for 80% (40/50) of all mutant cases (9.8% (40/407) of the entire cohort). Haplotype analysis carried out on all unrelated cases with these mutations revealed only two (c.4136_4137 delCT and c.1140 dupG) sharing the same haplotypes thus representing founder Saudi mutations. Remarkably, lifetime risk estimation for these founder mutations appears to approach 100% given their complete absence in healthy controls. BRCA1 mutant cases were significantly associated with positive family history (p <0.0001), grade 3 tumors (p = 0.0003) and loss of BRCA1 protein expression (p <0.0001). 85.0% (34/40) of all BRCA1 mutant cases were of serous histology. BRCA2mutant cases were associated with loss of BRCA2 protein expression (p=0.0102) and a trend towards younger age (p=0.0505). 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.
Citation Format: Abdul K. Siraj, Rong Bu, Kaleem Iqbal, Nabil Siraj, Maha Alrasheed, Laila Ghazwani, Tariq Masoodi, Sandeep Kumar Parvathareddy, Khawla S. Al-Kuraya. Identification of BRCA1 and BRCA2 mutation spectrum and their founder effect in epithelial ovarian cancer from Middle East [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4179.