Comprehensive BRCA1/2 mutation landscape in prostate cancer in the UAE and Arab population.

Prostate cancer (PCa) is the most common malignancy among men in the United Arab Emirates (UAE) and is often diagnosed at advanced stages with aggressive features. Germline mutations in DNA-repair genes, especially BRCA1 and BRCA2, increase PCa risk, with BRCA2 conferring up to 8.6-fold and BRCA1 a 3.7-fold risk. The objective is to determine the prevalence, zygosity, and clinical significance of BRCA1/2 mutations in high-grade PCa among UAE and Arab patients and describe their potential role in disease aggressiveness. A retrospective analysis was performed on 40 archived formalin-fixed, paraffin-embedded prostate tissues (2011-2022), comprising 23 PCa and 17 benign prostatic hyperplasia (BPH). Targeted exon sequencing was performed. Variants were classified using ACMG/AMP criteria using ClinVar and Varchat. Associations between mutation patterns, zygosity, and tumor grade were evaluated. BRCA1 mutations occurred in 47.5% of cases, all in exon 10, with 62.5% homozygosity; most frequent were c.794G>A and c.721G>A. BRCA2 mutations occurred in 55% of cases, mainly exon 11, with 68% homozygosity; c.5917A>C and c.5908T>A were most common. Homozygous mutations enriched in high-grade PCa (Grade Groups 3-5) suggested biallelic inactivation and homologous recombination repair deficiency. Several novel variants clustered in DNA repair domains, including BRCA1 coiled-coil and BRCA2 RAD51-binding. Our findings reveal a high prevalence of homozygous BRCA1/2 mutations, with the majority had aggressive disease phenotypes. Therefore, support the potential utility of PARP inhibitors as molecularly targeted therapeutic alternatives to conventional chemotherapy in mutation-positive patients. Furthermore, the identification of novel population-specific variants underscores the urgent need for ethnicity-informed genetic screening protocols, facilitating earlier detection of hereditary risk and enabling informed treatment stratification in United Arab Emirates and Arab men with PCa.