Frontiers in cell and developmental biology · 2026
Comprehensive BRCA1/2 mutation landscape in prostate cancer in the UAE and Arab population.
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Al Shareef Zainab M, Al-Shahrabi Rula M, Bhamidimarri Poorna Manasa, Yener Burcu, Bouzid Amal, Hamad Alaa Mohamed, Murad Shirin, Elbarkouky Ahmed, Saheb Sharif-Askari Fatemeh, Bendardaf Riyad, Hamoudi Rifat A, Hachim Mahmood Y
Аннотация
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSION: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSION: 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.