Somatic Mutation Profiling and Therapeutic Landscape of Breast Cancer in the MENA Region

Highlights: What are the main findings? Whole exome sequencing (WES) characterized the mutational landscape of breast cancer in MENA patients, revealing both known and novel potential driver mutations. Subtype-specific mutational signatures were identified. What is the implication of the main finding? OncoKB annotation uncovered actionable variants, pointing to potential new therapeutic opportunities for breast cancer. These findings expand knowledge in an underrepresented MENA population, supporting precision oncology efforts. Breast cancer remains a major global health challenge. Yet, genomic data from Middle Eastern and North African (MENA) populations are limited, restricting insights into disease drivers and therapeutic opportunities in this demographic. To address this gap, we performed whole-exome sequencing (WES) on 52 breast cancer samples, including 51 from the MENA region, to characterize somatic mutations and potential therapeutic targets. Across the cohort, 37,369 somatic variants matched entries in the COSMIC database, and driver prediction tools (BoostDM and OncodriveMUT) identified 2451 predicted driver mutations, including 648 known driver variants in genes such as TP53, PIK3CA, GATA3, PTEN, SF3B1, and KMT2C. In addition, 1803 novel predicted drivers were detected, many affecting DNA repair pathways, including homologous recombination (BRCA2, RAD51C), mismatch repair (MLH1, MSH2), and nucleotide excision repair (ERCC2, ERCC3), as well as regulators such as TP53 and ATM. Mutational signature analysis revealed a predominance of C>T substitutions and subtype-specific patterns, with SBS22 and SBS43 enriched in Luminal A tumors. Therapeutic annotation using OncoKB identified 223 actionable or likely oncogenic variants, highlighting potential targets for precision oncology. This study provides a comprehensive characterization of the breast cancer mutational landscape in MENA patients and offers a valuable resource for advancing genomic and therapeutic research in this demographic.