Genomic and epigenomic diversity of breast cancer across Western and MENA populations: implications for precision oncology.
Breast cancer is the most common malignancy in women worldwide and is increasingly recognized as a biologically diverse disease shaped by both molecular and ancestral context. Women from the Middle East and North Africa (MENA) populations, including Saudi Arabia, often present at a younger age and with more aggressive subtypes such as HER2-positive and triple-negative breast cancer (TNBC) compared with Western cohorts. These clinical patterns reflect a distinctive genomic background marked by high consanguinity, founder mutations in key susceptibility genes, and population-specific somatic alterations that are not fully captured in global reference datasets. This review brings together current evidence on somatic, germline, transcriptomic, and epigenomic diversity in breast cancer across Western and MENA populations, with a focus on Saudi cohorts. Drawing on a previously published systematic review of more than 2,500 MENA breast cancer cases, TP53 accounted for approximately 24% and PIK3CA for roughly 10% of curated somatic mutation records pooled across 44 studies (proportions of mutation calls, not per-patient prevalence); in a separate single-center Saudi cohort, only 3.7% of patients underwent BRCA testing, and 37.5% of this clinically selected, testing-referred subgroup carried a pathogenic variant, a figure that should not be read as general-population BRCA prevalence. Variants of uncertain significance exceeded 20% across several regional genomic studies. We summarize conserved driver events, such as recurrent TP53 and PIK3CA mutations, while highlighting regional features, including unique stop-gain and loss-of-function variants, a high copy-number burden, and early-onset disease linked to ancestral architecture. We also discuss emerging data on MENA-specific regulatory signatures, including immune-enriched and basal-myo transcriptomic clusters, CIMP-like methylation patterns, and non-coding RNA networks; these associations are numerically suggestive in available cohorts but have not reached statistical significance in existing studies and warrant validation in larger, dedicated MENA/Saudi cohorts before being considered established determinants of treatment response and resistance. Finally, we examine the clinical implications of this diversity for biomarker development, pharmacogenomics, and access to targeted therapies, and outline practical steps toward ancestry-aware precision oncology in the region.