A National Genomic Portrait of Breast Cancer Risk

BackgroundThe genetic architecture of Breast Cancer (BC) in Arab populations remains largely understudied, limiting the precision of current prevention and screening programs. The Emirati Genome Program (EGP), one of the worlds first nation-wide sequencing initiatives, offers an unprecedented opportunity to delineate inherited BC risk across an entire population. MethodsWe analyzed 436,780 EGP individuals, including 229,309 women, integrating whole-genome sequencing (WGS) with electronic health records (EHRs). We quantified the prevalence and penetrance of pathogenic and likely pathogenic (P/LP) variants across 13 NCCN-recommended BC genes, evaluated the performance of established polygenic risk scores (PRS), and reconstructed >48,000 pedigrees to measure familial aggregation. ResultsP/LP variants were identified in 0.84% of women, accounting for 5.2% of BC cases (mean age of 45.9{+/-}11.1 years). Highly penetrant BRCA1 c.4065_4068del (p.Asn1355fs) and BRCA2 c.2808_2811del (p.Ala938Profs) variants showed age-specific cumulative risks of 37.6% and 31% by age 60, respectively, and allele frequencies up to tenfold higher in the Emirati population than in global reference datasets. The European-derived PRS model (PGS000004) demonstrated strong performance, advancing 10-year BC risk onset by a decade for women in the top decile. Family-based PRS discriminated affected from unaffected individuals, revealing higher polygenic risk even within sister pairs. Integration of monogenic, polygenic, and familial data defined a national framework for risk stratification, identifying disease-free women potentially eligible for targeted prevention. ConclusionsNation-scale genome sequencing reveals, for the first time, the comprehensive landscape of inherited BC susceptibility within a Middle Eastern population. The integration of monogenic, polygenic, and familial data establishes a national framework for genomic risk stratification--transforming population genomics into a foundation for precision prevention and early detection in the UAE and beyond.