Abstract 1381: The Confluence Project: Largest multi-ancestry genome-wide association study of breast cancer identifies 469 susceptibility loci in over two million participants

Background: Genome wide association studies (GWAS) of breast cancer have identified over 230 susceptibility loci, yet much of its heritable risk remains unexplained. Moreover, previous large GWAS included mostly European-ancestry samples, restricting the scope of genetic variation studied and limiting the generalizability of polygenic risk scores trained in these studies. The Confluence Project is a large, international collaboration of breast cancer consortia, biobanks, and other individual studies, studying breast cancer in females, males, and carriers of breast cancer susceptibility genes. With over 300 studies from 62 countries, Confluence includes over 400,000 breast cancer cases and 1,600,000 controls, nearly tripling the effective sample size of previous GWAS and substantially increasing sample diversity (approximate number of cases / controls, by genetic ancestry group: African (AFR)= 24,000 / 67,500, East Asian (EAS) = 49,000 / 429,000, Admixed American (AMR) = 28,500 / 78,000). Confluence is designed as a resource to address a range of breast cancer genetic questions by contributors and the wider scientific community. Methods: We conducted a multi-ancestry GWAS of overall breast cancer risk (variants analyzed=47,790,460, min allele frequency = 0.03%). Individual-level genotyping data was available on 322,332 cases and 269,357 controls, including 53,058 BRCA1/2 carriers, 24,883 of which were breast cancer cases. This data was processed through a harmonized quality-control pipeline and imputed by array to the TOPMed reference panel. GWAS were performed separately by array using REGENIE, adjusting for the first ten principal components. Resulting summary statistics were combined with similar statistics from 18 external biobanks (101,579 cases and 1,373,259 controls) through fixed-effect meta-analysis. Novel signals were declared if located more than +/-1Mb from any known locus that were based on previously published GWAS. Results: We identified 469 independent genome-wide significant loci (P<5x10-8) of which 249 (53%) were novel. Among the 240 loci previously reported, 220 (92%) were associated at p<5x10-8. Assuming shared effect-sizes across populations, while accounting for ancestry-specific allele frequency differences, the 249 discovered loci increased the logit-scale variance relative to previously known loci from approximately 29% (in AFR) to 36% (in EAS). Conclusion: This study represents the largest and most ancestrally diverse GWAS of breast cancer. The novel loci identify new candidate genes, substantially improves the proportion of heritability explained, and lay the groundwork for an expanded understanding of breast cancer biology. Ongoing analyses will extend these findings to sex-, ancestry-, and subtype-specific risk, including BRCA1/2 carriers, and polygenic risk prediction. Citation Format: The Confluence Project - National Cancer Institute, African-ancestry Breast Cancer Genetic Consortium, Breast Cancer Association Consortium, Consortium of Investigators of Modifiers of BRCA1/2, Latin America Genomics of Breast Cancer Consortium, Male Breast Cancer Genetics Consortium. The Confluence Project: Largest multi-ancestry genome-wide association study of breast cancer identifies 469 susceptibility loci in over two million participants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1381.