Ultra-rare functional variants reveal early-onset breast cancer risk genes and pathways in the UK Biobank and All of Us Research Program.

EA-Pathways method: aggregation of ultra-rare germline coding variants weighted by Evolutionary Action, control-free

EA-Pathways, a control-free association method aggregating ultra-rare germline coding variants weighted by Evolutionary Action, was applied to UK Biobank women with breast cancer. It prioritized candidate risk genes across pathways enriched in known familial genes, including homology-directed DNA repair, TP53, and pexophagy. Ultra-rare, high-impact variants in 8 pathways were associated with 2-year-earlier disease onset, with replication in All of Us showing onset up to 9 years earlier in African ancestry.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

EA-Pathways offers a novel methodological approach to detecting breast cancer predisposition genes beyond known BRCA1/2 mutations. Identification of new pathways (pexophagy) and validation in a multi-ethnic independent cohort are strengths. These candidate genes are not yet clinically actionable but point toward biological mechanisms potentially targetable for ancestry-specific screening.

Clinical impact : 2/3 · Evidence strength : 2/3 · Novelty : 2/2 · Sample size : 1/1 · Journal quality : 1/1 → Total : 8/10