Identifying shared polygenic risk across cancers

BACKGROUND: Shared genetic susceptibility across cancers has been reported but is generally modest at the genome-wide level. Whether such shared polygenic risk exhibits structured convergence at regional or functional levels remains unclear. We investigated shared genetic risk across cancers by integrating local genetic correlation analyses with cross-cancer polygenic risk score (PRS) associations. METHODS: We estimated pairwise local genetic correlations across 16 specific cancers and one pan-cancer phenotype using SUPERGNOVA. Genome regions harboring multiple cancers with mutually correlated local genetic effects were annotated using genetic correlations with non-cancer phenotypes and associations from the GWAS Catalog. In parallel, cross-cancer PRS associations were evaluated, and significant cancer pairs were identified. Genome-wide PRSs for selected pairs were further decomposed into pleiotropy-informed and pathway-specific components to assess functional enrichment of shared polygenic risk. RESULTS: Genome-wide genetic correlation analyses identified 20 significantly correlated cancer pairs, whereas local analyses revealed 82 regions with shared genetic signals across 66 cancer pairs. Five regions exhibited mutually correlated cancer clusters, with enrichment in functional domains such as inflammatory functions. Cross-cancer PRS analyses identified five cancer pairs with shared polygenic risk. Decomposition of PRSs indicated that these cross-cancer associations were enriched in specific pleiotropy groups and immune-related pathways rather than reflecting diffuse genome-wide overlap. CONCLUSION: Our findings demonstrate that although shared genetic susceptibility across cancers is limited at the genome-wide level, it becomes evident when examined at regional and polygenic scales. Integrating local genetic correlation and PRS decomposition analyses reveals structured patterns of shared genetic risk, providing a framework for investigating cross-cancer polygenic susceptibility.