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Using summary statistics from genome-wide association studies for 37 cancer types (N\u2009=\u2009433\u00a0836), we identified extensive genome-wide and local genetic correlations among cancers. Through pairwise pleiotropic analysis, we identified 75\u00a0243 significant pleiotropic single nucleotide polymorphisms (SNPs) across 372 cancer pairs, among which 3472 were lead SNPs with potential regulatory functions. Using FUMA and MAGMA, we identified 2527 pleiotropic risk loci and 4272 candidate pleiotropic genes. Notably, genes such as TERT (5p15.33), POU5F1B (8q24.21), and FANCA (16q24.3) exhibited widespread pleiotropy across multiple cancer types. Pathway enrichment analysis highlighted the critical roles of pigment synthesis, metabolism, and apoptosis in skin-related cancers, while cross-cancer enrichment analysis emphasized pathways related to apoptosis, chromatin structure, and intermediate filaments. We also identified 33 novel functional genes harboring previously unreported cancer risk variants. Drug-gene interaction analysis revealed several repositionable FDA-approved drugs. Importantly, drug sensitivity assays demonstrated that bosutinib and cobimetinib exhibited promising therapeutic potential in breast cancer cell lines. Finally, we developed the PleioCancer database (https:\/\/gonglab.hzau.edu.cn\/PleioCancer\/), providing a comprehensive resource for cancer pleiotropy research. These findings have important implications for carcinogenesis cancer, prevention and treatment.<\/jats:p>","DOI":"10.1093\/bib\/bbag479","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T11:08:40Z","timestamp":1788520120000},"source":"Crossref","is-referenced-by-count":0,"title":["Large-scale pleiotropic analysis across cancers reveals shared genetic mechanisms and identifies novel functional genes"],"prefix":"10.1093","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-7225-5435","authenticated-orcid":false,"given":"Xiaohong","family":"Wu","sequence":"first","affiliation":[{"name":"Hubei Hongshan Laboratory, College of Informatics, Huazhong Agricultural University , No. 1 Shizishan Street, Hongshan District, Wuhan 430070, Hubei,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqing","family":"Yan","sequence":"additional","affiliation":[{"name":"Hubei Hongshan Laboratory, College of Informatics, Huazhong Agricultural University , No. 1 Shizishan Street, Hongshan District, Wuhan 430070, Hubei,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Cao","sequence":"additional","affiliation":[{"name":"Hubei Hongshan Laboratory, College of Informatics, Huazhong Agricultural University , No. 1 Shizishan Street, Hongshan District, Wuhan 430070, Hubei,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Wu","sequence":"additional","affiliation":[{"name":"Hubei Hongshan Laboratory, College of Informatics, Huazhong Agricultural University , No. 1 Shizishan Street, Hongshan District, Wuhan 430070, Hubei,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxing","family":"He","sequence":"additional","affiliation":[{"name":"Hubei Hongshan Laboratory, College of Informatics, Huazhong Agricultural University , No. 1 Shizishan Street, Hongshan District, Wuhan 430070, Hubei,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongyang","family":"Wang","sequence":"additional","affiliation":[{"name":"Hubei Hongshan Laboratory, College of Informatics, Huazhong Agricultural University , No. 1 Shizishan Street, Hongshan District, Wuhan 430070, Hubei,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1895-2993","authenticated-orcid":false,"given":"Jing","family":"Gong","sequence":"additional","affiliation":[{"name":"Hubei Hongshan Laboratory, College of Informatics, Huazhong Agricultural University , No. 1 Shizishan Street, Hongshan District, Wuhan 430070, Hubei,","place":["China"]},{"name":"College of Biomedicine and Health, Huazhong Agricultural University , No. 1 Shizishan Street, Hongshan District, Wuhan 430070, 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