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In this study, characterizing isogenic prostate cancer cell lines, we dissected the interplay between a germline variant at the 7p14.3 locus (rs1376350, G&amp;gt;A) and early recurrent prostate cancer\u2013specific mutation in the speckle-type POZ protein (SPOP) gene across human prostate adenocarcinomas. The transcriptomes of multiple edited models pointed to GLI3 and the Hedgehog signaling pathway in a genotype-specific manner, whereas SPOP mutation and androgen receptor stimulation promote GLI3 accumulation in the full-length, transcriptionally active form. This, in turn, triggers the cell-autonomous production of steroids that prostate cancer relies on, in line with the enhanced responsiveness of SPOP-mutated prostate cancer to androgen deprivation therapy. These data demonstrate that germline variants dictate prostate cancer somatic evolution and suggest opportunities to jointly model germline\u2013somatic relationship to help untangle the complexity of human cancer.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>Significant heritability is observed for common cancer types worldwide. The molecular mechanisms by which inherited genetics facilitate cancer initiation might transit through its cooperation with specific somatic events that then dictate the tumor features. Through a germline\u2013somatic tandem leading to steroid biosynthesis, we suggest a paradigm to study cancer initiation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-24-1904","type":"journal-article","created":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T10:45:15Z","timestamp":1749811515000},"page":"2166-2184","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Germline\u2013Somatic Liaison Dictates Cancer Subtypes via\n                    <i>de novo<\/i>\n                    Steroid Biosynthesis"],"prefix":"10.1158","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3016-9742","authenticated-orcid":false,"given":"Paola","family":"Gasperini","sequence":"first","affiliation":[{"name":"1Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, 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