Germline-somatic liaison dictates cancer subtype via de novo steroid biosynthesis.

The biological mechanisms underlying the cooperation between germline genetic variants and somatic mutations during carcinogenesis are rarely elucidated. Here, characterizing isogenic prostate cancer cell lines, we dissected the interplay between a germline variant at the 7p14.3 locus (rs1376350, G>A) and early recurrent prostate cancer-specific 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, while SPOP mutation and AR stimulation promote Gli3 accumulation in the full-length (FL) 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 men's prostate cancer somatic evolution and suggest opportunities to jointly model germline-somatic tandems to help untangle the complexity of human cancer.