Germline-somatic liaison dictates cancer subtype via de novo steroid biosynthesis. Academic Article uri icon

Overview

abstract

  • 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.

publication date

  • June 13, 2025

Identity

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-24-1904

PubMed ID

  • 40512155