Critical drivers of NEPC have been established, such as mutations in FOXA1 and SPOP in primary PCa, lineage plasticity induced by RB1 loss and TP53 dysfunction, as well as activation of the polycomb-repressive complex-2 (PRC2) such as EZH2 in advanced PCa 4, 5, 9, 11, 12. Here, SPOP is linked to posterior cortical atrophy.