Unravelling the molecular mechanisms of prostate cancer evolution from genotype to phenotype.

Prostate cancer (PC) is the most frequently diagnosed cancer and the second leading cause of cancer-related death in men in the Western society. Unfortunately, although the vast majority of patients are initially responsive to androgen-deprivation therapy (ADT), most cases eventually develop from hormone-sensitive prostate cancer (HSPC) to castration-resistant prostate cancer (CRPC). The main reason is PC heterogeneity and evolution during therapy. PC evolution is a continuously progressive process with combination of genomic alterations including canonical AR, TMPRSS2-ERG fusion, SPOP/FOXA1, TP53/RB1/PTEN, BRCA2. Meanwhile, signaling pathways including PI3K, WNT/β-catenin, SRC, IL-6/STAT3 are activated, to promote epithelial mesenchymal transition (EMT), cancer stem cell (CSC)-like features/stemness and neuroendocrine differentiation (NED) of PC. These improve our understanding of the genotype-phenotype relationships. The identification of canonical genetic alterations and signaling pathway activation in PC has shed more insight into genetic background, molecular subtype and disease landscape of PC evolution, resulting in a more flexible role of individual therapies targeting diverse genotype and phenotype presentation.