SUMMARY: Researchers from UCLA’s Departments of Human Genetics and Urology have identified a novel biomarker and actionable target for prostate cancer metastasis. BACKGROUND: Prostate cancer is one of the most commonly diagnosed cancers and the second leading cause of cancer death in men. Although most men present with localized, potentially curable disease, prostate cancers are highly heterogeneous in their response to treatment and about 30% of patients suffer relapses. Furthermore, castration resistant prostate cancers almost always arise from these reoccurrences. This makes effective treatment of early localized prostate cancer highly indicative of long-term prognosis. While it has been characterized that metastatic, castration-resistant prostate cancers (mCPRCs) have higher mutational burdens than in localized disease, current clinical prognostic factors can only explain a fraction of the heterogeneity. The relationship between prostate cancer genetics and disease prognosis remains largely elusive, but having a more rigorous understanding of the genetic factors that drive progression and aggression in pre- and post-treatment prostate cancer is paramount for improving individualized standards of care and advancing risk stratification guidelines. INNOVATION: UCLA researchers in the Department of Human Genetics have identified ZNRF3 loss as a novel, independent predictor of aggressive localized prostate cancer by analyzing the genetics of 1,844 independent cancers. They identified recurrent genomic loss of ZNRF3 in 10% of localized prostate cancers and 30% of mCPRC. Across multiple independent cohorts of patients with localized disease, those whose tumors harbored ZNRF3 loss had shorter progression-free survival time and/or were at significantly higher risk of metastatic relapse and prostate-cancer specific mortality. ZNRF3 loss was independently prognostic of these adverse clinical outcomes after correction for standard clinical prognostic factors, pathological predictors of aggressive disease, and validated molecular predictors of aggressive disease. Molecularly, ZNRF3 loss led to the strong upregulation of cell cycle progression, E2F/DREAM, and PRC1/2 pathways, which have established links to prostate cancer aggression. Therefore, ZNRF3 loss could be used to stratify patients for treatment intensification, and as a novel therapeutic target. POTENTIAL APPLICATIONS: ● Biomarker for and predictor of aggressive localized prostate cancer ● Improve treatment stratification of prostate cancer patients ● Potential target for novel therapeutic development ● Potential predictive biomarker for WNT- and cell-cycle-targeted therapies ADVANTAGES: ● Localized prostate cancers have elevated frequency of ZNRF3 gene mutation ● ZNRF3 genomic loss is associated with hallmarks of prostate cancer, including WNT activation and upregulation of cell cycle progression ● Marker allows early recognition of localized prostate cancers more likely to progress to mCPRC without intervention DEVELOPMENT-TO-DATE: Researchers have quantified the prevalence of ZNRF3 loss in a group of more than 1800 patients with either localized prostate cancer or mCPRC and determined global RNA abundance patterns related to the gene.