Transcriptome-wide association studies implicate RCC1 and PHACTR4 in prostate cancer survival

While prostate cancer (PrCa) is highly heritable, the genes associated with PrCa survival after diagnosis remain poorly understood. We aimed to identify genes associated with PrCa-specific survival through transcriptome-wide association studies (TWAS) using genetic predictors of gene expression in the prostate. We used the Transcriptome-Integrated Genetic Association Resource (TIGAR) to train expression prediction models separately using normal prostate, primary tumor, and metastatic tumor tissues. We performed TWAS using these models in data from the Malmö Diet and Cancer (MDC) study (discovery) and Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial (validation). We identified and validated seven genes associated with PrCa-specific survival at a common locus on chromosome 1. We found two genes using prediction models from normal prostate tissues and five with models from metastatic tumor tissues. Elevated RCC1 expression is linked to a shorter time to biochemical recurrence, while higher PHACTR4 expression was observed in tumors with a higher Gleason grade. The study is limited to European ancestry and can only show associations. Further research across other populations and experiments to establish causality will be needed. Our multi-tissue study identified novel genes associated with PrCa survival, particularly RCC1 and PHACTR4, providing new insights for potential genomic markers for PrCa survival.