Two large randomized trials evaluating the effect of PSA screening on prostate-cancer mortality, namely the Prostate, Lung, Colorectal, and Ovarian (PLCO) and the European Randomized Study of Screening for Prostate Cancer (ERSPC), showed that during the first decade of follow-up, PSA screening has at best a modest effect (20% relative reduction of PCA specific death in the ERSPC) on PCA mortality, with substantial risks of negative biopsy, over diagnosis and over-treatment [30,31]. This evidence concerns the gene KLK3 and Familial prostate cancer.