This study investigates the association between somatic Y chromosome loss and mortality in men, particularly in prostate cancer. Due to technical limitations, such as challenges in labeling and sequencing Y chromosome DNA, the status of the Y chromosome in cancer tissue remains unclear. The researchers developed a system to quantify Y chromosome gain or loss in patient-derived prostate cancer organoids. Their findings reveal Y chromosome loss in a significant proportion of metastatic castration-resistant prostate cancer (mCRPC) organoids, with a notable occurrence of Yq loss. Interestingly, potential associations were observed between mCRPC and Y chromosome nullisomy. The prevalence of Y chromosome loss was similar in primary and metastatic tissue, indicating that it may occur early in prostate cancer evolution rather than as a result of drug resistance or organoid derivation. This study paves the way for further investigations into the clinical implications of Y chromosome loss or gain in mCRPC.