Comprehensive genomic insights into the genetic causality and comorbidity in urological cancers.

While some urological cancer survivors may develop a second primary malignancy, the mechanism is unclear. We assess the causal associations and genetic comorbidity among urological cancers, including prostate (PCa), testicular (TC), bladder (BCa), and kidney cancer (KC). We revealed extensive causal associations among 6 of the 12 trait pairs, with a bidirectional interaction between PCa and TC (OR = 1.91, 95% confidence interval, 1.81-2.00, P = 5.41 × 10-142). We confirmed strong genome-wide and localized genetic correlations between PCa and TC, alongside tissue-specific heritability enrichment in prostate tissue for both of them. A total of 16 potential functional genes were identified, among which CHMP4C emerged as a shared risk factor for both PCa and TC, with links to poor prognosis. This study clarifies the genetic causality and comorbidity of urological cancers, showing PCa and TC share a similar genetic background. CHMP4C is a risk factor linked to poor prognosis in both, offering novel insights for clinical management.