Metastasis and recurrence patterns in the molecular subtypes of urothelial bladder cancer

Urothelial cancer of the urinary bladder frequently metastasizes to lymph-nodes, lungs, liver and bone. A taxonomy for molecular classification exists, but it is unknown if molecular subtypes show tropism for different organs. Here, we study 146 patients with de novo metastatic disease or recurrence after curative treatment. We classify primary tumors using two transcriptomic methods and immunostaining and identify enrichment and depletion of metastatic sites in molecular subtypes using permutation tests. We observed significant depletion of bone metastases in the Basal/squamous molecular subtype, whereas the Urothelial-like subtype entailed an enrichment for metastases to bone. The Genomically unstable subtype was depleted of lung metastases, but enriched for atypical sites, including six out of seven patients with brain metastases. Stroma-rich primary tumor samples were associated with local recurrence, but not with distant sites. Additionally, the proportion with brain or testis metastases differed between systemic chemotherapy regimens (GC vs MVAC) suggesting a sanctuary effect. In conclusion, molecular subtypes of urothelial bladder cancer are significantly associated with specific metastatic sites, suggesting that subtype-specific molecular determinants could exist at various steps in the metastatic cascade.