Molecular characterization of clear cell adenocarcinoma of the urinary bladder.

Clear cell adenocarcinoma (CCA) of the urinary tract is a rare genitourinary malignancy that primarily arises in the urethra and bladder. Due to its rarity, the molecular landscape of these tumours remains poorly characterized. In this large series, we aimed to molecularly characterize CCA to gain insights into its pathogenesis and identify potential targets for therapy. Formalin-fixed, paraffin-embedded tumour tissue blocks from 19 cases of CCA were subjected to molecular profiling using a targeted next-generation sequencing (NGS) panel. The most common alteration was a gain-of-function mutation in PIK3CA (74%), followed by mutations in KRAS (26%), ERBB2 (21%), SMAD4 (21%), RB1 (16%), TP53 (5%), MET (5%) and APC (5%). Thirteen tumours harboured co-mutations. Five cases showed concurrent PIK3CA and KRAS mutations, while the remaining tumours had either isolated PIK3CA alterations or co-occurring loss-of-function mutations in tumour suppressor genes, including RB1 point mutation, SMAD4 inactivation, APC truncation or TP53 inactivation. Eight patients died of disease, with a mean follow-up of 14 months (range, 3-31 months). Notably, all eight deceased patients and two of the surviving patients harboured PIK3CA mutations. In summary, we identified a distinct oncogenic pathway in CCA of the urinary bladder, most commonly involving activation of the PI3K/AKT/mTOR pathway through gain-of-function mutations in PIK3CA (74%) and/or KRAS (26%). These tumours frequently harbour loss-of-function mutations in tumour suppressor genes (TP53, SMAD4, RB1 and APC) and point/missense mutations of proto-oncogenes (ERBB2 and MET). Our study also highlights potential therapeutic targets for this aggressive malignancy.