CDKN1A/p21, RB1, ARID1A, FLG, and HRNR mutation patterns provide insights into urinary tract environmental exposure carcinogenesis and potential treatment strategies.

Bladder carcinoma has a 6% 5-year survival-rate for metastatic disease, with poorly understood links between genetic and environmental drivers of disease development, progression, and treatment response. Rhode Island has among the highest annual age-adjusted incidence rate of bladder cancer at 26.0/100,000, compared to 20.0 in the US, with a paucity of known driver genes for targeted therapies or predictive biomarkers. Bladder carcinomas have the highest frequency of alterations in CDKN1A/p21 (10%) across all cancer types analyzed in The Cancer Genome Atlas (TCGA) PanCancer Atlas Studies, displaying a predominance of truncating mutations (86%). We found that lung carcinomas lack CDKN1A truncating mutations, despite the shared role of tobacco as a risk factor for bladder cancer. Bladder carcinomas also have the highest frequency of RB1 alterations in TCGA (25%). We find that chromophobe renal cell carcinomas with CDKN1A and RB1 mutations are 100% truncating. Analysis of 1,868 bladder tumors demonstrated that truncating CDKN1A mutations co-occur with truncating RB1 mutations, suggesting an environmental exposure signature. Moreover, we found that HRNR and FLG mutations are enriched in tumors with CDKN1A alteration, suggesting potential novel roles in promoting bladder tumorigenesis. Association of HRNR with AKT activation offers possible therapeutic avenues, and FLG may provide insight into carcinogen exposure within the bladder. We suggest that because APOBEC mutations largely shape the bladder cancer mutational landscape, these events likely contribute to dysfunctional DNA repair genes, leading to frameshifts and the predominance of truncations in CDKN1A, RB1, ARID1A, or other drivers. We propose that patients with co-occurrence of CDKN1A and RB1 truncations may display enhanced responsiveness to targeted therapies combining cisplatin with ATR, ATM, CHK1, and CHK2 inhibitors, expanding therapeutic options for patients in need of improved precision treatments.