Grade progression in urothelial carcinoma can occur with high or low mutational homology: a first-step toward tumor-specific care in initial low-grade bladder cancer

Purpose Low-grade (LG) urothelial carcinomas of the bladder (UCB) are common malignancies that are costly to surveil and rarely progress to life threatening, high-grade (HG) malignancies. It is unknown if the progression of LG to HG is a result of second primary tumors or transformation of existing LG tumors. We examined tumor genetics in patients with grade progression in urothelial carcinoma and compared to patients with no progression. Results Five patients were identified with progression. Median time from initial LG diagnosis to HG diagnosis in those experiencing progression was 19 months. Progression with both high and low mutational homology was identified. Gene alterations associated with tumor grade progression in initial low grade tumors include FBN3, CIT and HECTD4. Materials and Methods An institutional cancer database at a tertiary referral center in the United States identified patients who progressed from LG to HG UCB. Histologic re-review was performed by a genitourinary pathologist. Whole exome sequencing with correction for germline mutations by buffy coat subtraction was performed. Mutations were assessed between LG tumors and subsequent same-patient HG tumors and for LG patients who did not progress. Individual genes were assessed as potential predictors of risk for progression. Conclusions Tumor grade progression occurred with both high mutational homology and low mutational homology, which may represent both true tumor progression and de-novo growth. Validation of the identified tumor genes that appeared associated with progression may provide a clinically valuable tool to providers managing patients with LG urothelial carcinomas.