The emerging role of somatic tumor sequencing in the treatment of urothelial cancer

The development of rapid genome sequencing has greatly enhanced our understanding of the molecular biology underlying many malignancies. Whole exome sequencing has highlighted the individualistic nature of malignancies on a patient-to-patient basis and begun to revolutionize therapeutic approaches. In recent years, whole genome sequencing of urothelial malignancies has identified a host of somatic mutations which contribute to growth, progression, and metastasis of urothelial carcinoma of the bladder and upper tract urothelial carcinoma. As genetic sequencing continues, additional targets will be identified, allowing development of novel therapeutic agents targeting cancer on a molecular level, with the goal of delivering highly individualized care based on the underlying mutational profile of the patient's malignancy. In this review, we aim to discuss known genetic alterations of urothelial malignancy and the implications these mutations carry in terms of prognostication and development of targeted therapeutic agents. We will focus on RNA-expression profiling and genomic DNA profiling, with a focus on comprehensive whole exome and whole genome sequencing relative to selected urothelial carcinoma-associated genes and circulating tumor DNA analysis.