LAUSR

Simple Summary Bladder cancer (BC) is a common cancer that causes high morbidity and mortality among affected patients. As a carcinogen-driven cancer, molecular oncology of BC has contributed to several fundamental concepts in cancer biology. Molecular insights into the divergent pathways for low- and high-grade BC development, heterogeneity in bladder tumors regarding recurrence and progression, genetic polymorphism, and the associated risk for developing BC among smokers, driver mutations, and molecular subtyping of muscle-invasive BC for prognostic predictions find commonality with other cancers and therefore, have advanced the field of molecular oncology. Similarly, research into lineage plasticity and tumor heterogeneity has revealed both challenges and opportunities in applying molecular approaches to patient care. The quest for finding a “PSA” for BC has contributed to novel technologies in the biomarker field. This review critically assesses and offers a perspective on the areas where molecular oncology could directly contribute to improving patient care. Abstract Within the last forty years, seminal contributions have been made in the areas of bladder cancer (BC) biology, driver genes, molecular profiling, biomarkers, and therapeutic targets for improving personalized patient care. This overview includes seminal discoveries and advances in the molecular oncology of BC. Starting with the concept of divergent molecular pathways for the development of low- and high-grade bladder tumors, field cancerization versus clonality of bladder tumors, cancer driver genes/mutations, genetic polymorphisms, and bacillus Calmette-Guérin (BCG) as an early form of immunotherapy are some of the conceptual contributions towards improving patient care. Although beginning with a promise of predicting prognosis and individualizing treatments, “-omic” approaches and molecular subtypes have revealed the importance of BC stem cells, lineage plasticity, and intra-tumor heterogeneity as the next frontiers for realizing individualized patient care. Along with urine as the optimal non-invasive liquid biopsy, BC is at the forefront of the biomarker field. If the goal is to reduce the number of cystoscopies but not to replace them for monitoring recurrence and asymptomatic microscopic hematuria, a BC marker may reach clinical acceptance. As advances in the molecular oncology of BC continue, the next twenty-five years should significantly advance personalized care for BC patients.