Opportunities of next-generation sequencing in non-muscle invasive bladder cancer outcome prediction

Bladder cancer (BC) is a common disease in both sexes and majority of cases present as non-muscle invasive BC (NMIBC). The percentage of NMIBC progressing to muscle invasive BC (MIBC) varies between 25% and 75% and currently there are no reliable biomarkers that may predict the outcome of high-risk (HR) NMIBC. Whilst The Cancer Genome Atlas (TCGA) project has identified genetic alteration in MIBC using next-generation sequencing (NGS), genetic data in HR-NMIBC outcome prediction using this new technology are limited. We reviewed data on NGS performed on DNA and RNA extracted from tissue, plasma and urinary samples obtained from patients with NMIBC. Analysis on different specimens revealed genetic alterations and microRNA alterations in common oncogenic pathways such as gene expression (TERT) and cell proliferation (PTEN, cyclin D). Validation of a 12-gene (CDC25B, KPNA2, BIRC5, COL18A1, MSN, UBE2C, COL4A1, FABP4, MBNL2, SKAP2, COL4A3BP, NEK1) progression score has shown significant association with progression. ARID1A mutations are associated with an increased risk of recurrence after Bacillus Calmette-Guerin (BCG) together with a high DNA damage repair (DDR) gene alterations in HR-NMIBC. Patients with progressive disease seem to have significantly higher levels of both plasma and urinary tumour DNA compared with patients with recurrence. Although experimental data appear promising, well-designed systematic studies are urgently needed to translate applicability to clinical practice.