FBXW7 loss of function contributes to worse overall survival and is associated with accumulation of MYC in muscle invasive bladder cancer

With a five-year overall survival of approximately 50%, there is an important clinical need to understand the molecular behavior of muscle-invasive bladder cancer (MIBC). FBXW7, a subunit of an E3-ubiquitin ligase complex, is a tumour suppressor gene. Mutations in FBWX7 have been described in an expanding number of human neoplasms, including 10% of MIBC, making it one of the most commonly mutated genes in MIBC. However, it has received little attention in MIBC up to now. We aimed to assess the role of FBXW7 as a tumour suppressor in MIBC. We studied clinical implications of FBXW7 mutation and expression using The Cancer Genome Atlas (TCGA) database (N=405). FBXW7 was silenced in human bladder cancer cell lines with Crispr-Cas9 in order to assess the functional significance of modulating FBXW7 in vitro. Low FBXW7 mRNA expression significantly correlated with worse overall survival (OS) in TCGA, and Cox regression analysis demonstrated that it was an independent predictor of OS. FBXW7 mRNA expression was low in the luminal-infiltrated, luminal and basal/squamous subtypes compared to the luminal-papillary subtype. Furthermore, deletion and putative mutations of FBXW7 correlated with worse OS in TCGA. GSEA analysis showed that MYC targets were enriched by low FBXW7 expression or the deletion/putative mutations. Consistent with this, upregulation of MYC protein was detected in FBXW7 knock out cells, and this was associated with the upregulation of numerous cell cycle genes. FBXW7 loss of function was significantly correlated with worse OS. Preliminary analysis suggests that this may be related to MYC accumulation and downstream cell cycle gene upregulation. MYC, which is a substrate for FBXW7, could potentially be targeted to attenuate MIBC growth.