High Prevalence of a Hotspot of Noncoding Somatic Mutations in Intron 6 of in Bladder Cancer.

Numerous pangenomic studies identified protein-coding genes and signaling pathways involved in bladder carcinogenesis. However, noncoding somatic alterations remain unexplored. A recent study revealed a mutational hotspot in intron 6 of gene in 2.7% of a large breast cancer series. As is highly expressed in bladder tissues, we investigated here the prevalence and the prognostic significance of these mutations in bladder cancer. We analyzed a cohort of 103 bladder cancers including 44 nonmuscle-invasive bladder cancers (NMIBC) and 59 muscle-invasive bladder cancers (MIBC). mutations were analyzed by high-resolution melting and Sanger sequencing, and expression levels were assessed using real-time quantitative RT-PCR. In NMIBC, somatic noncoding mutations occurred in 47.7% of samples and were negatively associated with mRNA levels. mutations had higher frequencies in nonsmoker patients and were associated with a prior history of NMIBC. overexpression was detected in 70.5% of samples. mutation and overexpression status were not associated with outcome. In MIBC, somatic mutations occurred in 44.1% of samples. Mutations were more frequent in females. overexpression was detected in 27.1% of the sample. A trend toward significance was observed between overexpression and better outcome. We identified the second most frequent mutational hotspot after promoter (∼70%) in bladder cancer, with a mutation rate of approximately 50%. IMPLICATIONS: The intronic mutational hotspot could be a promising clinical biomarker candidate to monitor tumor burden using circulating tumor DNA in bladder cancer.