Identification of the gene expression changes and gene regulatory aspects in ELF3 mutant bladder cancer

Background Recent genome-wide studies revealed the molecular subtypes and mutational landscape of bladder cancer, which is the 10th most common cancer causing many deaths. ELF3 is one of the frequently mutated genes in bladder cancer with 14% alteration rate. It mainly functions as an epithelial transcription factor and its proper function is critical for the urothelium development. However, the impact of ELF3 mutations in bladder cancer is currently unknown. Methods and results In this study, we analysed the gene expression data available for primary bladder cancer and bladder cancer cell lines according to the mutation status of ELF3. Our results show that de-regulated genes common in cell lines and primary tissue are primarily involved in ameboidal type cell migration and cell-cell junction organization. Additionally, we identify that ELF3-mutant cases in primary samples significantly overexpress PIK3C2B and ELF3 and PIK3C2B and ELF3 are significantly co-mutated in many cancer types. Our integrative analysis with existing Hi-C data further revealed the genes proximally located to ELF3, including PIK3C2B to be upregulated in ELF3 mutant cases, potentially as a result of truncated ELF3 protein product and subsequent changes in regulatory interactions. Conclusions Our results provide important insights about how ELF3 mutation contributes to bladder tumorigenesis and uncover previously unknown dependencies.

Automated summary

This study investigated the impact of ELF3 mutations on gene expression in bladder cancer and found that deregulated genes associated with cell migration and cell-cell junction organization were commonly affected. Additionally, the study identified the overexpression of PIK3C2B and the co-occurrence of ELF3 and PIK3C2B mutations in various cancer types. Integration with existing Hi-C data revealed the upregulation of genes proximally located to ELF3, including PIK3C2B, in ELF3 mutant cases. These findings provide important insights into the role of ELF3 mutations in bladder tumorigenesis and uncover previously unknown dependencies.