Targetable gene fusions and aberrations in genitourinary oncology

Gene fusions result from either structural chromosomal rearrangement or aberrations caused by splicing or transcriptional readthrough. The precise and distinctive presence of fusion genes in neoplastic tissues and their involvement in multiple pathways central to cancer development, growth and survival make them promising targets for personalized therapy. In genitourinary malignancies, rearrangements involving the E26 transformation-specific family of transcription factors have emerged as very frequent alterations in prostate cancer, especially theTMPRSS2-ERGfusion. In renal malignancies, Xp11 and t(6;11) translocations are hallmarks of a distinct pathological group of tumours described as microphthalmia-associated transcription factor family translocation-associated renal cell carcinomas. Novel druggable fusion events have been recognized in genitourinary malignancies, leading to the activation of several clinical trials. For instance,ALK-rearranged renal cell carcinomas have shown responses to alectinib and crizotinib. Erdafitinib has been tested for the treatment ofFGFR-rearranged bladder cancer. Other anti-fibroblast growth factor receptor 3 (FGFR3) compounds are showing promising results in the treatment of bladder cancer, including infigratinib and pemigatinib, and all are currently in clinical trials. This Review summarizes current knowledge of the main gene fusions in genitourinary malignancies, discusses their growing importance in the understanding of the biology of tumours, and highlights their potential use as targets for precision medicine approaches.