Targetable gene fusions and aberrations in genitourinary oncology

Abstract

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 the TMPRSS2ERG fusion. 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 of FGFR-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.

Key points

  • Gene fusions and rearrangements represent potentially targetable alterations in several different malignancies, including genitourinary tumours.

  • TMPRSS2ERG fusion is present in 40–50% of prostate cancers and has a critical role in tumorigenesis and progression by disrupting the androgen receptor differentiation of prostate cells.

  • FGFR3TACC fusion in urothelial carcinoma has proven to be an effective target of anti-fibroblast growth factor receptor (FGFR) compounds, such as erdafitinib, in phase II clinical trials.

  • Xp11 and t(6;11) translocations and their related fusion events represent the hallmark aberrations of the microphthalmia-associated transcription factor family translocated renal cell carcinomas.

  • Application of standardized and easy-to-use classification frameworks (such as ESMO Scale for Clinical Actionability (ESCAT) and OncoKB) to the multitude of gene fusions identifiable by next-generation sequencing is necessary to foster the translation of gene fusion research into effective clinical practice.

  • Results from site-agnostic, biomarker-guided trials including strong translational investigations would help move forwards our understanding of the pathobiology and druggability of rare, low-prevalence gene fusions.

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Fig. 1: Overview of the different mechanisms of gene fusions.
Fig. 2: Overview of protumoural mechanisms of gene fusions.
Fig. 3: Main gene fusions identified in prostate, kidney and bladder cancer.
Fig. 4: Example of fusion-targeted therapy in bladder cancer.

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F.P. and A.N. researched data for the article, made a substantial contribution to discussion of content, and wrote and reviewed/edited the manuscript before submission. M.B., L.M., S.M.A., R.M. and J.C. made a substantial contribution to discussion of content and reviewed/edited the manuscript before submission. J.S.R. made a substantial contribution to discussion of content, and wrote and reviewed/edited the manuscript before submission.

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Pederzoli, F., Bandini, M., Marandino, L. et al. Targetable gene fusions and aberrations in genitourinary oncology. Nat Rev Urol (2020). https://doi.org/10.1038/s41585-020-00379-4

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