FGFR Fusions in Cancer: From Diagnostic Approaches to Therapeutic Intervention

Abstract

Fibroblast growth factor receptors (FGFRs) are tyrosine kinase receptors involved in many biological processes. Deregulated FGFR signaling plays an important role in tumor development and progression in different cancer types. FGFR genomic alterations, including FGFR gene fusions that originate by chromosomal rearrangements, represent a promising therapeutic target. Next-generation-sequencing (NGS) approaches have significantly improved the discovery of FGFR gene fusions and their detection in clinical samples. A variety of FGFR inhibitors have been developed, and several studies are trying to evaluate the efficacy of these agents in molecularly selected patients carrying FGFR genomic alterations. In this review, we describe the most frequent FGFR aberrations in human cancer. We also discuss the different approaches employed for the detection of FGFR fusions and the potential role of these genomic alterations as prognostic/predictive biomarkers.

Keywords: FGFR fusions; FGFR inhibitors; cancer; fibroblast growth factor receptors; next generation sequencing.

Figure 1

DNA- and RNA-targeted sequencing approaches for detecting FGFR fusions. Hybrid capture methods use sequence specific probes complementary to a specific region of interest that are longer than PCR primers, whereas amplicon-based enrichment methods use primers specific to known fusion partners. The anchored multiplex PCR approach uses gene-specific primers and universal reverse primers that permit the amplification of both known and unknown genomic regions of interest. When DNA is used as starting material, hybrid capture probes can be designed to capture both exons and introns. RNA-based methods detect only functional transcripts, avoiding the difficulties of sequencing large intronic regions.