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.

WITHDRAWN: The epigenetic study of Fgfr2 as a potential biomarker in the differential diagnosis of intestinal metaplasia and gastric cancer

“…The high expressed levels of FGFR2 in colorectal [13], lung [14], gastric [15][16][17] cancer, coding mutations [18], and more recently, FGFR fusions that lead to pathway activation [19] have been demonstrated that the FGFR2 has a signi cant oncogenic potential across multiple cancer types. ROC analysis was employed to compare the predictive accuracy of the methylation status of patients with gastric cancer.…”

Targeting the Fibroblast Growth Factor Receptor (FGFR) in Advanced Cholangiocarcinoma: Clinical Trial Progress and Future Considerations

“…However, several other commercially available NGS platforms have employed both DNA and RNA sequencing for evaluation of FGFR gene rearrangements and fusions. DNA-based methods are more stable than RNA, but detection of novel fusions are limited when compared to RNA-based methods, particularly when large intronic regions are involved [ 56 ]. Often, RNA fusion analysis identifies more alterations than DNA fusion analysis, whereas DNA sequencing did not detect any fusions RNA sequencing was unable to [ 57 ].…”

“…However, WGS has the advantage of identifying a large number of rearrangements and characterizing breakpoints, including those in non-coding regions, and it is particularly useful for the discovery of novel fusions. WES offers the ability to evaluate DNA contained in all exonic regions of the genome [ 56 ]. WTS via RNA next-generation sequencing has the ability to detect rare or novel fusion events better than targeted RNA sequencing or DNA-based methods; one such test is the Caris MI Transcriptome™, which has received FDA Breakthrough Device designation for detection of novel FGFR biomarkers from FFPE tumor tissue [ 59 ].…”

Targeted RNA-sequencing for the evaluation of gene fusions in lung tumors: current status and future prospects

“…It is possible to characterize exact breakpoints, including those in non-coding regions. However, WGS is expensive and time consuming due to its enormous data output and intensive analysis [7]. An alternative to WGS can be whole exome sequencing (WES).…”

“…Currently there are different approaches available to detect fusions in a targeted setup: hybrid capture-based methods, amplicon-based methods and anchored multiplex PCR (see Figure 1). Various off-the-shelf panels are available for all approaches as summarized by De Luca et al and compared by Heydt et al [7,12]. Hybrid capture-based approaches have the advantage to cover larger areas including flanking regions of the target area.…”