# Illuminating the FGFR fusion landscape in Chinese patients: unveiling novel molecular insights and clinical implications

## TL;DR

This study explores FGFR gene fusions in Chinese cancer patients, revealing new patterns and the importance of RNA testing for accurate detection and treatment guidance.

## Contribution

The study provides the first comprehensive profiling of FGFR fusions in a large Chinese cohort and identifies novel breakpoint hotspots and fusion mechanisms.

## Key findings

- FGFR fusions occurred at 0.96% incidence in the Chinese cohort, with a notable 40% rate in parotid gland carcinoma.
- Distinct breakpoint patterns were identified, including hotspots in FGFR1 intron17 and FGFR3's 3’ untranslated region.
- RNA validation is critical as 46% of rare FGFR fusions lacked detectable RNA transcripts, highlighting the need for orthogonal methods.

## Abstract

Despite the increasing approval and ongoing clinical trials of FGFR-targeted therapies, accurately detecting FGFR fusions remains a challenge due to limited research, low incidence rates, complex fusion partner distribution, and unique kinase domain distribution.

We conducted a multicenter study to comprehensively profile FGFR fusions in the largest Chinese pan-cancer cohort to date, comprising 118 FGFR fusions from 114 individuals. Both DNA- and RNA-based sequencing approaches were utilized to reveal novel and fundamental features of FGFR fusion.

Our research reveals an incidence rate of 0.96% for FGFR rearrangements within this Chinese cohort, including a high incidence rate of FGFR fusions (40%) in parotid gland carcinoma. However, this is based on a small sample size of 5 tumors and should be interpreted cautiously pending validation in larger cohorts. We also uncovered distinct breakpoint distribution patterns across various FGFR rearrangements. For example, a primary breakpoint in intron17 of FGFR2 was predominant (21/22), while FGFR1/3 breakpoints displayed substantial diversity. For the first time, we identified “hot” breakpoints in FGFR1 intron17, exon18, and FGFR3's 3’ untranslated region. These findings underline the importance of incorporating these regions in targeted sequencing to ensure comprehensive detection of FGFR1/3 fusions. Notably, we observed a predilection for intrachromosomal distribution in common FGFR1/2/3 fusions. In contrast, most novel fusions (12/15) exhibited an interchromosomal distribution pattern, indicating variations in the fusion formation mechanism. Importantly, our study demonstrates the substantial incremental value of RNA-NGS or other orthogonal methods in confirming the functionality of FGFR rearrangements initially identified by DNA sequencing. In our cohort, 46% (6/13) of rare FGFR1/2/3 fusions lacked detectable RNA transcripts; however, this does not definitively indicate non-functionality as factors such as low RNA quality, expression below detection limits, or nonsense-mediated decay may contribute. Therefore, RNA-based validation is critical for accurately identifying potentially targetable FGFR fusions and guiding therapy.

Our findings offer critical novel insights into functional FGFR fusions and bear considerable clinical implications for identifying individuals whose tumors are most likely to respond favorably to FGFR-targeted therapies.