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Characterization of FGFR1 Locus in sqNSCLC Reveals a Broad and Heterogeneous Amplicon
Claire Rooney1, Catherine Geh1, Victoria Williams2
1AstraZeneca, Oncology Innovative Medicines, Alderley Park, Macclesfield, United Kingdom.
Abstract:
FGFR1 amplification occurs in ~20% of sqNSCLC and trials with FGFR inhibitors have selected FGFR1 amplified patients by FISH. Lung cancer cell lines were profiled for sensitivity to AZD4547, a potent, selective inhibitor of FGFRs 1-3. Sensitivity to FGFR inhibition was associated with but not wholly predicted by increased FGFR1 gene copy number. Additional biomarker assays evaluating expression of FGFRs and correlation between amplification and expression in clinical tissues are therefore warranted. We validated nanoString for mRNA expression analysis of 194 genes, including FGFRs, from clinical tumour tissue. In a panel of sqNSCLC tumours 14.4% (13/90) were FGFR1 amplified by FISH. Although mean FGFR1 expression was significantly higher in amplified samples, there was significant overlap in the range of expression levels between the amplified and non-amplified cohorts with several non-amplified samples expressing FGFR1 to levels equivalent to amplified samples. Statistical analysis revealed increased expression of FGFR1 neighboring genes on the 8p12 amplicon (BAG4, LSM1 and WHSC1L1) in FGFR1 amplified tumours, suggesting a broad rather than focal amplicon and raises the potential for codependencies. High resolution aCGH analysis of pre-clinical and clinical samples supported the presence of a broad and heterogeneous amplicon around the FGFR1 locus. In conclusion, the range of FGFR1 expression levels in both FGFR1 amplified and non-amplified NSCLC tissues, together with the breadth and intra-patient heterogeneity of the 8p amplicon highlights the need for gene expression analysis of clinical samples to inform the understanding of determinants of response to FGFR inhibitors. In this respect the nanoString platform provides an attractive option for RNA analysis of FFPE clinical samples.
Insights
FGFR1 amplification in lung cancer is complex. Gene expression, not just copy number, is crucial for predicting response to FGFR inhibitors, suggesting broader biomarker analysis is needed.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- FGFR1 amplification is found in approximately 20% of squamous non-small cell lung cancer (sqNSCLC).
- Current trials often select patients for FGFR inhibitor therapy based on FGFR1 amplification detected by Fluorescence In Situ Hybridization (FISH).
- Sensitivity to FGFR inhibitors like AZD4547 is linked to, but not solely predicted by, increased FGFR1 gene copy number.
Purpose of the Study:
- To investigate the correlation between FGFR1 gene amplification, FGFR1 mRNA expression, and sensitivity to FGFR inhibition in sqNSCLC.
- To evaluate the utility of the nanoString platform for analyzing gene expression in clinical tumor tissues.
- To characterize the genomic landscape of the FGFR1 amplicon in sqNSCLC.
Main Methods:
- Profiling of lung cancer cell lines for sensitivity to AZD4547.
- FISH analysis to determine FGFR1 amplification in a cohort of 90 sqNSCLC tumors.
- mRNA expression analysis using the nanoString platform for 194 genes, including FGFRs, in clinical tumor tissues.
- High-resolution array comparative genomic hybridization (aCGH) analysis.
Main Results:
- 14.4% of sqNSCLC tumors showed FGFR1 amplification by FISH.
- While FGFR1 expression was higher in amplified samples, significant overlap existed with non-amplified samples.
- Increased expression of neighboring genes (BAG4, LSM1, WHSC1L1) on the 8p12 amplicon was observed in FGFR1-amplified tumors.
- aCGH confirmed a broad and heterogeneous amplicon around the FGFR1 locus.
Conclusions:
- FGFR1 gene copy number alone is insufficient to predict response to FGFR inhibitors in sqNSCLC.
- Gene expression analysis, alongside copy number status, is essential for understanding treatment response determinants.
- The nanoString platform is a viable option for RNA analysis of FFPE clinical samples, aiding in biomarker discovery.
