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Pan-tumor landscape of fibroblast growth factor receptor 1-4 genomic alterations
K Murugesan1, A Necchi2, T C Burn3
1Cancer Genomics Research, Foundation Medicine, Inc., Cambridge, USA.
Background:
Selective tyrosine kinase inhibitors targeting fibroblast growth factor receptor (FGFR) 1-4 genomic alterations are in development or have been approved for FGFR-altered cancers (e.g. bladder cancer and advanced intrahepatic cholangiocarcinoma). Understanding FGFR inhibitor-resistance mechanisms is increasingly relevant; we surveyed the pan-tumor landscape of FGFR1-4 genomic alterations [short variants (SVs), gene rearrangements (REs), and copy number alterations (CNAs)], including their association with tumor mutational burden (TMB) and the genomic comutational landscape.
Patients And Methods:
Comprehensive genomic profiling of 355 813 solid tumor clinical cases was performed using the FoundationOne and FoundationOne CDx assays (Foundation Medicine, Inc.) to identify genomic alterations in >300 cancer-associated genes and TMB (determined on ≤1.1 megabases of sequenced DNA).
Results:
FGFR1-4 SVs and REs occurred in 9603/355 813 (2.7%), and CNAs in 15 078/355 813 (4.2%) samples. Most common FGFR alterations for bladder cancer, intrahepatic cholangiocarcinoma, and glioma were FGFR3 SVs (1051/7739, 13.6%), FGFR2 REs (618/6641, 9.3%), and FGFR1 SVs (239/11 550, 2.1%), respectively. We found several, potentially clinically relevant, tumor-specific associations between FGFR1-4 genomic alterations and other genomic markers. FGFR3 SV-altered bladder cancers and FGFR1 SV-altered gliomas were significantly less likely to be TMB-high versus unaltered samples. FGFR3 SVs in bladder cancer significantly co-occurred with TERT and CDKN2A/B alterations; TP53 and RB1 alterations were mutually exclusive. In intrahepatic cholangiocarcinoma, FGFR2 REs significantly co-occurred with BAP1 alterations, whereas KRAS, TP53, IDH1, and ARID1A alterations were mutually exclusive. FGFR1 SVs in gliomas significantly co-occurred with H3-3A and PTPN11 alterations, but were mutually exclusive with TERT, EGFR, TP53, and CDKN2A/B alterations.
Conclusions:
Overall, our hypothesis-generating findings may help to stratify patients in clinical trials and guide optimal targeted therapy in those with FGFR alterations.
Insights
This study surveyed fibroblast growth factor receptor (FGFR) genomic alterations across over 350,000 tumors. Findings reveal specific FGFR alterations and co-occurring mutations in cancers like bladder, liver, and brain, aiding targeted therapy development.
Area of Science:
- Oncology
- Genomics
- Cancer Research
Background:
- Fibroblast growth factor receptor (FGFR) inhibitors are emerging therapies for FGFR-altered cancers, including bladder cancer and intrahepatic cholangiocarcinoma.
- Understanding resistance mechanisms to FGFR inhibitors necessitates a comprehensive analysis of FGFR alterations.
- This study investigates the pan-tumor landscape of FGFR1-4 genomic alterations (short variants, rearrangements, copy number alterations) and their associations with tumor mutational burden (TMB) and co-occurring genomic events.
Purpose of the Study:
- To survey the pan-tumor landscape of FGFR1-4 genomic alterations.
- To investigate the association of FGFR alterations with tumor mutational burden (TMB).
- To identify co-occurring genomic alterations with FGFR alterations across various cancer types.
Main Methods:
- Comprehensive genomic profiling of 355,813 solid tumor clinical cases using FoundationOne and FoundationOne CDx assays.
- Identification of FGFR1-4 short variants (SVs), gene rearrangements (REs), and copy number alterations (CNAs).
- Analysis of tumor mutational burden (TMB) and co-occurring/mutually exclusive genomic alterations.
Main Results:
- FGFR1-4 SVs and REs occurred in 2.7% of samples, while CNAs occurred in 4.2%.
- Specific FGFR alterations were identified as common in bladder cancer (FGFR3 SVs), intrahepatic cholangiocarcinoma (FGFR2 REs), and glioma (FGFR1 SVs).
- Tumor-specific associations were found between FGFR alterations and other genomic markers, including TMB levels and co-occurring mutations (e.g., TERT, CDKN2A/B in bladder cancer; BAP1 in cholangiocarcinoma; H3-3A, PTPN11 in glioma).
Conclusions:
- The identified FGFR alterations and their genomic co-occurrences provide a foundation for stratifying patients in clinical trials.
- These findings can guide the optimal selection of targeted therapies for patients with FGFR-altered cancers.
- Further research into these associations may elucidate FGFR inhibitor resistance mechanisms.
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