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Updated: Aug 5, 2026
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
Mutational Landscape of FGFR4 Across Malignancies: A Cross-Cancer Analysis of the AACR Project GENIE Database
Henna Ali1, Tyler Gengnagel1, Salem Birkholz1
1School of Medicine, Creighton University, Omaha, NE 68178, USA.
Background/Aim:
Fibroblast growth factor receptor 4 (FGFR4) is a tyrosine kinase involved in cell growth, proliferation, and angiogenesis. While FGFR1-3 are well studied in cancer, FGFR4 remains relatively understudied, and the distribution of its mutations across cancers and patient populations is not well defined.
Materials And Methods:
A retrospective pan-cancer analysis was performed using the AACR Project GENIE v12 database via cBioPortal. Tumors with somatic FGFR4 mutations were included, excluding copy number alterations and structural variants. Mutations were grouped by hotspot (amino acid 401) and major protein domains. Comparative analyses assessed cancer type distribution, demographics, mutation burden, and co-occurring genomic alterations using chi-square testing with multiple comparison correction.
Results:
A total of 4565 tumor samples (4283 patients) were analyzed. FGFR4 alterations were observed across diverse malignancies, most commonly non-small cell lung cancer, colorectal cancer, and melanoma. Mutations clustered primarily in the tyrosine kinase and immunoglobulin I-set domains, with no significant variation in distribution across cancer types. Sex was not associated with the mutation group, while race and ethnicity showed significant differences. The FGFR4 hotspot 401 group demonstrated a higher mutation burden, driven by a subset of hypermutated tumors, and showed enrichment for co-occurring alterations in chromatin remodeling, DNA repair, tumor suppressor, and receptor tyrosine kinase genes; however, sensitivity analyses indicated this association was largely attributable to mutation burden rather than a mutation-specific effect. Domain-based mutation groups had lower mutation burdens and fewer co-alterations.
Conclusions:
FGFR4 alterations occur across a broad range of cancers with consistent domain-level patterns. The hotspot 401 mutation shows a higher mutation burden and co-alteration frequency driven largely by a subset of hypermutated tumors, rather than acting as an isolated driver.
Insights
Fibroblast growth factor receptor 4 (FGFR4) mutations are found across many cancers, with hotspot mutations linked to higher mutation burden. These FGFR4 alterations are not isolated drivers but occur within broader genomic contexts.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Fibroblast growth factor receptor 4 (FGFR4) is a tyrosine kinase crucial for cell growth, proliferation, and angiogenesis.
- While FGFR1-3 are extensively studied in cancer, FGFR4 remains under-investigated, with undefined mutation distribution across cancer types and patient demographics.
Purpose of the Study:
- To define the distribution of FGFR4 mutations across various cancer types and patient populations.
- To investigate the genomic context and mutation burden associated with FGFR4 alterations.
Main Methods:
- A retrospective pan-cancer analysis of the AACR Project GENIE v12 database was conducted.
- Somatic FGFR4 mutations were analyzed, excluding copy number alterations and structural variants, and grouped by hotspot (amino acid 401) and protein domains.
- Comparative analyses included cancer type distribution, demographics, mutation burden, and co-occurring genomic alterations.
Main Results:
- FGFR4 alterations were identified in 4565 tumor samples across diverse malignancies, notably non-small cell lung cancer, colorectal cancer, and melanoma.
- Mutations predominantly clustered in the tyrosine kinase and immunoglobulin I-set domains, with consistent distribution across cancer types.
- The hotspot 401 mutation group exhibited a higher mutation burden and enriched co-occurring alterations, largely driven by hypermutated tumors, rather than specific mutation effects.
Conclusions:
- FGFR4 alterations are present in a wide spectrum of cancers, displaying consistent domain-level mutation patterns.
- The hotspot 401 mutation is associated with increased mutation burden and co-alteration frequency, primarily due to hypermutated tumor subsets, indicating it is not an isolated driver.
