1. Overview
FGFR2 (Fibroblast Growth Factor Receptor 2) and FGFR3 (Fibroblast Growth Factor Receptor 3) are members of the fibroblast growth factor receptor family involved in regulating cell growth, differentiation, migration, and angiogenesis. FGFR2 resides on chromosome 10 and is also known as CD332 or KGFR, while FGFR3 is referred to by several alternative names, including ACH, CEK2, JTK4, CD333, and HSFGFR3EX.
Gain-of-function mutations in FGFR2 and FGFR3 can lead to constitutive receptor activation and have been implicated in oncogenic transformation. FGFR2 mutations are associated with several solid tumors, while FGFR3 mutations are particularly common in low-grade bladder papillary carcinoma and certain skeletal disorders.
2. Symptoms
FGFR2 and FGFR3 mutations do not produce a uniform symptom profile, as clinical manifestations depend on the tissue affected and the nature of the mutation. FGFR2 mutations are commonly associated with craniosynostosis syndromes such as Crouzon and Apert syndromes, characterized by abnormal skull and facial bone development.
FGFR3 mutations primarily affect bone growth and maintenance, leading to skeletal dysplasias including achondroplasia, hypochondroplasia, and thanatophoric dysplasia. In oncologic settings, symptoms relate to tumor type and location, such as bladder, endometrial, gastric, lung, or other cancers.
3. Causes
FGFR2 and FGFR3 abnormalities arise due to genetic mutations that alter receptor function. Loss-of-function mutations in FGFR2 impair ligand binding or kinase activity, resulting in reduced signaling and developmental defects. In contrast, gain-of-function mutations cause ligand-independent receptor activation, promoting abnormal cellular proliferation and tumorigenesis.
FGFR3 mutations often result in constitutive activation of the receptor and are strongly linked to skeletal dysplasia and urothelial carcinoma. Gene fusions involving FGFR2 or FGFR3 further enhance oncogenic signaling and contribute to cancer progression.
4. Risk Factors
Risk factors associated with FGFR2 and FGFR3 mutations include inherited genetic syndromes affecting skeletal development and the presence of somatic mutations in tumor tissues. FGFR2 intronic single-nucleotide polymorphisms have been linked to an increased risk of estrogen receptor–positive breast cancer.
Activating FGFR2 mutations or gene amplifications are observed in endometrial, gastric, lung, and other cancers, while FGFR3 hotspot mutations such as S249C are frequently seen in bladder and urothelial carcinomas. Germline FGFR3 mutations are rare and primarily lead to skeletal abnormalities rather than cancer predisposition.
5. Prevention and Clinical Management
Clinical management of FGFR2 and FGFR3 mutations focuses on accurate detection, risk stratification, and therapeutic targeting. Testing is indicated in individuals with suspected craniosynostosis syndromes, skeletal dysplasias, and cancers known to harbor FGFR alterations, including bladder, endometrial, gastric, lung, and cholangiocarcinoma.
Detection methods include fluorescence in situ hybridization (FISH), next-generation sequencing (NGS), immunohistochemistry (IHC), and denaturing high-performance liquid chromatography (DHPLC). Plasma is the preferred specimen for molecular analysis, as serum clotting can release genomic DNA that interferes with results. EDTA or citrate-anticoagulated samples are recommended, with careful processing and storage to preserve circulating tumor DNA.
FGFR2 and FGFR3 mutations have significant therapeutic implications. These alterations serve as actionable targets for FGFR inhibitors, with several agents approved or designated for clinical use. FGFR2 rearrangements or fusions in advanced cholangiocarcinoma are treated with inhibitors such as pemigatinib, infigratinib, and futibatinib. FGFR3 mutations or FGFR2 fusions in metastatic urothelial carcinoma are treated with erdafitinib.
Prognostically, low FGFR2 expression is associated with unfavorable clinicopathological features, while high FGFR3 expression in bladder cancer is linked to improved progression-free survival. Thus, FGFR mutation testing plays a critical role in diagnosis, prognosis, and personalized treatment planning.
