Fibroblast Growth Factor Receptors (FGFRs) are proteins that regulate cellular activities like cell growth and division. Changes in the genes responsible for making these proteins can lead to a variety of health conditions. These genetic alterations can affect how cells behave, leading to disorders that range from developmental issues to cancers.
What are Fibroblast Growth Factor Receptors?
Fibroblast Growth Factor Receptors are a group of four related proteins—FGFR1, FGFR2, FGFR3, and FGFR4—located on the surface of cells. Their structure includes a segment outside the cell that binds to activating proteins called Fibroblast Growth Factors (FGFs), a part that crosses the cell membrane, and an internal component that transmits signals. The binding of an FGF protein triggers this internal part, initiating a cascade of signals within the cell.
This signaling process guides cell growth, specialization into different cell types, and organized cell movement. These functions are particularly active during embryonic development, helping to form tissues and organs correctly. In adults, FGFR signaling is involved in tissue repair and the formation of new blood vessels, a process known as angiogenesis.
How FGFR Genes Can Mutate
The instructions for building each FGFR protein are encoded in a specific gene. A gene mutation is a change in the DNA sequence that can alter the resulting protein’s structure and function. Certain mutations cause the FGFR protein to become overactive, sending growth signals constantly, even when no FGF protein is present.
Common alterations include a point mutation, where a single building block in the DNA is changed, which can be enough to lock the receptor in an “on” position. Another change is gene amplification, where a cell makes too many copies of an FGFR gene, leading to an excessive number of receptors. A third mechanism is a chromosomal translocation, where part of the FGFR gene attaches to a different gene, creating a new fusion protein that is perpetually active.
These mutations can arise in two ways. Germline mutations are inherited from a parent and are present in every cell of the body from birth, often leading to developmental syndromes. In contrast, somatic mutations are not inherited but are acquired during a person’s life. These mutations are confined to specific tissues, such as a tumor, and are a common factor in the development of various cancers.
Conditions Linked to FGFR Mutations
Alterations in FGFR genes are associated with a diverse set of medical conditions, affecting bone development, skull formation, and cell growth in various tissues. The specific condition that develops depends on which FGFR gene is affected and the nature of the mutation.
A significant category of these disorders is skeletal dysplasias, which are conditions affecting bone and cartilage growth. The most well-known is achondroplasia, the most common form of dwarfism, which is almost always caused by a specific mutation in the FGFR3 gene. This mutation impairs the process of converting cartilage into bone, leading to shortened limbs. Other related conditions include hypochondroplasia, a milder form of short-limbed dwarfism, and thanatophoric dysplasia, a severe neonatal disorder, both linked to different mutations in FGFR3.
Craniosynostosis syndromes are another group of conditions, characterized by the premature fusion of the bones of the skull. This early fusion can affect brain growth and lead to distinct facial features. Apert syndrome, Crouzon syndrome, and Pfeiffer syndrome are prominent examples, often linked to mutations in FGFR1 and FGFR2.
Somatic FGFR mutations are also recognized as drivers of cancer. These acquired mutations can give cancer cells a survival and growth advantage. They are found in a variety of malignancies, including urothelial (bladder) cancer, where FGFR3 mutations are common, and cholangiocarcinoma (bile duct cancer), which is often associated with FGFR2 fusions. FGFR alterations are also implicated in some lung, breast, and gastric cancers.
Identifying FGFR Mutations
Detecting mutations in FGFR genes is a specialized process that involves analyzing an individual’s genetic material. The method used depends on whether the suspected condition is an inherited syndrome or a cancer. Identifying the specific genetic alteration is important for confirming a diagnosis and can influence management decisions.
For congenital conditions caused by suspected germline mutations, genetic testing is performed on a blood or saliva sample. From this sample, DNA is extracted and analyzed to look for changes in the FGFR genes. This testing can confirm a diagnosis in a child showing symptoms of a condition like achondroplasia or a craniosynostosis syndrome. Prenatal diagnosis may be an option for families with a known history of an FGFR-related disorder.
In the context of cancer, the focus shifts to finding somatic mutations within tumor cells. This process, known as molecular profiling, involves analyzing a sample of the tumor tissue from a biopsy. A less invasive technique called a liquid biopsy, which analyzes tumor DNA circulating in the bloodstream, can sometimes be used. These samples are often examined using Next-Generation Sequencing (NGS), a technology that can rapidly detect various alterations.
Managing Conditions Caused by FGFR Mutations
The strategies for managing conditions caused by FGFR mutations are tailored to the specific disorder. For developmental syndromes, the focus is on addressing the functional and physical challenges that arise. For cancers driven by these mutations, treatment is increasingly aimed at blocking the faulty signaling pathway.
In children with skeletal dysplasias and craniosynostosis syndromes, management is often multidisciplinary. Surgical interventions may be necessary to correct the premature fusion of skull bones or to address issues like spinal cord compression in achondroplasia. Supportive care, including physical therapy and monitoring for complications like sleep apnea or hearing loss, is also part of long-term management. For achondroplasia, a therapy called vosoritide is available, which works by counteracting the effects of the overactive FGFR3 signaling to promote bone growth.
For cancers with identified FGFR alterations, the development of targeted therapies has changed the treatment landscape. These drugs, known as FGFR inhibitors, are designed to specifically block the activity of the mutated FGFR proteins, thereby halting the growth signals that fuel the cancer. Several FGFR inhibitors, including erdafitinib and pemigatinib, have been approved for treating specific cancers, such as certain types of bladder cancer and bile duct cancer. These medications are prescribed after molecular testing confirms the presence of an actionable FGFR mutation in the tumor.