Germline Variant of FGFR4 and Associated Cancer

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(Last Updated On: April 4, 2020)
A crystal structure of fibroblast growth factor and its receptor
A crystal structure of fibroblast growth factor and its receptor. Credit: Takuma-sa via Wikimedia Commons

Researchers have found a new approach treating growth factor receptor (FGFR4) associated cancer that recruits STAT3 and activate and express cell growth and proliferation-associated genes. All human beings have 99.9% similar genetic material, but they have 0.1% dissimilar genetic makeup. Yes! Only a 0.1 % difference in genetic material means a lot and makes individuals unique. We have different susceptibility to autoimmune diseases and also we have different allergic susceptibility different appearances and social behavior and everything. All these unique characters and properties are determined by only 0.1 % difference in the genetic DNA.


The genetic factor is one among the different causes of cancer such as exposure to ionizing radiation and exposure to the carcinogenic agents, that play an important role in whether we will develop cancer or not. Genetic factor includes defects in DNA sequence such as mutations that can be acquired during the course of time from external factors or it can be acquired from parents through inheritance.

If the genetic defect is in somatic chromosomal DNA it will not pass through inheritance and if the genetic defect is in germline DNA it will pass through the inheritance to the offspring. One such cancer-associated mutation in the germline DNA is rs351855 that can be passed to the offspring through the inheritance.

The mutation, rs351855 was first discovered by a team of researchers led by Axel Ullrich in patients with breast cancer a decade ago. It is associated with the growth of many types of malignant tumors. Research shows, almost 50 percent of the cancer patients harbor this mutation with poor prognosis. This mutation is associated with rapid and aggressive growing tumors that can resist any treatment. Patients with rs351855 mutation produce defective growth factor receptors in which one unit is defective. It is found that the receptor for the fibroblast growth factor (FGFR4) is expressed as a defective receptor in which Gly at 388 positions is replaced by Arg. This defective protein is termed as FGFR4p.Arg388 variant.

Normally cells do not divide out of control because of tight regulation of the cell cycle. They only divide when they receive a signal from outside of the cell and these signals are picked up by the growth factor cell surface receptors such as FGFR4. These signals are then passed through the growth factor receptors into the interior of the cells through a cascade of signaling molecules.

Growth factor receptors are the tyrosine kinase receptors that belong to the enzyme-linked cell surface receptors. They get dimerized and activated by their respective ligands (growth factors) and get auto-phosphorylated (trans-phosphorylation) in the cytoplasmic tyrosine kinase domain. Once tyrosine residue in the tyrosine kinase domain is trans-phosphorylated, they recruit downstream signaling proteins to form a signal cascade.

The cytoplasmic signal transducer and activator of transcription-3 (STAT3) are one of such downstream signaling molecules that form a cascade of signaling involved in the growth factor signaling and pass the signal to the nucleus where the targeted genes are activated and expressed to process the cell division.

However, when STAT3 binds with the defective receptor, then it is activated abnormally and leads to the activation and expression of the target genes for growth and proliferation in an abnormal way leading to cancerous growth.

Scientists have now found for the first time that the growth of cells with rs351855 mutation can be inhibited by inactivating or blocking STAT3 and that is a good prospect and will provide a new strategy to treat cancer patients containing this germline gene variant. This strategy is not only useful for cancer patients with rs351855 mutation but can also be useful for other types of germline gene mutations that may recruit STAT3 signaling in an abnormal way.

This approach is one step forward closer to the treatment of cancers related to the germline mutations that activate the growth factor receptor-associated cell growth and proliferation by recruiting the STAT3 signaling molecule.

Reference: Nature, International weekly journal of science (Germline variant FGFR4 p.G388R exposes a membrane-proximal STAT3 binding site)

Article DOI: 10.1038/nature16449

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