The RET gene provides instructions for building a protein that plays a role in cellular communication. This protein functions like a master switch, helping to control how cells respond to their surroundings. Its proper operation is fundamental for the orderly growth and development of cells in the body.
The Normal Function of the RET Gene
The RET gene is classified as a proto-oncogene, regulating healthy cell growth, division, and maturation. The protein it creates is a receptor tyrosine kinase, which is found spanning the outer membrane of a cell. This unique positioning allows one part of the protein to extend outside the cell, ready to receive signals, while another part remains inside to transmit them.
When growth factors, which are molecules that encourage development, attach to the external portion of the RET protein, chemical reactions are triggered inside the cell. These reactions then instruct the cell to undergo specific changes, such as dividing into new cells or developing into specialized cell types. This controlled signaling is important during human development.
The RET gene is involved in the formation of several types of nerve cells during embryonic development. It is involved in the development of nerves in the gut, known as the enteric nervous system, which controls digestion. It also contributes to the normal formation of the kidneys and parts of the autonomic nervous system, which regulates involuntary body functions.
Diseases Caused by RET Gene Mutations
RET gene mutations disrupt its normal function, leading to various medical conditions. These mutations fall into two categories: those that cause the gene to be overly active, termed “gain-of-function,” and those that lead to a reduced or absent function, known as “loss-of-function.”
Gain-of-function mutations are associated with the development of certain cancers because they cause the RET protein switch to become stuck in the “on” position, prompting uncontrolled cell growth. Hereditary cancer syndromes like Multiple Endocrine Neoplasia type 2 (MEN2A and MEN2B) and Familial Medullary Thyroid Carcinoma (FMTC) are caused by germline RET mutations. All three conditions involve a high risk of medullary thyroid carcinoma (MTC), a type of thyroid cancer.
MEN2A presents with MTC in nearly all affected individuals, pheochromocytoma (a tumor of the adrenal glands) in about 50% of cases, and parathyroid adenoma or hyperplasia in 20-30%. This form of MEN2 often manifests in early adulthood. MEN2B is a more aggressive subtype, with MTC often appearing in infancy or early childhood, pheochromocytoma in approximately 50%, and additional features such as mucosal neuromas on the lips and tongue, distinctive facial characteristics, and a marfanoid body habitus. Familial Medullary Thyroid Carcinoma (FMTC) is characterized solely by MTC, which is less aggressive and occurs later in life, typically in middle age.
Beyond these hereditary syndromes, somatic (non-inherited) RET gain-of-function mutations or rearrangements are also found in some sporadic cancers. These include 1-2% of non-small cell lung cancers and 10-20% of papillary thyroid cancers. These rearrangements involve parts of the RET gene fusing with other genes, leading to continuous activation of the RET protein and driving tumor growth.
Conversely, “loss-of-function” mutations in the RET gene are linked to developmental disorders. The RET protein’s signaling is impaired or absent, preventing proper cell development.
Hirschsprung disease is a condition caused by these inactivating RET mutations. It results in the absence of nerve cells, called ganglion cells, in segments of the colon. This lack of proper nerve formation disrupts the coordinated muscle contractions needed for digestion, leading to severe constipation, bowel obstruction, and an enlarged colon. The condition stems from the failure of enteric neural crest cells to properly migrate, proliferate, and differentiate during the early development of the intestinal nervous system.
Genetic Testing and Screening
Genetic testing for RET gene mutations provides important information for individuals and their families. Testing is recommended for individuals diagnosed with medullary thyroid cancer, even without a family history, as about 25-30% of these cases are found to have a germline RET mutation. People with a strong family history of MEN2-related cancers are also candidates for testing. Infants with Hirschsprung disease symptoms are also tested to identify a RET mutation as the underlying cause.
The process of genetic testing involves obtaining a small sample of blood or saliva. Laboratories then use methods like next-generation sequencing (NGS) to analyze the DNA for RET gene mutations or rearrangements. NGS can detect both point mutations, which are single changes in the DNA, and gene fusions, where parts of the RET gene join with another gene.
A positive test result indicates the presence of a RET mutation, which helps confirm a diagnosis and guides medical management. If one parent carries a RET mutation, each child has a 50% chance of inheriting it. Predictive testing allows for early identification of at-risk individuals, enabling preventative measures or close surveillance before symptoms develop, which can significantly influence long-term health outcomes.
Targeted Treatments for RET-Altered Cancers
Treatment strategies for cancers driven by RET mutations have advanced with targeted therapies. These therapies are designed to specifically block the overactive RET protein, unlike traditional chemotherapy which broadly affects all rapidly dividing cells. This focused approach reduces side effects while effectively combating the cancer.
Two notable drugs in this class are selpercatinib (Retevmo) and pralsetinib (Gavreto), both selective RET inhibitors. These medications work by binding to the ATP-binding site within the RET kinase domain, which is a part of the protein responsible for transmitting growth signals. By occupying this site, the drugs prevent ATP from attaching, blocking the activation of the RET protein and stopping the downstream signaling pathways that promote cancer cell growth and survival. This selectivity minimizes off-target effects common with earlier, less specific multi-kinase inhibitors.
Selpercatinib and pralsetinib are approved for treating RET-driven non-small cell lung cancers and thyroid cancers, including medullary and papillary types. Selpercatinib has also received a “tissue-agnostic” approval, meaning it can be used for any RET-fusion-positive cancer, regardless of its origin.
Other management strategies are also employed. Prophylactic thyroidectomy, the surgical removal of the thyroid gland, is recommended for individuals with high-risk germline RET mutations. This includes MEN2B patients as early as before 6 months of age, and MEN2A/FMTC patients before age 5 or based on specific mutation types. This surgery aims to prevent the development or spread of medullary thyroid carcinoma.
Ongoing surveillance, involving regular blood tests to monitor specific markers like calcitonin and imaging studies, is also a part of long-term care to detect any signs of disease recurrence or progression, especially after surgery.