Genes, fundamental units of heredity, contain instructions that guide cellular processes like growth and division. Normal genes, called proto-oncogenes, can undergo mutations, transforming them into oncogenes. Oncogenes promote uncontrolled cell growth and division, potentially causing cancer. The RET gene is one such proto-oncogene that, when altered, can become an oncogene and contribute to the development of various cancers.
The Normal Role of RET
The RET gene, or “REarranged during Transfection,” typically functions as a proto-oncogene within the body. It encodes a protein known as a receptor tyrosine kinase (RTK), which spans the cell membrane and plays a role in cellular communication. This RTK is involved in cell signaling pathways that regulate cell proliferation, differentiation, growth, survival, and migration.
The RET protein has a large extracellular domain, a transmembrane domain, and an intracellular tyrosine kinase domain. In its normal state, RET is activated by specific soluble ligands from the glial cell line-derived neurotrophic factor (GDNF) family, along with a co-receptor. This activation is important for the healthy development of various tissues, including the central and peripheral nervous systems, the kidneys, and neuroendocrine cells like those in the thyroid and adrenal glands.
When RET Undergoes Oncogenic Transformation
The normal RET proto-oncogene can transform into an activated oncogene through specific alterations, leading to uncontrolled cell growth and division. Two primary mechanisms facilitate this oncogenic transformation: point mutations and gene fusions.
Point mutations involve specific changes in the DNA sequence of the RET gene. These changes can lead to the constant activation of the RET protein, even without its usual signaling molecules. Such mutations are common in inherited cancer syndromes. For instance, mutations in the extracellular domain can cause the RET receptors to improperly group together, leading to continuous activation. Similarly, mutations in the kinase domain can trigger activation of the RET protein even when it is in a single, unclustered form.
Gene fusions occur when the RET gene abnormally combines with another gene, resulting in a hybrid protein. This chimeric protein can become constitutively active, meaning it is always “on,” driving uncontrolled cell proliferation. These fusions commonly involve the 3′ sequence of RET, which contains its tyrosine kinase domain, joining with the 5′ sequence of various partner genes that often contain dimerization domains. Such fusions are common in sporadic cancers, which are not inherited.
Cancers Associated with RET Alterations
RET alterations, encompassing both point mutations and gene fusions, are associated with various specific cancers, where they play a significant role in disease development. Medullary thyroid carcinoma (MTC) has a strong association with RET mutations. These mutations are particularly prevalent in inherited conditions like Multiple Endocrine Neoplasia type 2 (MEN2) syndromes, including MEN2A and MEN2B, and are also found in sporadic MTC cases. Activating RET gene abnormalities occur in over 90% of hereditary and approximately 40-60% of sporadic MTC cases.
Papillary thyroid carcinoma (PTC) is another thyroid cancer where RET alterations are observed. In PTC, RET fusions are found in about 10-20% of cases, often involving fusions with genes like CCDC6 and NCOA4. Non-Small Cell Lung Cancer (NSCLC) also features RET fusions in a distinct subset of patients, accounting for approximately 1-2% of all lung adenocarcinomas. These fusions are more common in younger, never-smoking patients and are often associated with adenocarcinoma histology.
Beyond these primary associations, RET alterations are identified in a range of other tumor types, though less commonly. These include some gastrointestinal cancers, breast cancer, bladder cancer, pancreatic cancer, and certain neuroendocrine tumors like pheochromocytoma and paraganglioma. The presence of RET alterations in these cancers underscores their importance for diagnosis and can influence the prognosis.
Targeting RET in Cancer Treatment
The understanding of the RET oncogene has advanced the development of targeted therapies, aligning with precision medicine, which tailors treatments to a patient’s specific genetic profile.
RET inhibitors are a class of targeted drugs designed to block the activity of the altered RET protein. These inhibitors can curb the growth of cancer cells that depend on this overactive pathway. Unlike older multikinase inhibitors that had broader activity and more side effects, newer selective RET inhibitors like selpercatinib and pralsetinib are potent and specific to RET. These selective inhibitors have shown promising results in clinical trials, offering improved efficacy and a more tolerable side effect profile for patients with RET-driven cancers.
Testing for RET alterations is a diagnostic step in identifying suitable patients for these therapies. Techniques such as next-generation sequencing, performed on tumor tissue or through liquid biopsies, can detect these genetic changes. This molecular profiling enables clinicians to select the most appropriate treatment, supporting a personalized approach, matching therapeutic options to the specific genetic drivers of a patient’s cancer.