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RET Gene: Mutation, Cancer & Treatment

RET is a proto-oncogene encoding a receptor tyrosine kinase. Mutations in the RET gene can drive several cancers, including thyroid cancer and the hereditary MEN2 syndrome.

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Things worth knowing about "RET"

RET is a proto-oncogene encoding a receptor tyrosine kinase. Mutations in the RET gene can drive several cancers, including thyroid cancer and the hereditary MEN2 syndrome.

What is RET?

RET (Rearranged during Transfection) is a proto-oncogene that encodes a membrane-bound receptor tyrosine kinase. This protein plays a central role in cell development, particularly in the formation of the nervous system and kidneys. The RET gene is located on chromosome 10q11.2 and is expressed in several tissue types, including the thyroid gland, adrenal medulla, and nerve cells.

Biological Function

The RET protein acts as a receptor for a group of growth factors known as the GDNF family (Glial Cell Line-Derived Neurotrophic Factor). When activated by one of these ligands, RET triggers intracellular signaling pathways that regulate cell growth, migration, and survival.

Promotion of enteric nervous system development (the nervous system of the gut)
Regulation of kidney and ureter development
Support of the survival and differentiation of nerve cells

RET Mutations and Associated Diseases

Mutations in the RET gene can lead to permanent, uncontrolled activation of the kinase. This promotes excessive cell growth and can trigger tumor diseases. Two main types of RET mutations are distinguished:

Germline Mutations (Hereditary)

Germline mutations in the RET gene are inherited from parents and are associated with the following conditions:

Multiple Endocrine Neoplasia Type 2 (MEN2A and MEN2B): A hereditary tumor syndrome comprising medullary thyroid carcinoma, pheochromocytoma, and parathyroid tumors.
Familial Medullary Thyroid Carcinoma (FMTC): A hereditary form of medullary thyroid carcinoma without additional endocrine tumors.
Hirschsprung Disease: A congenital condition in which nerve cells are absent from the large intestine, causing severe constipation. Certain inactivating RET mutations cause this disease.

Somatic Mutations (Acquired)

Somatic mutations arise during a person's lifetime and are confined to tumor cells. Relevant tumor types with somatic RET alterations include:

Medullary Thyroid Carcinoma (MTC): Approximately 40–50% of sporadic MTC cases harbor somatic RET mutations.
Papillary Thyroid Carcinoma: RET rearrangements (RET/PTC fusions) are frequently observed in this cancer type.
Non-Small Cell Lung Cancer (NSCLC): RET fusions are present in 1–2% of cases.
Colorectal Carcinoma and Other Solid Tumors: Rare RET alterations have been reported.

Diagnosis

The diagnosis of RET mutations is performed through molecular genetic testing:

Germline Blood Analysis: When a hereditary RET mutation is suspected, genetic testing is performed on a blood sample.
Tumor Tissue Analysis (Next Generation Sequencing, NGS): Somatic mutations, fusions, and amplifications are identified in tumor tissue.
FISH and RT-PCR: Additional methods used to detect RET rearrangements in tumor specimens.

Treatment: RET Inhibitors

The identification of RET as an oncogenic driver has led to the development of targeted therapies. RET inhibitors are precision medicines that block the overactive RET kinase:

Selpercatinib (LOXO-292): A highly selective RET inhibitor approved for RET-altered NSCLC, medullary thyroid carcinoma, and other RET fusion-positive cancers.
Pralsetinib (BLU-667): Another selective RET inhibitor with a similar indication profile.
Cabozantinib and Vandetanib: Older multikinase inhibitors that also inhibit RET, but with less specificity.

Treatment with RET inhibitors is a cornerstone of precision oncology: only patients whose tumors harbor a RET alteration are candidates for this approach.

Genetic Counseling

Individuals with a confirmed germline RET mutation should seek genetic counseling. Family members can be tested for the mutation to assess individual cancer risk early and initiate preventive measures when appropriate.

References

Drilon A. et al. - Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer. New England Journal of Medicine, 2020.
Wells S.A. et al. - Vandetanib in Patients with Locally Advanced or Metastatic Medullary Thyroid Cancer. Journal of Clinical Oncology, 2012.
National Comprehensive Cancer Network (NCCN) - Clinical Practice Guidelines in Oncology: Thyroid Carcinoma, Version 2024.

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