The RET Oncogene Test - Molecular Genetics and Clinical Implications

• RET stands for rearranged during transfection.
• RET is a protooncogene and is located on chromosome 10q11.2.
• RET encodes a receptor tyrosine kinase which is expressed in thyroid, adrenal, neural, urogenital and testis germ cells.
• RET protein has an extracellular portion, a transmembrane portion and an intracellular portion.
• RET is involved in the activation of several intracellular signal transduction pathways.

The hybrid oncogene, which is called RET/PTC, is frequently present in thyroid cancers and results from double-stranded DNA breaks in the RET gene. These fusion oncogenes are particularly common in patients who have been exposed to radiation such atomic explosions.

Medullary thyroid carcinoma (MTC) is derived from the neural crest C cells and is caused by new mutations (75% of cases) or inherited mutations (25% of cases). This means that all children of patients with medullary thyroid cancer should be tested for RET mutations. There is often a correlation between the type of mutation and the clinical features of the disease.

It is likely that the action of the RET oncogene alone is not sufficient to cause hereditary medullary thyroid cancer. Many researchers believe that additional genetic defects, such as chromosomal deletions or amplifications, are also involved in the development of the disease.

Hirschsprung's disease is one of the most common causes of intestinal obstruction in newborns and is characterized by a lack of ganglia (nervel tissue) in regions of the intestine. More than 100 different RET mutations have been described in this disease. The RET mutations associated with thyroid cancer are generally gain-of-function mutations, whereas those seen in Hirschsprung's disease are usually loss-of-function mutations.

The detection of RET mutations in patients with hereditary medullary thyroid carcinoma has had huge impact in clinical practice. Family members who carry a copy of the mutated RET gene can be detected by the RET oncogene test (DNA analysis). Since the thyroid gland is an expendable organ whose function can be replaced by oral administration of a drug (thyroxin), the thyroid gland can be removed (thyroidectomy). Therefore the operation is curative if done at a young age before the cancer develops, or while it is still confined to the thyroid gland.

The timing of thyroidectomy depends on the site of the RET mutation:

• Thyroidectomy is indicated at a very early age i.e in the first months of life, in patients at highest risk - those with mutations in codon 918 or 883.
• Thyroidectomy is recommended at 5 years of age in patients at higher risk - those with mutations in codons 611, 618, 620, and 634.
• Thyroidectomy is advisable between 5-10 years of age in patients at high risk- those with mutations in codons 609, 768, 790, 791, 804, or 891.

Targeting the RET Pathway in Thyroid Cancer, by S.Wells & M.Santoro, in Clinical Cancer Research, December 2009, Vol 15, P7119