• What is RET?
  • RET in Thyroid Cancer
  • Clinical Trials


The RET gene (rearranged during transfection; Takahashi, Ritz, and Cooper 1985), located on chromosome 10, encodes a receptor tyrosine kinase (RTK) belonging to the RET family of RTKs. This gene plays a crucial role in neural crest development. Binding of its ligands, the glial cell line derived neurotrophic factor (GDNF) family of extracellular signaling molecules (Airaksinen, Titievsky, and Saarma 1999), induces receptor phosphorylation and activation. Activated RET then phosphorylates its substrates, resulting in activation of multiple downstream cellular pathways (Figure 1; Phay and Shah 2010).

Genomic alterations in RET are found in several different types of cancer. Activating point mutations in RET can give rise to the hereditary cancer syndrome, multiple endocrine neoplasia 2 (MEN2; Salvatore et al. 2000).  Somatic point mutations in RET are also associated with sporadic medullary thyroid cancer (Ciampi and Nikiforov 2007; Salvatore et al. 2000). Oncogenic kinase fusions involving the RET gene are found in ~1% of non-small cell lung cancers (Pao and Hutchinson 2012).


Figure 1.
Schematic of the RET signaling pathway. RET activation involves binding of glial cell line derived neurotrophic factor (GDNF)-family ligands as well as interaction with GFR alpha receptors, resulting in activation of intracellular MAPK and PI3K pathways. The letter "K" within the schema denotes the tyrosine kinase domain.

Related Pathways

Contributors: Allan V. Espinosa, M.D., Jill Gilbert, M.D.

Suggested Citation: Espinosa, A., J. Gilbert. 2015. RET. My Cancer Genome https://www.padiracinnovation.org/content/disease/thyroid-cancer/ret/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

RET in Thyroid Cancer

RET fusions

Approximately 10–20% of sporadic papillary thyroid cancers (PTCs) harbor RET fusions. The prevalence of RET rearrangements is higher in patients with a history of radiation exposure (50–80%) and in young adults and pediatric populations (40–70%; Ciampi and Nikiforov 2007).

Multiple different RET rearrangements have been described in PTCs, but RET/PTC1 (CCDC6-RET; 60–70%; Nikiforov 2008; Nikiforov and Nikiforova 2011; Nikiforov et al. 1997); RET/PTC2 (PRKAR1A-RET; 5%; Nifikorov et al. 1997), and RET/PTC3 (NCOA4-RET; 20–30%; Mochizuki et al. 2010) account for the vast majority of cases. These oncogenic rearrangements consist of various 5’ partners fused to the kinase domain of RET, leading to constitutive activation of the RET kinase (Pierotti et al. 1996).

RET mutations

Both germline and somatic mutations can occur in RET. Virtually all patients with multiple endocrine neoplasia 2 (MEN 2) harbor germline mutations in RET. MEN 2 is divided into three distinct syndromes: MEN 2A, MEN 2B, and Familial Medullary Thyroid Cancer (see Table 1). Somatic mutations are associated with as many as 50% of sporadic medullary thyroid cancers.

Table 1. MEN2 Syndromes.
Syndrome MTC Pheochromocytoma Parathyroid hyperplasia Mucosal neuromas
2A + + +
2B + + +
Familial Medullary Thyroid cancer +
NOTE: MTC = medullary thyroid cancer.

At least 19 different codons in 7 exons of RET have been found to be mutated. However, the majority of mutations in most familial and sporadic MTCs involve codons 634 and 918 (Nikiforov 2008).


Figure 1.
Schematic of RET fusions found in papillary thyroid cancer.


Contributors: Allan V. Espinosa, M.D., Jill Gilbert, M.D.

Suggested Citation: Espinosa, A., J. Gilbert. 2015. RET in Thyroid Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/thyroid-cancer/ret/ (Updated June 18).

Last Updated: June 18, 2015

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