The RET gene (rearranged during
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
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
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.
Suggested Citation: Espinosa, A., J. Gilbert. 2015. RET. My Cancer
(Updated December 7).
Last Updated: December 7, 2015
RET in Thyroid Cancer
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
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.
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.
|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
Figure 1. Schematic of RET fusions found
in papillary thyroid cancer.
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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