RET gene

The RVT proto-onco gene encodes a transmembrane receptor tyrosine kinase that is activated through mutations involving the cysteine rich or kinase  domains, and structural rearrangements leading to the fusion of RET to the five’ upstream partner.

RET fusions create a protein that is overexpressed on the surface of cancer cells.

 

Changes by RET nutations result in ligand independent signaling and oncogenic enesis.

 

 RET is constantly sending signals into the cell to grow and develop. 

 

There are several RET-fusion mutations.

 

The most common mutation is KIF5B, and others are NCOA4, CCDC6, TRIM33. 

 

KIF5B is the most common, between 70% and 90% of cases. 

 

RET fusions act in the process of oncogenesis.

RET rearrangements are observed in 1-2% of non-small cell lung cancers and in 60% of sporadic cases of medullary thyroid cancer and 90% of hereditary medullary thyroid cancer.

RETBmutations are found in nearly all cases of hereditary, medullary thyroid cancers associated with multiple endocrine neoplasia type 2A and 2B syndromes, whereas mutations in RET are present in 25 to 50% of cases of sporadic medullary thyroid cancer.

Mutations in RET, a transmembrane proto-oncogene located on chromosome 10q11.2, are responsible for MEN2. 

The protein produced by RET is critical during embryonic development of the enteric nervous system and kidneys. 

RET consists of 3 domains, including a cysteine-rich extracellular receptor domain, a hydrophobic transmembrane domain, and an intracellular tyrosine kinase catalytic domain.

RET germline mutations are present in virtually all patients with MEN2A and  MEN2B, and somatic RET mutations are present in approximately 50% of sporadic MTCs. 

In sporadic MTC that is RET mutation–negative, mutations in genes involving the RAS pathway—HRAS, KRAS, or (rarely) NRAS—are often found. 

Germline RET mutations result in hereditary multiple endocrine neoplasia 2A (MEN2A) and MEN2B resulting in nearly complete penetrance of medullary thyroid cancer in gene carriers.

These hereditary syndromes account for 25% of all diagnose cases of medullary thyroid cancer.

The remaining 75% of cases of sporadic medullary thyroid cancer, approximately 60% harbor somatic RET mutations.

In non-medullary thyroid cancers arise from follicular cells that include papillary, poorly differentiated, anaplastic and Hurtle cell thyroid cancer, RET fusions are found in fewer than 10% of differentiate thyroid cancer and even more uncommon in anaplastic carcinoma.

RET fusion incidence is higher thyroid cancer diagnosed in children and young adults.

RET fusions is increased in patient linked environmental radiation exposure induced thyroid cancer,

RET mutations are associated with more aggressive type medullary thyroid cancer.

RET mutations are also observed in papillary renal cell carcinoma, breast, colon and pancreatic cancers.

RET mutations are associated with a high risk of brain metastases in non-small cell lung cancer.

A single-pass transmembrane receptor tyrosine kinase that is vital for the normal development of several tissues in cell types, particularly of neural and genitourinary tissues and for homeostasis.

Implicated as a driver of several tumor types.

Normally expressed on neurons, sympathetic and parasympathetic ganglia, testis germ cells, urogenital tract cells, adrenal medullary cells, and thyroid C cells.

RET ligands are members of the glial cells derived neurotrophic factor family, and ligand binding results in RET auto phosphorylation and activation downstream cellular alliteration, cell migration and differentiation pathways including: RAS/MAPK/ERK, PI3K/AKT, and phospholipase C-gamma

Loss of function mutation was associated with Hirschsprung disease.

Gain of function mutations are associated with malignancies including non-small cell lung cancer, and medullary thyroid carcinoma.

RET activating point mutations are commonly found in medullary thyroid cancer, amounting to more than 60% of such cases.

RET gene rearrangement found in more than 10% of papillary thyroid tumors, 1-2% of non-small cell lung cancers, and one percent of breast, Colorectal, pancreatic, and esophageal cancers.

RET has  been identified as a driver in some melanoma and chronic myelomonocytic leukemias.

Selpercatinib is a ATP-competitive highly selective small molecule inhibitor of RET kinase-it has efficacy, including intracranial activity, with low-grade toxicity in patients with RET fusion positive NSCLC were previously failed platinum based chemotherapy or who were previously untreated.

Selpercatinib approved for cancers with a rearranged transfection gene fusion (RET).

Selpercatinib treatment resulted in superior progression-free survival and treatment failure-free survival as compared with cabozantinib or vandetanib  in patients with RET-mutant medullary thyroid cancer (LIBRETTO investigators.