This gene is a known cancer gene.

This gene is a known cancer gene.

Proto-oncogene tyrosine-protein kinase receptor RET, activates the MAPK pathway for cell proliferation and the PI3K/AKT pathway for cell survival. RET activating mutations and rearrangements are common in medullary thyroid carcinomas. 25-30% of medullary thyroid carcinomas are associated with germline RET mutations. In these germline mutations, the most commonly affected codons are 609, 611, 618, 620 (exon 10) and 634 (exon 11), encoding for the extracellular cysteine-rich domain, and codons 768 (exon 13) and 804 (exon 14) of the intracellular tyrosine kinase domain. Sporadic RET mutations have been reported in 61.5% of medullary thyroid carcinomas. In sporadic cases, the M918T mutation is most commonly reported and may indicate a poor prognosis. Given these identified molecular alterations, therapies targeting the RET signaling pathway have been used and shown to provide advantages over traditional cytotoxic therapy with regard to disease response. There are multiple ongoing clinical trials on cabozantinib (tyrosine kinase inhibitor), sorafenib (multikinase inhibitor), and everolimus (mTOR inhibitor).

Proto-oncogene tyrosine-protein kinase receptor RET, activates the MAPK pathway for cell proliferation and the PI3K/AKT pathway for cell survival. Certain inherited mutations in the RET proto-oncogene predispose individuals to the multiple endocrine neoplasia type 2 (MEN 2) cancer syndromes including MEN 2A and 2B, and familial medullary thyroid carcinoma. Somatic mutations in RET are rare in squamous cell carcinoma of the lung and are found in 2-3% of cases. RET E623K lies within the extracellular domain of the RET protein, but has not been characterized and therefore its effect on RET protein function is unknown. RET E623K has been reported as a benign germline mutation in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/24906/). These results should be interpreted in the clinical context.