RETProto-Oncogene: A Review and Update of Genotype–Phenotype Correlations in Hereditary Medullary Thyroid Cancer and Associated Endocrine Tumors

Abstract

Hereditary medullary thyroid carcinoma (MTC) is caused by autosomal dominant gain-of-function mutations in the RET proto-oncogene. Associations between specific RET mutations (genotype) and the aggressiveness of MTC and presence or absence of other endocrine neoplasms (phenotype) are well documented. Mutations in six exons (10, 11, 13, 14, 15, and 16) located in either cysteine-rich or tyrosine kinase domains cause one of three distinctive clinical subtypes: familial MTC, multiple endocrine neoplasia (MEN) type 2A (including variants with Hirschsprung's disease and cutaneous lichen amyloidosis), and MEN 2B. Hallmarks of MEN 2A include MTC, pheochromocytoma, and hyperparathyroidism. MEN 2B is associated with an earlier onset of MTC and pheochromocytoma, the absence of hyperparathyroidism, and the presence of striking physical stigmata (e.g., coarse facies, ganglioneuromatosis, and marfanoid habitus). Familial MTC is not associated with other endocrine neoplasms; however, the accurate distinction between familial MTC and MEN 2A may be difficult in kindreds with small size, incomplete histories, or a predominance of young individuals who may not have yet fully manifested the syndrome. Genetic testing detects greater than 95% of mutation carriers and is considered the standard of care for all first-degree relatives of patients with newly diagnosed MTC. Recommendations on the timing of prophylactic thyroidectomy and the extent of surgery are based upon a model that utilizes genotype-phenotype correlations to stratify mutations into three risk levels. 531

In Vitro and In Vivo Activity of Cabozantinib (XL184), an Inhibitor of RET, MET, and VEGFR2, in a Model of Medullary Thyroid Cancer

“…RET is an RTK that is specifically expressed in tissues of neuroectodermal origin, which include the C cells of the thyroid from which MTC arises. The finding of activating point mutations in RET at high frequency in both sporadic and familial MTC (8,13,(16)(17)(18)(19) suggests a pivotal role for RET activation in the development of MTC, which is further emphasized by the finding that disease course is influenced by the exact nature of the activating mutation. For example, the common activating point mutation M918T is a strong negative prognostic indicator for metastasis-free survival and overall survival, with 10-year survival rates of 55% in patients with M918T mutations compared to 85% for patients lacking this mutation (21).…”

“…The receptor tyrosine kinase rearranged during transfection (RET) plays a causative role in MTC pathogenesis (13,14). Somatic mutations in the RET gene are present in 20-80% of sporadic MTC cases (15,16), and are associated with a worse prognosis (17,18), while > 95% of patients with familial MTC and MEN2 carry germline RET mutations (13,19).…”

“…Somatic mutations in the RET gene are present in 20-80% of sporadic MTC cases (15,16), and are associated with a worse prognosis (17,18), while > 95% of patients with familial MTC and MEN2 carry germline RET mutations (13,19). Activating point mutations in RET are believed to be key early events in MTC pathogenesis, and the specific mutation correlates with tumor aggressiveness and patient prognosis (13,20).…”

Characterization of Wild-Type and Mutated RET Proto-Oncogene Associated with Familial Medullary Thyroid Cancer

“…MTC may occur sporadically or as part of the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN 2), which is classified into three clinically distinct subtypes: MEN 2A, MEN 2B, and familial MTC (FMTC) (Kouvaraki et al, 2005). MEN 2 syndromes are inherited as an autosomal dominant condition and therefore, 50% of the patient's first-degree relatives are at risk of carrying the mutated gene.…”

Multiple endocrine neoplasia type 2A in two families with the familial medullary thyroid carcinoma associated G533C mutation of the RET proto-oncogene

“…MEN2 is caused by germline gain-of-function mutations of the RET proto-oncogene (RET) (2). Mutations affecting the cysteine-rich extracellular domain encoded in RET exons 10-15 have been associated with MEN2A; a single point mutation in RET exons 15 and 16 has been associated with MEN2B; mutations at certain codons in various exons of RET (5,8,(11)(12)(13)(14)(15)(16) have been associated with familial medullary thyroid carcinoma (FMTC) (1,(3)(4)(5)(6)(7). However, the G533C mutation in exon 8 of the RET is a rare mutation and has been mainly associated with FMTC (8).…”