RET oncogene in MEN2, MEN2B, MTC and other forms of thyroid cancer

Abstract

SummaryHereditary medullary thyroid carcinoma (MTC) is caused by specific autosomal dominant gain-of function mutations in the RET proto-oncogene. Genotype-phenotype correlations exist that help predict the presence of other associated endocrine neoplasms as well as the timing of thyroid cancer development. MTC represents a promising model for targeted cancer therapy, as the oncogenic event responsible for initiating malignancy has been well characterized. The RET proto-oncogene has become the rational target for molecularly designed drug therapy. Tyrosine kinase inhibitors targeting activated RET are currently in clinical trials for the treatment of patients with MTC. This review will provide a brief overview of MTC and the associated RET oncogenic mutations, as well as a summary of the therapies designed to strategically interfere with pathologic activation of the RET oncogene. KeywordsMultiple endocrine neoplasia; tyrosine kinase inhibitors; thyroid cancer; oncogenes; clinical trial Introductory overview of the disease: epidemiology and pathophysiologyThyroid cancer represents approximately 1% of malignancies occurring in the United States, accounting for an estimated 33,550 cancer diagnoses and 1,530 cancer deaths per year. Of these cancers, 2% to 3% are due to medullary thyroid cancer (MTC) [1]. MTC is a rare calcitoninproducing tumor that arises from the thyroid gland parafollicular C cells, which are derived from the embryonic neural crest. While the majority of patients with MTC have sporadic disease, 25% to 30% of cases are due to hereditary forms of MTC [2]. The presentation of disease in hereditary MTC is usually bilateral and multicentric, compared with a single, unilateral thyroid tumor found in sporadic cases [3].Hereditary MTC is classified according to three distinct clinical subtypes (Table 1 Summary of current optimal therapeutic practicesMTC is relatively unresponsive to radiation therapy and to standard chemotherapeutic regimens [8,9]. Various chemotherapeutic regimens, including alkylating agents, antimetabolites, and anthracyclines have shown no proven benefit in patients with metastatic MTC [10][11][12]. Radiation therapy has only a palliative role in the treatment of MTC [13]. Surgery remains the only standard treatment for patients with MTC: total thyroidectomy that is performed before MTC grows or spreads beyond the gland is currently the only curative therapy.Once MTC metastasizes, it has a tendency to spread to local and regional lymph nodes, and more distantly to lung, liver, and bone [8]. Although MTC is often widely metastatic, it tends to be a slow growing tumor. Patients with metastatic disease continue to have 5 and 10 year survival rates of 80% and 70%, respectively [14]. However, and despite its slow growth, the average survival for MTC is lower than that for other more common types of thyroid cancer, such as papillary and follicular carcinoma which have a 90% to 94% 5-year survival rate, respectively [15]. Decreased survival in MTC can be correlated with the stage of diagnos...

RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma

“…46 However, approximately 2% to 5% of MEN2 families do not have RET mutations, and many cases of sporadic MTC do not carry RET mutations. 47,48 The absence of RET mutations suggests the existence of additional loci predisposing to MEN2 and sporadic MTC. Other genes, including those encoding components of the retinoblastoma (RB) and P53 tumorsuppressor pathways and RAS proto-oncogene may be involved in MTC formation.…”

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).…”

“…In comparison, survival rates at 10 years are 100% for stage I, 93% for stage II, and 71% for stage III (7). MTC occurs either sporadically (75% of cases) or via heritable germline mutations (25% of cases), exemplified by the inherited syndromes multiple endocrine neoplasia (MEN) syndromes MEN2A, MEN2B, and familial MTC (8,9) As MTC is generally unresponsive to standard chemotherapy and radiotherapy (10), nearly all MTC patients are treated with surgery, typically involving total thyroidectomy and extensive lymph-node dissection (8). However, most patients with sporadic MTC present with metastatic disease, and fewer than half are candidates for curative surgery (11,12).…”

Functional characterization of the MTC-associated germline RET-K666E mutation: evidence of oncogenic potential enhanced by the G691S polymorphism

“…Somatic rearrangements of RET are present in about one-third of papillary thyroid carcinomas (reviewed in Greco et al (2009)), whereas specific germline activating mutations of RET are causally involved in hereditary medullary thyroid carcinoma (MTC), including multiple endocrine neoplasia type 2A (MEN2A, OMIM 171400), type 2B (MEN2B, OMIM 162300), and familial MTC (FMTC; OMIM 155240) syndromes (Lodish & Stratakis 2008). Activating RET mutations involved in hereditary MTC forms are also present in a fraction of sporadic MTCs.…”