**2. ATA Recommendations for MTC management**

Since hMTC can be prevented by prophylactic thyroidectomy, the American Thyroid Association (ATA) suggests that all patients with MTC should be offered germline RET mutation testing for mutation discovery and improved patient and family treatment (particularly in RET-positive cases) [44, 56]. Nevertheless, the updated ATA has altered the existing risk categories for hMTC. It is now recommended to undertake genotype to phenotype correlation of disease in order to identify mutations that enhance the risk levels of patients with MTC, hence determining the necessity of prophylactic thyroidectomy and the extent of surgical resection.

Recommendations for the scheduling of prophylactic thyroidectomy and surgical area resection are derived on genotype-phenotype correlations used to categorize mutation risk levels. The preceding ATA advice categorized risk based on four mutation levels: A, B, C, and D. ATA-D mutations, especially codons 883 (exon 15) and 918 (exon 16), were related with the lowest age of onset, the greatest incidence of metastasis, and the highest fatality rate. In the most recent amended ATA guideline, a new "highest risk" (HST) category has been created, which covers patients with MEN2B and the RET codon M918T mutation [46].

ATA-C mutations, including mutations at codon 634 (exon 11), were assumed to provide a decreased risk of aggressive MTC. This category has been renamed "high risk" (H) in the new ATA guideline and now covers patients with MEN2A and RET codon C634 mutations. ATA-B mutations, including mutations at codons 609, 611, 618, 620 (exon 10) and 630, carry a decreased risk for severe MTC mutations (exon 11). ATA-A mutations are associated with the lowest risk. When they have preventive thyroidectomy at age 4 years, these patients have lower serum calcitonin levels, a lower tumor stage, and a better rate of biochemical cure compared to ATA-B mutation carriers of the same age. RET mutations at codons 768, 790, 791 (exon 13), 804 (exon 14), and 891 (exon 15) are seen in ATA-A mutations. The revised ATA guideline combines the current A and B levels into a new category, "moderate risk" (MOD), which includes patients with hMTC and RET codon mutations other than M918T and C634 (**Tables 1** and **2**) [12, 58].



*RET Proto-Oncogene Mutations: Impact on Diagnosis,Treatment and Prognosis of MTC DOI: http://dx.doi.org/10.5772/intechopen.108941*


**Table 1.**

*Genotype-phenotype correlations and risk levels for different populations of aggressive MTC according to ATA.*


**Table 2.**

*Correlation between the genetic findings and the phenotype of the respective Iranian population.*

#### **3. Geographical pattern of** *RET* **mutations in various populations**

This phenomenon, known as allelic heterogeneity, occurs when different mutations at the same locus result in the same phenotype. A diverse mutation pattern has been

identified in this gene as a result of the characterization of multiple RET proto-oncogene mutations. It suggests that these mutations in distinct populations are related with a slightly diverse phenotype in various countries. Despite the identification of codon 634 of the RET proto-oncogene as a hot spot codon in the evolution of MEN2A and FMTC, the amino acid alteration at this codon is almost unique to each group. The identification of RET mutations in MTC patients was examined extensively in a number of diverse groups, which are briefly summarized in this section (**Table 3**) [59].


*RET Proto-Oncogene Mutations: Impact on Diagnosis,Treatment and Prognosis of MTC DOI: http://dx.doi.org/10.5772/intechopen.108941*


#### **Table 3.**

*RET mutational spectrum in different populations.*

#### **4. Conclusion**

RET mutations do not simply determine MTC formation. These cancers likely carry mutations in additional genes, and it may be necessary to be aware of these mutations in order to consider combination therapy. This may provide new targets for the combination of RET inhibitors with other drugs that target these pathways [7]. Although a number of patients with refractory MTC have been treated with a variety of TKIs over the past few years, it is still unclear if the RET genotype of tumor cells influences clinical response to these medications [38, 54].

The thyroid cancer is the most prevalent endocrine cancer. In terms of diagnosis and preventive treatment, MTC has the strongest hereditary component among other kinds of thyroid cancer, according to ATA standards. MEN2B RET proto-oncogene mutations appear to be predominantly fixed at the M918T location in exon 16. However, mutations associated with MEN2A and FMTC vary amongst populations. For diagnosis, it will be important to evaluate and identify population-specific trends in point mutations [12]. Although there are several approaches in the treatment of RETassociated cancers; including monoclonal antibodies, kinase inhibitors, adaptorprotein binding inhibitors, dimerization inhibitors and gene therapy. Searching for specific inhibitors of RET kinase is a promising strategy. Indeed, reagents such as antioxidants, which abrogate RET dimerization, may also be useful in the treatment of MTC and PTC. Moreover, recent advances in RNA interference technology are providing a novel tool for cancer therapy [23].

More research is required and comprehensive clinical studies must be undertaken, but the preliminary findings are encouraging and optimistic. In the fight against cancer, the in-depth study of cancer and the identification of solid therapeutic targets and effective pharmacological agents have once again proven fruitful.
