**1. Introduction**

Thyroid cancer represents 90% of malignant tumors of the endocrine system and is the cause of 0.5% of all deaths from cancer in man [1–3]. Thyroid cancer is quite frequent, as in adults in autopsy findings it has been observed with a frequency ranging from 4 to 36% [4]. In the clinical setting, thyroid cancer is found in 6–10% of thyroid nodules [5]. Thyroid cancer is observed with greater prevalence in female as compared to male patients with a rate of 2–3/1 [6]. The incidence of thyroid cancer was rising until recently in the USA; however, its incidence now has leveled off. The main types of thyroid cancer are the two types of differentiated follicular thyroid carcinoma, namely papillary and follicular, representing 70–80% and 15–20%, respectively, and medullary and anaplastic thyroid carcinomas with a frequency of 5–8% and 3–5%, respectively (**Figure 1**) [7]. The etiology of thyroid cancer includes genetic mutations, head and neck irradiation, and iodine deficiency [8]. The diagnosis is

**Figure 1.** *Histological types of thyroid cancer.*

based on history, clinical examination, biochemical and imaging examination, and fine needle aspiration biopsy [9]. Treatment of differentiated and medullary thyroid carcinoma is total or near total thyroidectomy, including lymph node dissection [10, 11]. In differentiated thyroid carcinoma, radioactive iodine is administered for the destruction of thyroid remnants [12]. In anaplastic thyroid carcinoma, an effort is made for resection of as much as possible of the tumor. In all cases, thyroxine treatment is administered [13]. The prognosis of differentiated thyroid cancer is good and 10-year prognosis in papillary thyroid cancer is 93%, in follicular thyroid cancer is 85%, in medullary thyroid cancer 75%, and in anaplastic thyroid cancer 2–6 months, while rarely more than a year [14].

Although, most cases of thyroid cancer are curable, if thyroid cancer loses the ability to concentrate iodine and thus becomes refractory to radioiodine and if thyroid cancer becomes a progressive disease the need for targeted treatment becomes necessary [15]. Novel treatment methods for the management of advanced thyroid cancer have emerged after extensive research efforts, which have revolutionized thyroid cancer treatment [16–22]. Research in the area of the biology of thyroid cancer and in particular the discovery of somatic genetic mutations [23, 24] involved in the pathophysiology of thyroid cancer as well as research in the treatment of other cancer types with tyrosine kinase inhibitors [25] have led to the application of tyrosine kinase and angiogenetic factor inhibitors in the treatment of thyroid cancer [26]. In cases of renal cancer, the application of tyrosine kinase inhibitors led to the appearance of hypothyroidism due to the destruction of the thyroid gland [27, 28]. Thus, tyrosine kinase entered the field of radioactive iodine refractory and advanced thyroid cancer [29]. Multi-kinase and angiogenetic factor inhibitors have revolutionized the treatment of radioiodine refractory and advanced thyroid cancer [29]. The need for genetic mutation testing before treatment is initiated [30, 31] has been recognized in patients with radioiodine refractory and advanced thyroid cancer to enable targeted treatment.

### **2. Molecular genetics in the etiology of thyroid cancer**

The etiology of thyroid cancer is not known, although there are factors known to induce its development, such as ionizing radiation and iodine deficiency. Recent progress in molecular genetics has shown that thyroid cancer is due to genetic mutations either germline or somatic (**Figure 2**) [32]. These mutations lead to the inactivation of *Thyroid Cancer: From Genes to Treatment – Recent Developments DOI: http://dx.doi.org/10.5772/intechopen.111701*

**Figure 2.** *Molecular targets in thyroid cancer.*

onco-suppressor genes, which inhibit the formation of cancer or to the activation of oncogenes, which act on normal cells and lead to cancer development.

Papillary thyroid carcinoma is the most common thyroid cancer and represents approximately 80% of cases. Papillary thyroid carcinomas frequently harbor genetic changes leading to the activation of the mitogen-activated protein kinase (MAPK) signaling pathway [33]. These genetic alterations are mainly the RET/PTC rearrangement and point mutations of the BRAF and RAS genes. Mutations involving the above-mentioned genes are observed in more than 70% of papillary carcinomas and are mutually exclusive, meaning that if one mutation is found the other is not observed [32]. Genetic changes observed in follicular carcinomas, which represent the second in frequency type of thyroid cancer, are RAS mutations and PAX8-PPARγ rearrangement [33]. The discovery of these mutations led to extensive research and the discovery of therapeutic agents for the successful management of iodine refractory or advanced thyroid cancer.

In papillary thyroid cancer, the most common genetic mutation which has been observed is the gene rearrangement of the RET gene, which leads to increased expression of tyrosine kinase [34]. Thus, the thyroid cell is led to increased growth and multiplication and finally to tumor formation.

Follicular thyroid cancer presents with mutations in RAS oncogenes, which cause cell growth and multiplication [33]. The presence of RAS mutations is also observed in papillary carcinomas with follicular differentiation. Ionizing radiation is a known etiologic factor for thyroid cancer. It appears that small energy sources are transferred with radiation to the cells, leading subsequently to RAS gene mutations.

Anaplastic thyroid carcinoma has mutations in p53 gene [35, 36]. The p53 gene is a translational factor that is involved in the regulation of apoptosis and the cell cycle. It appears that this is the final step in the formation of thyroid cancer with the most malignant phenotype, which is added to the already existing genetic changes.

Medullary thyroid cancer presents with mutations in RET oncogene [37]. There has been progress in the pathogenesis of medullary thyroid carcinoma both in the hereditary and sporadic medullary thyroid carcinoma. The RET gene is involved in the pathogenesis of hereditary and sporadic medullary thyroid carcinoma. Mutations observed in the germ cells are detected in all the cells of the organism and their detection in the DNA of blood leucocytes forms the basis of finding carriers of the MEN2 syndrome. The MEN2 syndrome diagnosis is based on finding medullary thyroid cancer, pheochromocytoma, and parathyroid adenoma. In 97% of patients mutations in the RET gene have been observed in the DNA of blood leucocytes. In sporadic

medullary thyroid carcinoma, somatic RET mutations at the level of the thyroid tumor have been observed.

### **3. Genetic mutations and thyroid cancer**

#### **3.1 BRAF**

The most studied point mutation in thyroid cancer is that of the BRAF gene [33, 34]. The BRAFv600E somatic mutation is involved in approximately 45% of papillary thyroid cancer and tall cell variant and in 25% of anaplastic thyroid cancer. This somatic mutation of thyroid cells is related to the substitution of valine with glutamate and leads to the activation of BRAF kinase, which phosphorylates several targets and in particular mitogen-activated protein kinase (MEK) and extracellular signal-regulated kinase (ERK) [38]. The BRAFv600E mutation is associated with tumor aggressiveness and a poor prognosis, as it leads to higher tumor size and metastasis, either lymph node or distant metastasis.

#### **3.2 RET/PTC**

The RET proto-oncogene codes for a cell membrane receptor tyrosine kinase. Within the thyroid, RET is expressed in parafollicular C cells, within which it can be activated by chromosomal rearrangement. In RET/PTC the 3′ portion of the RET gene is fused to the 5′ portion of various unrelated genes [39]. The RET/PTC1 and RET/PTC3 account for most of the rearrangements observed in papillary carcinomas. RET/PTC is tumorigenic in thyroid follicular cells and is detected in approximately 20% of papillary thyroid carcinomas. Papillary thyroid carcinomas with RET/PTC rearrangement present at a younger age, have lymph node metastases and may have a favorable prognosis.

#### **3.3 RAS**

Another frequent driver of somatic mutation involved in the pathogenesis of thyroid cancer is that of the RAS gene [40], which lies upstream of BRAF. N-RAS, H-RAS, and K-RAS are members of the RAS family and those most commonly involved in thyroid cancer are the N-RAS and H-RAS and can constitutively activate the MAPK and PI3K/AKT pathways. RAS somatic mutations are present in 40–50% of follicular thyroid cancer, 15% of papillary thyroid cancer, follicular variant thyroid cancer, and 50% of anaplastic thyroid cancer. The K-RAS mutation is considered an activator of the MAPK pathway as compared to N-RAS mutation, which is an activator of the PI3K-AKT pathway. In papillary thyroid cancer genetic mutations of the RAS gene are mutually exclusive with the mutations of the BRAF gene.

#### **3.4 RET point mutations**

In medullary thyroid carcinomas, RET is activated by point mutations, as compared to its activation by chromosomal rearrangement in papillary thyroid cancer. Germline mutations are observed in MEN2A, MEN2B, and familial medullary thyroid carcinoma [41]. In MEN2A most mutations affect codon 634, whereas in MEN2B germline mutations affect codon 918, whereas in sporadic medullary thyroid carcinomas, somatic mutations of RET are observed [42].

#### **3.5 VEGF**

Angiogenesis has a key role in tumor initiation and progression and lymphangiogenesis is crucial for metastasis formation. Thus, angiogenesis and lymphangiogenesis are targets of cancer treatment. Angiogenesis involves the activation of VEGFR2, a tyrosine kinase receptor that is expressed in vascular endothelial cells. The expression of VEGFR2, a tyrosine kinase receptor is induced by VEGF-A produced by neoplastic and immune cells within the tumor.

Hypoxia within the tumor induces the activation of transcriptional factor hypoxia-inducible factor-1 alpha (HIF-1α), which leads to expression of VEGF-A. HIF-1α is expressed mainly in anaplastic thyroid cancer cells.

Thyroid cancer aggressiveness is associated with increased angiogenesis and the expression of VEGF/VEGFR, PDGF/PDGFR, and EGF/EGFR [43, 44]. In differentiated thyroid cancer, VEGFR and VEGFR-2 are overexpressed and contribute to tumor progression and aggressiveness. In particular, in papillary thyroid cancer, VEGF expression is related to local and distant metastatic disease.

#### **3.6 EGFR**

The EGFR cell surface protein is a member of the ErbB family of receptors. In epithelial carcinoma, EGFR mutations have been observed. EGFR has been found to be related to thyroid cancer progression and invasiveness and its overexpression has been observed in anaplastic thyroid cancer [45].

#### **3.7 Tumor suppressor genes**

The gene tumor protein P53 (TP53) encodes the tumor suppressor gene p53. The loss of its expression leads to a loss of control of cell growth and cell apoptosis. The p53 gene is mutated in anaplastic thyroid cancer and is involved in its pathogenesis [35, 46].
