Introduction

The Natural Thyroid Diet

The Natural Thyroid Diet

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The association between ionizing radiation and thyroid cancer is well established. It was first proposed in 1950 in children who received X-ray therapy in infancy for an enlarged thymus (1). During the following decades, numerous reports have documented an increased incidence of thyroid neoplasms in children after external radiation for different benign conditions of the head, neck and thorax (2). Since the early 1960s, when the use of radiotherapy for benign conditions was abandoned, the incidence of radiation-associated thyroid malignancy in children gradually decreased (3). Currently, radiation therapy for malignancy continues to be a source of radiation-associated thyroid cancer (4). An increased risk of thyroid cancer has also been linked to environmental irradiation. This was documented in survivors of atomic bomb explosions in Japan in 1945(5), and in residents of the Marshall Islands exposed to fallout after detonation of a thermonuclear device on the Bikini atoll in 1954 (6). In the U.S., exposure to radioiodines from atmospheric nuclear tests in Nevada in the 1950s has been suggested to lead to an excess of thyroid neoplasms (7, 8). In April 1986, an accident at the Chernobyl Nuclear Power Station in the former USSR produced the most serious environmental disasters ever recorded and led to a dramatic increase in the frequency of childhood thyroid cancer in contaminated areas of Belarus, Ukraine, and western Russia (9, 10). This tragic disaster has created one of the most striking paradigms of radiation-induced thyroid tumors and allowed significant progress in the understanding of the molecular pathways induced by radiation. In this chapter, I

review the genetic events and molecular mechanisms underlying radiation carcino-genesis in the thyroid gland.

RET/PTC REARRANGEMENTS

Over the last decade, rearrangements of the RET proto-oncogene have been identified as the most common genetic event in thyroid tumors associated with radiation exposure.

The RET proto-oncogene is located on chromosome 10q11.2 and encodes a cell membrane receptor tyrosine kinase (11, 12). The receptor consists of three functional domains: an extracellular domain containing a ligand-binding site, a transmembrane domain, and an intracellular domain that includes a region with protein tyrosine kinase activity. The ligands for RET receptor are neurotrophic factors of the glial cell-line derived neurotrophic factor (GDNF) family, including GDNF, neurtulin, artemin, and persephin (13). Binding of a ligand causes the receptors to dimerize, leading to autophosphorylation of the protein on tyrosine residues and initiation of intracellular signaling cascade. Wild-type RET is expressed in neuronal and neural-crest derived tissues including thyroid parafollicular C-cells, but not in thyroid follicular cells. In thyroid follicular cells, RET can be activated by fusion to different constitutively expressed genes. The product of this rearrangement is a chimeric oncogene named RET/PTC (PTC for papillary thyroid carcinoma).

Structure of RET/PTC oncogenes

Since the original report on RET activation by rearrangement in papillary thyroid carcinomas (14), three major types of the rearrangement have been identified: RET/PTC1, RET/PTC2, and RET/PTC3 (Figure 1). All of them are formed by

Figure 1. Schematic representation of the wild type RET gene and three major types of RET/PTC rearrangement. The 3' portion of RET participating in the fusion encodes the tyrosine kinase domain (black box) but lacks the transmembrane and extracellular domains. The genes fused with RET encode dimerization domains, either coiled-coil domain (CC) or cysteine residues forming disulfide bonds during dimerization (C18, C39), allowing ligand-independent dimerization and activation of the truncated RET receptor. Block arrows indicate breakpoints.

Figure 1. Schematic representation of the wild type RET gene and three major types of RET/PTC rearrangement. The 3' portion of RET participating in the fusion encodes the tyrosine kinase domain (black box) but lacks the transmembrane and extracellular domains. The genes fused with RET encode dimerization domains, either coiled-coil domain (CC) or cysteine residues forming disulfide bonds during dimerization (C18, C39), allowing ligand-independent dimerization and activation of the truncated RET receptor. Block arrows indicate breakpoints.

fusion of the tyrosine kinase domain of RET to the portion of different genes. In RET/PTC 1, RET is fused to the H4 (also known as D10S170) gene (14) and in RET/PTC3 to the ELE1 (RFG or ARA70) gene (15, 16). RET/PTC 1 and RET/PTC3 are paracentric inversions since both genes participating in the rearrangement are located on chromosome 10q (17, 18). In contrast, RET/PTC2 is formed by reciprocal translocation between chromosomes 10 and 17, resulting in RET fusion to the terminal sequence of the regulatory subunit of the cyclic AMP-dependent protein kinase A (Figure 1).

Recently, several novel types of RET/PTC have been described, most of them in papillary carcinomas from patients with the history of radiation exposure. Five novel types (RET/PTC5, RET/PTC6, RET/PTC7, RET/KTN1, RET/RFG8) were found in post-Chernobyl tumors (20-23), and two other in tumors from patients subjected to therapeutic external radiation (RET/PCM-1, RET/ ARFP) (24, 25). All novel types of RET/PTC are translocations and resulted from the fusion of the intracellular domain of RET to heterologous genes located on different chromosomes (Figure 2).

Figure 2. Schematic representation of the novel RET/PTC types found in papillary carcinomas associated with radiation exposure. Each fusion involves the tyrosine kinase (TK) domain of RET and the 5' portion of different genes that encode one or more putative coiled-coil domains (CC) essential for dimerization and RET TK activation. Chromosomal location of the RET fusion partners is shown in brackets. Arrows indicate breakpoints.

Figure 2. Schematic representation of the novel RET/PTC types found in papillary carcinomas associated with radiation exposure. Each fusion involves the tyrosine kinase (TK) domain of RET and the 5' portion of different genes that encode one or more putative coiled-coil domains (CC) essential for dimerization and RET TK activation. Chromosomal location of the RET fusion partners is shown in brackets. Arrows indicate breakpoints.

The genes fused with RET are constitutively expressed in thyroid follicular cells and drive the expression of the chimeric RET/PTC oncogene. In addition, these partners provide a dimerization domain essential for ligand-independent activation of the RET tyrosine kinase (26, 27). It allows ligand-independent dimerization of the chimeric protein and autophosphorylation of the truncated RET receptor. Indeed, it has been demonstrated that tyrosines 1015 and 1062, which are autophosphorylated in the wild-type RET only upon ligand binding, are constitutively phosphorylated in the RET/PTC chimeric protein (28). The ligand-independent activation of the RET tyrosine kinase is considered essential for the transformation of thyroid cells (29).

Another important role of the genes fused with RET is in determining a subcel-lular localization of the chimeric protein which lacks the transmembrane domain and cannot be anchored to the cell membrane. In RET/PTC3 protein, for instance, the N-terminal coiled-coil domain of ELE1 (RFG) not only mediates oligomerization of the receptor and chronic kinase activation, but is also responsible for the compartmen-talization of the chimeric protein at plasma membrane level, where most of the normal ELE1 (RFG) protein is distributed (30). Thus, different types of RET/PTC chimeric proteins, which have a similar RET tyrosine kinase portion but different N-terminal domains, may be distributed in varies cytoplasmic compartments, allowing them to interact with distinct sets of signaling proteins. This may provide an explanation for some variations in biological properties recently found between different RET/PTC types (reviewed in (31).

RET/PTC prevalence in sporadic and radiation-associated tumors

The prevalence of RET/PTC in papillary carcinomas varies significantly in different studies and geographic regions. In the U.S., the five largest series of adult papillary carcinomas showed the frequency ranging from 11% to 43% (32-36), with the cumulative incidence of 35%. A comparable rate of30-40% have been found in series from Canada (37)) and Italy (34, 38, 39). In other regions, a wide variation in frequency of RET/PTC has been reported, ranging from 3% in Saudi Arabia (40) to 85% in Australia (41). A higher overall prevalence of RET/PTC has been noted in papillary carcinomas from children and young adults (38, 42-44). Among sporadic tumors of all age groups, RET/PTC 1 is the most common type, comprising up to 60-70% of all rearrangements, whereas RET/PTC3 accounts for 20-30% of positive cases and RET/PTC2 for less than 10% (32, 36, 39).

An unusually high incidence of RET/PTC rearrangements has been documented in papillary carcinomas from patients with the history of radiation exposure, including those subjected to either accidental or therapeutic irradiation (Table 1).

In children affected by the Chernobyl nuclear accident, 67-87% of papillary carcinomas removed 5-8 years after exposure and 49-65% of tumors removed 7-11 years after the accident harbored RET/PTC (42, 45-48). Remarkably, in tumors developed less than 10 years after the accident, RET/PTC3 was the most common type, whereas those developed after the longer latency had predominantly RET/PTC 1 (Table 2). In patients subjected to therapeutic X-ray irradiation for benign or malignant conditions, the prevalence of RET/PTC was also significantly higher than in the general

Table 1. Prevalence of RET/PTC rearrangements in radiation-induced thyroid cancer

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