Abstract

April 26, 2006 was the 20th anniversary of the Chernobyl Nuclear Plant Accident. At that time there was no reliable information concerning the massive amount of radioactive materials that escaped from the reactor. We know however that Belarus, Russia and Ukraine, were exposed to huge amounts of radioactive materials. In exposed children and adolescents a dramatic increase in the incidence of thyroid cancer has been observed while the adult population does not seem to be affected by the radioiodine contamination. Yet 20 years of observation may not be sufficient to evaluate the full radiological consequences of this accident. Therefore, the current characteristics of so-called “Chernobyl thyroid cancer” need to be reviewed including long-term risk for thyroid cancer after radiation exposure at the level of clinical and molecular epidemiology.

Introduction

Thyroid cancer is the most common type of human solid tumors associated with external ionizing radiation exposure, especially if irradiation occurs in neonates, infants and children (1). The health impacts of the Chernobyl accident have recently been reviewed by the World Health Organization (WHO) (2). Since the Chernobyl accident, specific attention has been paid to an internal exposure of the thyroid gland and its close relationship with childhood thyroid cancer (3). The appropriate prophylaxis of iodine administration just after the accident like in Poland (4) could contribute to mitigate the increase of childhood thyroid cancer and also decrease the future risk of thyroid cancer occurrence. Iodine deficiency is another risk factor of radiation-induced thyroid cancer around Chernobyl (5).
Childhood thyroid cancers are originally quite uncommon and have a fairly good prognosis despite of the aggressive manifestations. Incidence of thyroid cancer in children dramatically increased around Chernobyl from 1990 until 2000, probably attributed to short-lived radioactive iodines. About 5000 childhood and adolescent cases of thyroid cancers have been diagnosed from 1990 until 2005 around Chernobyl with fewer than 20 deaths reported (6).
The knowledge gained in the last 20 years provides valuable information for the advancement of thyroid cancer research. Here, clinical and epidemiological data will be summarized and genetic and molecular aspects of Chernobyl thyroid cancer briefly discussed.

Clinical characteristics of Chernobyl thyroid cancer

Papillary carcinoma is the most common malignant tumor of the thyroid in both adults, adolescents and children. There have been already several reports of an association between radioactive iodine exposure and childhood thyroid cancer prevalence but the interpretation of data still needs some straightforward refining (7-11). Adult thyroid cancers include disease types that range from an indolent small-size solitary malignant nodule to the fulminant and lethal anaplastic carcinoma. Definitely, differences do exist between adult and childhood papillary thyroid cancers. For example, childhood thyroid cancers display a higher incidence of regional lymph node metastasis, extension outside the thyroid capsule and lung metastasis. The initial comparative study of post-Chernobyl thyroid cancer in Belarus and naturally occurring thyroid cancer in Europe clearly demonstrated that individuals 5 year-old or less at the time of accident accounted for the majority of thyroid cancer patients substantiating a necessity of careful monitoring of the subjects of younger age at radiation exposure (12). The prognosis of operated childhood thyroid cancer in Belarus is quite favorable so far (13). There is no clear evidence at a moment that the incidence of thyroid cancer has increased among those exposed who were adult in 1986 (14,15), however the role of adult radiation exposure, either by radioactive iodines or externally, remains to be clarified.
In 1991, the Chernobyl Sasakawa Medical Aid Project was launched. Until 2001, nearly 200,000 schoolchildren were screened. The results point to the necessity of a cooperative multidisciplinary thyroid cancer research system of the long-term health care of exposed individuals (16,17). Along with a summary of clinical data on Chernobyl thyroid cancer, the project will include the current understanding of the molecular mechanisms of radiation-induced thyroid cancer in children and adolescents. It will focus of how to further assist the long-term follow-up of the operated patients and will outline the approaches for the identification of high risk groups for the disease.

Age distribution of thyroid cancer morbidity after the Chernobyl accident

A dramatic increase of childhood thyroid cancer was observed in the early 1990s in Belarus (Fig1). The peak incidence of childhood thyroid cancer after the Chernobyl accident is now over, shifting from adolescents to young adult aged more than 20 year-old. Time trends of thyroid cancer incidence are similar among the three affected countries, supporting the concept that subjects of younger age at the time of radiation exposure had, and continue to have, an elevated risk of developing thyroid cancers. Despite of shortage of accurate dosimetry data for individual children, comparative studies in Gomel region, Belarus showed a significant effect of exposure to short-lived radioactive fallout after Chernobyl since, at the time of accident, the frequency of thyroid cancer in zero up to 3 year old children increased dramatically (9). Today, new cases are mainly found in 20 to 30 year old patients.
The difference between early- and late-onset thyroid papillary thyroid cancers after the Chernobyl accident, is under investigation but so far no clinical differences besides of age-related particularities of genetic background have been registered between childhood and adult papillary thyroid cancers.

How can we distinguish between radiation-induced and sporadic thyroid cancers?

High doses of ionizing radiation produce bulk damages in biological objects inducing cell death. In contrast, low doses induce mainly numerous DNA double strand breaks, deletions, point mutations and/or chromosomal instability. It is therefore reasonable to postulate that radiation induced papillary thyroid cancer could have specific molecular markers. Three major approaches for molecular discrimination between radiation-induced and sporadic thyroid cancers can be used: 1) mutational studies in radiation-induced and sporadic thyroid tumors, 2) comparative gene expression studies, and 3) genomic studies including molecular epidemiology in patients who developed radiation-associated thyroid cancers.
Gene analysis resulted in the discovery of fusions between RET located on chromosome 10q11.2 and other genes are specifically found in papillary thyroid cancer tissues. These are collectively called RET/PTC rearrangements and represent chimeric genes. Among 16 different types of RET/PTCs, RET/PTC1 and RET/PTC3 are the most common variants accounting for about 90% of all chimeric genes (18). The prevalence of RET/PTC rearrangements ranges from 11% to 43% in sporadic papillary thyroid cancers and 50-80% in patients with a history of radiation exposure. In children affected by the Chernobyl accident, RET/PTC3 was the most common type in tumors developed less than 10 years after the accident, whereas papillary thyroid cancers which occured after a longer latency, had predominantly RET/PTC1 (19). However, the high prevailance all the RET/PTC rearrangements is characteristic of papillary cancer in young patients and not specific for irradiation. Another type of gene rearrangement, AKAP9-BRAF fusion, has been found in 11% of early onset papillary thyroid cancers but in 0% of tumors with the longer latency after the accident (20). Point mutation analysis of RAS-RAF-MAPK cascade genes, such as BRAF and RAS were also performed . They showed no significant difference of the mutational frequency between radiation-induced and sporadic thyroid cancers when similar age groups of patients were compared (21,22). The BRAF point mutation around Chernobyl is rare in childhood thyroid cancer and similar to other areas in comparison with adult papillary thyroid cancer (23).
As a whole, analysis of the mutational spectrum of the Chernobyl thyroid malignancies demonstrates that gene rearrangements leading to the activation of MAPK signaling pathway appear to play a perceptible role in radiation-induced papillary thyroid cancer. Yet, none of the cancer genes or impaired tumor suppressor genes has proved a marker of radiation etiology and gene expression patterns in radiation-related papillary thyroid cancers are similar to those in sporadic ones (24). Therefore at a moment there is no established “radiation signature” or any specific target gene has been identified.

Necessity of molecular epidemiology investigations

In view of the absence of genetic markers to distinguish between radiation-induced and sporadic papillary thyroid cancers, further genomic studies may give us critical hints of radiation sensitivity and tumor-prone susceptibility in man. Since our understanding is very limited as for why thyroid tumorigenesis occurs in a relatively small number of exposed individuals, large scale molecular epidemiology investigations in thoroughly designed cohorts around Chernobyl can potentially identify at the biochemical or molecular level specific exogenous and/or host factors which play a role in human cancer causation. Pilot studies suggest that molecular epidemiological methods targeting single nucleotide polymorphisms of DNA damage response and cell cycle control genes may be a promising tool in the area of radiation-induced carcinogenesis (25).

Chernobyl Tissue Bank

The considerable progress in our knowledge concerning radiation-induced leukemia mechanisms in children (26) may lead us to similar progress in radiation-induced thyroid cancer. One can surmise that the risk of radiation-induce thyroid cancer in a population may be largely attributable to a small number of predisposed individuals in whom clonally expanded translocation-carrying pre-cancer cells have accumulated. The high frequency of RET/PTC rearrangement has been predominantly seen in the early onset cancers in young age group of children after the Chernobyl accident; it seems to be declining gradually with patients’ aging. The immature or precursor stem-cell like thyrocyte may be considered a preexisting initiated cell that might harbor a RET/PTC rearrangement. Indeed, RET/PTC rearrangement alone is unlikely to be sufficient to transform human thyrocyte. Thus, it is essential to elucidate genetic particularities of patients with radiation-induced thyroid cancers.
A research bank of biological samples and data has been established as an international cooperative project, the so called “Chernobyl Tissue Bank” (27) which is open to the scientific community. This is likely to favor markedly progess in this area of research.

Summary and conclusion

Today, 20 years after the Chernobyl accident, the large increase in thyroid cancer incidence among those exposed in childhood and adolescence continues. In contrast, no clearly demonstrated increase in the incidence of other cancers can be attributed to radiation exposure from the accident (28). Although radiation-induced thyroid cancer is a well-recognized medical phenomenon based on wide-ranged epidemiological studies, molecular signature(s) and other details of papillary thyroid cancer remain to be further clarified to pinpoint differential diagnostic criteria not only in childhood and adult thyroid cancers but also in radiation-induced and sporadic cancers (29). The latest study in Hiroshima and Nagasaki Atomic Bomb survivors in Japan has indicated that a biological effect from a single brief external exposure to ionizing radiation nearly 60 years in the past still occurs and can be detected (30). In childhood, once exposed even to low doses of ionizing radiation, either externally or internally, the cancer-prone cell damage within the thyroid gland can be preserved for a long time. Today, special attention should be paid to a high risk group of individuals who have been exposed to radioactive iodines just after the Chernobyl accident and who are now 20 to 30 year-old. Elucidation of the molecular mechanisms of radiation-induced thyroid cancer is expected to contribute to the disease prevention and treatment in the coming future.