The RET gene encodes a receptor tyrosine kinase that is expressed in neural crest-derived cell lineages. The RET receptor plays a crucial role in regulating cell proliferation, migration, differentiation, and survival through embryogenesis. Activating mutations in RET lead to the development of several inherited and noninherited diseases. Germline point mutations are found in the cancer syndromes multiple endocrine neoplasia (MEN) type 2, including MEN 2A and 2B, and familial medullary thyroid carcinoma. These syndromes are autosomal dominantly inherited. The identification of mutations associated with these syndromes has led to genetic testing to identify patients at risk for MEN 2 and familial medullary thyroid carcinoma and subsequent implementation of prophylactic thyroidectomy in mutation carriers. In addition, more than 10 somatic rearrangements of RET have been identified from papillary thyroid carcinomas. These mutations, as those found in MEN 2, induce oncogenic activation of the RET tyrosine kinase domain via different mechanisms, making RET an excellent candidate for the design of molecular targeted therapy. Recently, various kinds of therapeutic approaches, such as tyrosine kinase inhibition, gene therapy with dominant negative RET mutants, monoclonal antibodies against oncogene products, and nuclease-resistant aptamers that recognize and inhibit RET have been developed. The use of these strategies in preclinical models has provided evidence that RET is indeed a potential target for selective cancer therapy. However, a clinically useful therapeutic option for treating patients with RET-associated cancer is still not available.

https://www.umcg.nl/SiteCollectionDocuments/Zorg/ZOB/S/Schildklierkanker/RET%20as%20a%20diagnostic%20and%20terapeutic%20target.pdf

RET as a diagnostic and therapeutic target in sporadic and hereditary endocrine tumors

/pdf/health-effects-of-the-chernobyl-accident-and-special-health-4t3u0josfb.pdf

Health Effects of the Chernobyl Accident and Special Health Care Programmes

After the Chernobyl nuclear accident (April 26, 1986), childhood thyroid carcinoma had a great increase in Belarus and Ukraine, as a consequence of the exposure to iodine radioactive fallout. The epidemiological and clinical features of the disease were studied in 472 patients less than 21 yr old at diagnosis, with differentiated thyroid carcinoma, representing 97.7% of all thyroid carcinomas diagnosed in Belarus between May, 1986, and December, 1995. The results were compared with those of 369 subjects of the same age group, with naturally occurring thyroid carcinoma, observed in Italy and France. Between 1986 and 1989, the number of thyroid cancer cases per year ranged from 3-8 and increased to 31 in 1990, to 66 in 1991, to 72 in 1992, to 93 in 1993, to 96 in 1994, and to 90 in 1995. The age at diagnosis was 14 yr or less in 78.8% (children group) and more than 14, but less than 21, yr in the remaining subjects (adolescents group). Mean (+/- SD) age at the time of the accident was 4.4 +/- 3.4 yr (3.2 +/- 2.3 in children and 8.9 +/- 2.7 in adolescents), the majority of the patients (62.9%) being 5 yr old or less. The time interval between the accident and the diagnosis (latency period) decreased progressively from 7.5 +/- 1.6 yr in children 0-2 yr old at the time of the accident to 6.0 +/- 1.6 yr in those 9-11 yr old. Since 1993, the yearly distribution of new cases showed a decrease in the subjects 9 yr old or more at the time of the accident but not in those 5 yr old or less. This could not be accounted for by a shift of exposed subjects to an age group at diagnosis not included in this study, because only subjects less than 12 yr of age at the time of the accident were considered in this analysis. Mean age at diagnosis in Belarus patients was 11.3 +/- 3.1 yr (10.1 +/- 2.3 in children and 15.7 +/- 1.4 in adolescents), whereas, among patients with naturally-occurring thyroid carcinomas from Italy and France, the majority of cases were diagnosed after 14 yr of age (mean age at diagnosis: 14.6 +/- 4.2 yr). The female-to-male ratio was significantly higher in Italy and France (2.5/1), compared with the ratio of patients from Belarus (1.6/1). Most of the tumors were papillary in both series, but a relatively high proportion of follicular carcinomas (P = 0.0001) was found in Italy/France (15.2%), as opposed to 5.3% in Belarus. Extrathyroidal extension and lymph node metastases were more frequent in Belarus (49.1%, P = 0.0001; and 64.6%, P = 0.002, respectively) with respect to Italy/France (24.9% and 53.9%, respectively). Thyroid lymphocytic infiltration and circulating antithyroperoxidase antibody were more frequent in Belarus patients. Our analysis of Belarus thyroid cancer patients less than 21 yr old showed that the post-Chernobyl increase in thyroid carcinomas involved both children and, to a much lesser extent, adolescents. Subjects 5 yr old or less at the time of the accident accounted for the majority of the patients. No evidence of a decrease in the number of new cases was observed in this age group, as opposed to older subjects. These data support the concept that subjects who were younger at the time of radiation exposure had, and continue to have, a greater risk of developing thyroid carcinoma and strongly suggest that this age group should be carefully monitored in the future. When compared with naturally occurring thyroid carcinoma of the same age group observed in Italy and France, the post-Chernobyl Belarus thyroid carcinomas affected younger subjects, were less influenced by gender, were virtually always papillary, had a greater aggressiveness at presentation, and were more frequently associated with thyroid autoimmunity.

/pdf/post-chernobyl-thyroid-carcinoma-in-belarus-children-and-4vfhqhcv1z.pdf

Post-Chernobyl thyroid carcinoma in Belarus children and adolescents: comparison with naturally occurring thyroid carcinoma in Italy and France.

26 April 2006 marks the 20th anniversary of the Chernobyl accident. On this occasion, the World Health Organization (WHO), within the UN Chernobyl Forum initiative, convened an Expert Group to evaluate the health impacts of Chernobyl. This paper summarises the findings relating to cancer. A dramatic increase in the incidence of thyroid cancer has been observed among those exposed to radioactive iodines in childhood and adolescence in the most contaminated territories. Iodine deficiency may have increased the risk of developing thyroid cancer following exposure to radioactive iodines, while prolonged stable iodine supplementation in the years after exposure may reduce this risk. Although increases in rates of other cancers have been reported, much of these increases appear to be due to other factors, including improvements in registration, reporting and diagnosis. Studies are few, however, and have methodological limitations. Further, because most radiation-related solid cancers continue to occur decades after exposure and because only 20 years have passed since the accident, it is too early to evaluate the full radiological impact of the accident. Apart from the large increase in thyroid cancer incidence in young people, there are at present no clearly demonstrated radiation-related increases in cancer risk. This should not, however, be interpreted to mean that no increase has in fact occurred: based on the experience of other populations exposed to ionising radiation, a small increase in the relative risk of cancer is expected, even at the low to moderate doses received. Although it is expected that epidemiological studies will have difficulty identifying such a risk, it may nevertheless translate into a substantial number of radiation-related cancer cases in the future, given the very large number of individuals exposed.

https://iopscience.iop.org/article/10.1088/0952-4746/26/2/001/pdf

Cancer consequences of the Chernobyl accident: 20 years on

Summary The Chernobyl nuclear accident on 26 th April, 1986, led to a massive release of radionuclides into the environment. Although vast areas of Europe were affected by Chernobyl-related ionising radiation, the accident had the greatest impact in Belarus, Ukraine, and the Russian Federation. Epidemiological studies that have investigated the link between the Chernobyl accident and cancer have largely focused on malignant diseases in children, specifically thyroid cancer and leukaemia. There is good evidence to suggest that rates of thyroid cancer in children from the countries that were formally part of the Soviet Union have risen as a consequence of the Chernobyl accident. The findings for childhood leukaemia are less conclusive. Overall rates for this disease do not seem to have been affected by the Chernobyl-related ionising radiation, but there may be a larger risk of infant leukaemia in contaminated areas of Europe. Among adult populations, there is no strong evidence to suggest that risk of thyroid cancer, leukaemia, or other malignant disease has increased as a result of the Chernobyl accident.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470204502007271.pdf

Chernobyl-related ionising radiation exposure and cancer risk: an epidemiological review

Based on the results of131I thyroid activity measurements in three districts of the Chernigov region (Ukraine), individual doses were calculated and an approach of the age dependence of the average thyroid exposure was derived. Using the relationships between the thyroid doses and the137Cs deposition as well as the location relative to the Chernobyl Nuclear Power Plant (NPP), age-dependent average thyroid doses were extrapolated also for those settlements of this region where no monitoring measurements have been carried out. The highest doses were found in the west of the region with the lowest distance to the Chernobyl NPP. In this part, the highest mean of the thyroid dose in a settlement was 3.3 Gy for infants and 0.5 Gy for adults. The collective thyroid dose was 31000 and 27 000 person-Gy for children and adults, respectively. Based on this assessment, 140 and 21 excess thyroid cancer cases are predicted for children and adults, respectively. In the years 1989 to 1991, in the whole contaminated territory of the Ukraine 0.4–1.2 cases per 100000 children were observed. Although the absolute numbers are very small, this indicates the possibility of an increase in thyroid cancer morbidity among children. The same trend also seems to be indicated in the Chernigov region. A careful epidemiological study in the future is necessary to enable a final evaluation of radioinduced cancers in this region.

Thyroid dose assessment for the Chernigov region (Ukraine): estimation based on 131I thyroid measurements and extrapolation of the results to districts without monitoring.

The thyroid cancer incidence in the Ukraine among those born in the period 1968–1986 was analyzed with the aim to identify the enhancement due to the Chernobyl accident. Since any Ukrainian data referring to the time period before the accident are scarce and the variation of spontaneous incidences in other countries is immense, the Ukrainian incidences in the period 1986–1989 were used to estimate the baseline risk. Following 1990, the incidence in the southern part of the Ukraine increased by about 30%, independent of age. In the other parts the increase of the incidence depended on age at exposure. In the age group of 9-year-old children, the incidences in three regions defined as the `high-dose area', the northern, and the middle oblasts, increased by factors of 50, 20, and 6, respectively. These rates (1991–1995) are well above spontaneous rates in other countries. In the age group of 17-year-old juveniles, the incidence increased by a factor of 6 for the `high dose area' and in the three northern oblasts, whereas in the nine `middle' oblasts it was similar to the incidence of the `southern' Ukraine. These rates are within the range found in other countries.

Thyroid cancer incidence in the Ukraine after the Chernobyl accident: comparison with spontaneous incidences.

In the Zhytomyr region, about 52 000 measurements of the 131I activity in thyroids were performed. On the basis of these measurements, individual doses have been assessed for the people monitored and age-dependent average doses have been estimated for those settlements with more than 11 direct measurements. In order to estimate the pattern of thyroid exposure in the Zhytomyr region, these doses have been interpolated or extrapolated to population groups who were not monitored during May–June 1986. For this purpose, a model has been developed based on a correlation between thyroid dose estimates with the 137Cs deposition and the co-ordinates of the settlements relative to Chernobyl. Collective doses of people who were born in the years 1968 to 1986 were calculated. The radiation-induced thyroid cancer incidence in the period 1991 to 1995 was assessed by subtracting the spontaneous incidence from the observed incidence. The result is considerably lower than that observed in longer periods after external exposures. Possible reasons for this difference are discussed.

Thyroid dose and thyroid cancer incidence after the Chernobyl accident: assessments for the Zhytomyr region (Ukraine)

The children's thyroid exposure to radioiodine is one of the most serious consequences of the Chernobyl accident. The collective dose to children aged 0-18 in the entire Ukraine was estimated to be 400000 person-Gy. The dose estimates were calculated on the basis of measurements of thyroid content of {sup 131}I for about 108000 people in Ukraine aged 0-18 years in May-June 1986. Up to the end of 1994, 542 thyroid cancers throughout the Ukraine have been reported in children and young adults who were aged 0-18 at the time of the accident. Rates of thyroid cancer have climbed, from about 0.7 per million children aged 0-14 in 1986 to more 7 per million in 1994. Rates increased most in region closest to Pripyat'. Between 1990 and 1994, 9 of the 14,580 people who had been children at the time of the accident in Pripyat' developed thyroid cancer. This corresponds to an annual incidence of 123 cases per million persons. The estimated average thyroid dose in Ukrainian children varies by several orders of magnitude. There is a more than 30-fold gradient in thyroid cancer incidence rates corresponding to the gradient in thyroid doses from {sup 131}I. A preliminary investigation shows an excess in the annual incidence rate of thyroid cancer, throughout the northern territory of Ukraine, corresponding to the average doses to thyroid from {sup 131}I. Coefficients of regression of excess cancers versus thyroid dose have been calculated.

Radiation risk assessment of the thyroid cancer in Ukrainian children exposed due to Chernobyl

The thyroid doses of 49 360 inhabitants of Pripjat evacuated after the accident at Chernobyl were reconstructed During their evacuation most of the evacuees passed through highly contaminated territories The evaluation of a large-scale public survey showed that only about 50% of the evacuees had left the contaminated areas within 5 days and that 30% of them stayed there for more than 30 days As a first step, the model of dose estimations was improved, and thyroid doses were assessed for the group of evacuees for whom the131I activity in the thyroids was measured The131I incorporation during the first 5 days after the accident was described by a single-intake model (inhalation); later incorporations were assumed to be proportional to the radioiodine activity in milk As a second step, the correlation between the calculated doses andindividual parameters (place of residence in Pripjat, intake of stable iodine, and age at the time of the accident) was described by an empirical equation This equation was applied to all evacuees who completed the questionnaires of the public survey Previous dose assessments were found to overestimate the thyroid doses especially for the younger evacuees On the basis of these estimations, collective doses and the resulting radiation risks for thyroid cancer were assessed for different age groups

I. A. Kairo

Papers

Thyroid dose assessment for the Chernigov region (Ukraine): estimation based on 131I thyroid measurements and extrapolation of the results to districts without monitoring.

Thyroid cancer incidence in the Ukraine after the Chernobyl accident: comparison with spontaneous incidences.

Thyroid dose and thyroid cancer incidence after the Chernobyl accident: assessments for the Zhytomyr region (Ukraine)

Radiation risk assessment of the thyroid cancer in Ukrainian children exposed due to Chernobyl

Estimation of 131I thyroid doses for the evacuees from Pripjat