Резюме. Внаслідок аварії на Чорнобильській атомній електростанції (ЧАЕС) значна кількість радіоактивних речовин потрапила в навколишнє середовище. Радіоактивні ізотопи йоду, переважно 131I, стали основним дозоутворювальним фактором для населення, особливо дітей та підлітків. Для вивчення віддалених наслідків опромінення в ранньому віці в рамках класичного проспективного когортного дослідження за співробітництва ДУ «Інститут ендокринології та обміну речовин ім. В.П. Комісаренка НАМН України» (ІЕОР, Україна) та Національного інституту раку США (National Cancer Institute, NCI, USA) були створені дві когорти. Основна УкрАм когорта (діти та підлітки на момент аварії) була сформована в 1998-2000 роках. In Utero УкрАм когорта включала осіб, опромінених в утробі матері (пренатально). Вперше вона була обстежена у 2002-2006 роках. Обидві когорти продовжують спостерігатись понад 25 та понад 20 років відповідно. Епідеміологічні методи спостереження когорт мінялися в часі, періоди активного скринінгу чергувались із періодами пасивного чи комбінованого спостереження членів когорт. Мета: описати хронологію довготривалого (20-27 років) спостереження основної та In Utero УкрАм когорт, дати характеристику різних епідеміологічних процедур, обґрунтувати необхідність подальшого спостереження та визначити пріоритетні задачі дослідження на перспективу. Матеріал і методи. Протягом періоду спостереження основна когорта мала чотири активні скринінги обстеження за період 1998-2008 рр., когорта In Utero після першого обстеження (2002-2006 рр.) у 2007-2008 роках спостерігалась пасивно. З 2009 року спостереження когорт синхронізовано. Пасивний скринінг здійснюється завдяки обстеженням в ІЕОР та співпраці (лінкейджу записів) із Національним канцер-реєстром України. Наступний активний скринінг (п’ятий та другий) було здійснено у 2012-2015 роках. Пасивний скринінг когорт супроводжувався демографічним анкетуванням, що дозволяло оновити контактні дані, певну медичну інформацію та вітальний статус членів когорти. Результати. Узагальнено рекомендації кількох груп експертів: Agenda for Research on Chornobyl Health (ARCH), Expert Group on Thyroid Health Monitoring after Nuclear Accidents (TMNUC) та експертів Наукового комітету ООН з дії атомної радіації (НКДАР ООН, United Nations Scientifіc Committee on the Effects of Atomic Radiation, UNSCEAR) щодо актуальних результатів та пріоритетів для перспективних післячорнобильських досліджень. Обґрунтована необхідність подальшого спостереження двох УкрАм когорт та вказані ключові напрямки майбутніх досліджень УкрАм Проєкту. Висновки. На основі багаторічних спостережень основної та In Utero УкрАм когорт (понад 25 та понад 20 років) отримані фундаментальні результати щодо ризику раку щитоподібної залози (ЩЗ) для осіб, опромінених у дитячому віці чи пренатально. Продовження спостереження вказаних когорт на період 40-60 років після аварії може принципово доповнити наявні знання щодо радіаційного ризику опромінення 131I у віддалений період та вдосконалити процедури радіаційного захисту для найбільш вразливих груп населення на випадок ядерних аварій.

Резюме. У статті наведено огляд основних результатів, отриманих за завершеною у 2024 році науково-дослідною роботою (НДР). Метою дослідження було продовжити моніторинг захворюваності на рак щитоподібної залози (РЩЗ) в дітей та підлітків України, постраждалих внаслідок Чорнобильської катастрофи, а також визначити можливість зв’язку між проліферативною активністю, інвазійними властивостями пухлин, наявністю BRAFV600E мутації та розвитком рецидивів захворювання при радіогенній та спорадичній папілярній тиреоїдній карциномі (ПТК). Матеріал і методи. У роботі використано дані Національного канцер-реєстру України (НКРУ), клініко-морфологічного реєстру (КМР) та бази даних Чорнобильського банку тканин (ЧБТ); застосовано епідеміологічні, гістологічні, імуногістохімічні (ІГХ) та статистичні методи дослідження. Результати. До аналітичної бази даних включено 22 966 осіб. Динаміка захворюваності серед опромінених характеризувалася висхідними часовими трендами протягом післячорнобильського періоду. Визначалася суттєва різниця між найбільш і найменш постраждалими регіонами України, яка у 2021 році становила 1,9 раза. При дослідженні гістопатологічних характеристик ПТК при підвищенні Кі67 проліферативного індексу (Кі67 ПІ) визначено, що незалежно від етіології BRAFV600E-позитивні ПТК характеризувалися вищим Кі67 ПІ порівняно з BRAFV600E-негативними ПТК. У радіогенних BRAFV600E-негативних ПТК підвищення Кі67 ПІ було асоційовано з ризиком розвитку рецидивів метастазів. Висновки. Аналіз захворюваності на РЩЗ серед постраждалих внаслідок Чорнобильської аварії дітей та підлітків України має бути обмежений періодом з 1986 по 2021 рік. При радіогенних ПТК, на відміну від спорадичних, підвищення Кі67 ПІ пов’язано з гіршим післяопераційним прогнозом, а саме зі збільшенням ймовірності розвитку рецидивів метастазів, що асоційовано виключно з BRAFV600E-негативним статусом пухлин.

Background: Although childhood exposure to radioactive iodine-131 (I-131) is an established risk factor for thyroid cancer, evidence for an association with thyroid nodules is less clear. The objective of this study is to evaluate the association between childhood I-131 exposure and prevalence of ultrasound-detected thyroid nodules overall and by nodule histology/cytology (neoplastic/suspicious/non-neoplastic), size (<10 mm/>= 10 mm), and number (single/multiple). Methods: This is a cross-sectional study of radiation dose (mean = 0.53 gray, range: 0.0003-31 gray) and screen-detected thyroid nodules conducted in 1998-2000 (median population age 21.5 years) in a cohort of 13,243 residents of Ukraine who were under 18 years at the time of the Chornobyl accident on April 26, 1986. Excess odds ratios per gray (excess odds ratio [EOR]/Gy) and confidence intervals (CIs) were estimated using logistic regression. Results: Among 13,078 eligible individuals, we identified 358 (2.7%) with at least one thyroid nodule. Significantly increased dose-response associations were found for all nodules and nodule groups with doses <5 Gy except individuals with non-neoplastic nodules. Among individuals with doses <5 Gy, the EOR/Gy for neoplastic nodules (5.35; CI: 2.19-15.5) was significantly higher than for non-neoplastic nodules (0.24; CI: 0.07-0.74), but the EOR/Gy did not vary by nodule size or number. Conclusions: Childhood exposure to I-131 is associated with an increased risk of thyroid nodules detected 12-14 years following exposure, and the risk for neoplastic nodules is higher than for non-neoplastic nodules. Analyses of incident thyroid nodules may help clarify dose-response patterns by nodule characteristics and provide insights into thyroid nodule etiology.

Increased thyroid cancer incidence has been one of the principal adverse health effects of the Chornobyl (Chernobyl) nuclear power plant accident. Accurate dose estimation is critical for assessing the radiation dose-response relationship. Current dosimetry estimates for individuals from the Chornobyl Tissue Bank (CTB) are based only on the limited information on their places of residence at the time of the accident and/or at the time of surgery for thyroid cancer. The present study aimed to assess whether additional residential and dietary history data collected during personal interviews would substantially impact dose estimates. This paper presents an assessment of thyroid doses from 131I intake for the 197 exposed individuals from the CTB with pathologically confirmed papillary thyroid cancer. Thyroid doses, which had been calculated for these individuals in 2010, were revised in this study using the recently substantially revised ‘Thyroid Dosimetry 2020 system for Ukraine’ (TDU20). In addition, residence and diet history data were collected during personal interviews with individuals for whom dosimetry-related data were scarce. The arithmetic mean of thyroid doses estimated in this study was 510 mGy (previously 700 mGy), while the median was 81 mGy (previously 120 mGy). A rather wide range of thyroid doses from zero to 11.9 Gy (previously up to 15.0 Gy) was observed among study participants. The uncertainties in doses were characterized by the geometric standard deviation of 1,000 individual stochastic doses. As a result, the geometric standard deviation varied from 1.3 to 5.3 with an overall arithmetic mean of 2.7 and a median of 2.9. This study clearly showed that the use of individual questionnaire data in dose assessment of individuals who completed personal dosimetry interviews had a noticeable impact on the thyroid dose values: the thyroid doses changed by more than 100 mGy in 31 out of 104 (29.8

The radiation-related risk of breast cancer among women following the Chornobyl accident remains uncertain. During pregnancy, there is rapid cell proliferation in the breast while radioactive iodine from fallout exposure can concentrate in lactating breast tissues. We conducted a standardized incidence ratio (SIR) analysis of breast cancer in a cohort of 2,631 women who were lactating and/or pregnant at any time during the 2-month period of radioiodine fallout (April 26, 1986-June 30, 1986). There were 37,151 person-years of follow-up, and 26 incident breast cancers were identified through linkage with the National Cancer Registry of Ukraine. Breast cancer rates among pregnant or lactating women were compared to the general population rates, and SIRs were adjusted for oblast, urban/rural, age, and calendar year. The SIR was not significant for women pregnant at the time of the accident (SIR = 0.75; 95% CI 0.44, 1.18) or for women lactating anytime within 2 months of the accident (SIR = 0.96; 95% CI 0.48, 1.68). However, there was a non-significantly elevated risk for women lactating at the time of accident (SIR = 1.30, 95% CI 0.40, 3.01). The increased SIR for breast cancer among lactating women is consistent with the results of a similar study in Belarus and indicates the need to quantify the radiation risk of breast cancer in a larger study of women lactating during the period of fallout exposure.

This study revised the thyroid doses for 2582 Ukrainian in utero cohort members exposed to Chornobyl fallout (the Ukrainian in utero cohort) based on revision of: (i) 131I thyroid activity measured in the Ukrainian population, (ii) thyroid dosimetry system for entire Ukraine, and (iii) 131I ground deposition densities in Ukraine. Other major improvements included: (i) assessment of uncertainties in the thyroid doses considering shared and unshared error, and (ii) accounting for intake of short-lived radioisotopes of tellurium and iodine (132Te+132I and 133I). Intake of 131I was the major pathway for thyroid exposure, its median contribution to the thyroid dose was 97.4%. The mean prenatal and postnatal thyroid dose from 131I was 87 mGy (median = 17 mGy), higher than previous deterministic dose of 72 mGy (median = 12 mGy). For 39 individuals (1.5%) the dose exceeded 1.0 Gy, while the highest dose among the cohort members was 2.7 Gy. The geometric standard deviation (GSD) of 1000 individual stochastic doses varied from 1.9 to 5.2 with a mean of 3.1 and a median of 3.2. The lowest uncertainty (mean GSD = 2.3, median GSD = 2.2) was found for the subjects whose mothers were measured for 131I thyroid activity, while for individuals, whose mothers were not measured, the mean and median GSDs were 3.4. Uncertainties in thyroid doses were driven by shared errors associated with the parameters of the ecological model.

Thyroid doses from intake of radioiodine isotopes (131I, 132Te+132I, and 133I) and associated uncertainties were revised for the 13,204 Ukrainian-American cohort members exposed in childhood and adolescence to fallout from the Chornobyl nuclear power plant accident. The main changes related to the revision of the 131I thyroid activity measured in cohort members, the use of thyroid-mass values specific to the Ukrainian population, and the revision of the 131I ground deposition densities in Ukraine. Uncertainties in doses were assessed considering shared and unshared errors in the parameters of the dosimetry model. Using a Monte-Carlo simulation procedure, 1,000 individual stochastic thyroid doses were calculated for each cohort member. The arithmetic mean of thyroid doses from intake of 131I, 132Te+132I, and 133I for the entire cohort was 0.60 Gy (median = 0.22 Gy). For 9,474 subjects (71.6% of the total), the thyroid doses were less than 0.5 Gy. Thyroid doses for 42 cohort members (0.3% of the total) exceeded 10 Gy while the highest dose was 35 Gy. Intake of 131I contributed around 95% to internal thyroid exposure from radioiodine isotopes. The geometric standard deviation of individual stochastic thyroid doses varied among cohort members from 1.4 to 4.3 with an arithmetic mean of 1.6 and a median of 1.4. It was shown that the contribution of shared errors to the dose uncertainty was small. The revised thyroid doses resulted, in average, in around 40% decrease for cohort members from Zhytomyr Oblast and an increase of around 24% and 35% for the cohort members from Kyiv and Chernihiv Oblast, respectively. Arithmetic mean of TD20 doses for the cohort was around 8% less than that estimated in TD10, 0.60 Gy vs. 0.65 Gy, respectively; however, global median of TD20 doses somewhat increased compared to TD10: 0.22 Gy vs. 0.19 Gy, respectively. The difference between TD10 and TD20 was mainly due to a revision of the individual 131I thyroid activity measured in the cohort members.

Background: Children and adolescents exposed to radioactive iodine-131 (I-131) in fallout from the 1986 Chernobyl nuclear accident appear to be at increased risk of thyroid cancer and benign thyroid nodules. The prenatal period is also considered radiosensitive, and the fetal thyroid can absorb I-131 from the maternal circulation. Objectives: We aimed to estimate the risk of malignant and benign thyroid nodules in individuals exposed prenatally. Methods: We studied a cohort of 2582 subjects in Ukraine with estimates of I-131 prenatal thyroid dose (mean = 72.6 mGy), who underwent two standardized thyroid screening examinations. To evaluate the dose-response relationship, we estimated the excess OR (EOR) using logistic regression. Results: Based on a combined total of eight cases diagnosed at screenings from 2003 to 2006 and 2012 to 2015, we found a markedly elevated, albeit not statistically significant, dose-related risk of thyroid cancer (EOR/Gy = 3.91, 95% CI:-1.49, 65.66). At cycle 2 (n = 1,786), there was a strong and significant association between I-131 thyroid dose and screen-detected large benign nodules (>= 10 mm) (EOR/Gy = 4.19, 95% CI: 0.68, 11.62; P = 0.009), but no significant increase in risk for small nodules (<10 mm) (EOR/Gy = 0.34, 95% CI:-0.67, 2.24; P = 0.604). Conclusions: The dose effect by nodule size, with I-131 risk for large but not small nodules, is similar to that among exposed children and adolescents in Belarus. Based on a small number of cases, there is also a suggestive effect of I-131 dose on thyroid cancer risk.

Department of Fundamental and Applied Problems of Endocrinology, Institute of Endocrinology and Metabolism, Kyiv, Ukraine Department of Epidemiology, Radiation Effects Research Foundation, Hiroshima, Japan Laboratory of Morphology of Endocrine System, Institute of Endocrinology and Metabolism, Kyiv, Ukraine Department of Medical Consequences of the Chernobyl accident and International Cooperation, Institute of Endocrinology and Metabolism, Kyiv, Ukraine Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD Laboratory of Endocrine Regulation of Immunogenesis, Institute of Endocrinology and Metabolism, Kyiv, Ukraine Department of General Endocrine Pathology, Institute of Endocrinology and Metabolism, Kyiv, Ukraine

BACKGROUNDThe issue of whether radiation-induced thyroid cancer is pathologically different from sporadic remains not fully answered. This study compared structural characteristics and invasive features of papillary thyroid carcinoma (PTC) in two age-matched groups: patients who were children (≤4 years old) at the time of the Chernobyl accident and who lived in three regions of Ukraine most contaminated by radioactive iodine 131I ("radiogenic" cancer), and those who lived in the same regions but who were born after 1987 and were not exposed to 131I ("sporadic" cancer). Further, the histopathologic features of PTC were analyzed in relation to age and individual 131I thyroid dose.METHODSThe study included 301 radiogenic and 194 sporadic PTCs. According to age at surgery, patients were subdivided into children (≤14 years old), adolescents (15-18 years old), and adults (19-28 years old). Statistical analyses included univariate tests and multivariable logistic regression within and across the age subgroups. Analyses of morphological features related to 131I doses were conducted among exposed patients on categorical and continuous scales controlling for sex and age.RESULTSAmong children, radiogenic PTC displayed a significantly higher frequency of tumors with a dominant solid growth pattern, intrathyroidal spread, extrathyroidal extension, lymphatic/vascular invasion, and distant metastases. Exposed adolescents more frequently displayed extrathyroidal extension, lymphatic/vascular invasion, and distant metastases. Exposed adults more frequently had intrathyroidal spread and extrathyroidal extension. The frequency of PTC with dominant papillary pattern and oxyphilic cell metaplasia was significantly lower in radiogenic compared to sporadic tumors for all age groups. Manifestations of tumor aggressiveness were most frequent in children compared to adolescents and adults regardless of etiology.CONCLUSIONSRadiogenic PTC is less likely to demonstrate a dominant papillary growth pattern and more likely to display more aggressive tumor behavior than sporadic PTC. Histopathologic tumor aggressiveness declines with patient age in both radiogenic and sporadic cases.

Background: Children and adolescents exposed to radioactive iodine-131 (I-131) in fallout from the 1986 Chernobyl nuclear accident appear to be at increased risk of thyroid cancer and benign thyroid nodules.The prenatal period is also considered radiosensitive, and the fetal thyroid can absorb I-131 from the maternal circulation.Objectives: We aimed to estimate the risk of malignant and benign thyroid nodules in individuals exposed prenatally.Methods: We studied a cohort of 2582 subjects in Ukraine with estimates of I-131 prenatal thyroid dose (mean = 72.6 mGy), who underwent two standardized thyroid screening examinations.To evaluate the dose-response relationship, we estimated the excess OR (EOR) using logistic regression.Results: Based on a combined total of eight cases diagnosed at screenings from 2003 to 2006 and 2012 to 2015, we found a markedly elevated, albeit not statistically significant, dose-related risk of thyroid cancer (EOR/Gy = 3.91, 95% CI: -1.49, 65.66).At cycle 2 (n = 1,786), there was a strong and significant association between I-131 thyroid dose and screen-detected large benign nodules ($10 mm) (EOR/Gy = 4.19, 95% CI: 0.68, 11.62; P = 0.009), but no significant increase in risk for small nodules (,10 mm) (EOR/Gy = 0.34, 95% CI: -0.67, 2.24; P = 0.604). Conclusions:The dose effect by nodule size, with I-131 risk for large but not small nodules, is similar to that among exposed children and adolescents in Belarus.Based on a small number of cases, there is also a suggestive effect of I-131 dose on thyroid cancer risk.

Iodine 131 (I-131), the principal component of nuclear fallout from the Chernobyl accident, concentrates in the thyroid gland and may pose risks to fetal development. To evaluate this, neonatal outcomes following the accident in April of 1986 were investigated in a cohort of 2582 in utero-exposed individuals from northern Ukraine for whom estimates of fetal thyroid I-131 dose were available. We carried out a retrospective review of cohort members' prenatal, delivery and newborn records. The relationships of dose with neonatal anthropometrics and gestational length were modeled via linear regression with adjustment for potentially confounding variables. We found similar, statistically significant dose-dependent reductions in both head circumference (−1.0 cm/Gy, P = 0.005) and chest circumference (−0.9 cm/Gy, P = 0.023), as well as a similar but non-significant reduction in neonatal length (−0.6 cm/Gy, P = 0.169). Gestational length was significantly increased with increasing fetal dose (0.5 wks/Gy, P = 0.007). There was no significant (P > 0.1) effect of fetal dose on birth weight. The observed associations of radioiodine exposure with decreased head and chest circumference are consistent with those observed in the Japanese in utero-exposed atomic bomb survivors.

To evaluate risk of thyroid neoplasia nearly 30 years following exposure to radioactive iodine (I‐131) from the 1986 Chernobyl nuclear accident, we conducted a fifth cycle of thyroid screening of the Ukrainian‐American cohort during 2012–2015, following four previous screening cycles started in 1998. We identified 47 thyroid cancers (TC) and 33 follicular adenomas (FA) among 10,073 individuals who were <18 years at the time of the accident and had a mean I‐131 dose of 0.62 Gy. We found a significant I‐131 dose response for both TC and FA, with an excess odd ratio per Gy of 1.36 (95% CI: 0.39–4.15) and 2.03 (95% CI: 0.55–6.69), respectively. The excess risk of malignant and benign thyroid neoplasia persists nearly three decades after exposure and underscores the importance of continued follow‐up of this cohort to characterize long‐term pattern of I‐131 risk.

Background: Serum thyroglobulin (Tg) is associated with the presence of thyroid disease and has been proposed as a biomarker of iodine status. Few studies have examined factors related to serum Tg in populations environmentally exposed to ionizing radiation and living in regions with endemic mild-to-moderate iodine deficiency.Methods: We screened 10,430 individuals who were living in Ukraine and under 18 years of age at the time of the 1986 Chernobyl Nuclear Power Plant accident for thyroid disease from 2001 to 2003. We estimated the percent change (PC) in serum Tg associated with demographic factors, iodine-131 thyroid dose, and indicators of thyroid structure and function using linear regression. We also examined these relationships for individuals with and without indications of thyroid abnormality.Results: Mean and median serum Tg levels were higher among participants with abnormal thyroid structure/function. Percent change in serum Tg increased among females, smokers and with older age (p-values < 0.001), and Tg increased with increasing thyroid volume, and serum thyrotropin (p-values for trend < 0.001). We found no evidence of significant associations between iodine-131 thyroid dose and Tg. Serum Tg levels were inversely associated with iodized salt intake (PC = -7.90, 95% confidence interval: -12.08, -3.52), and over the range of urinary iodine concentration, the odds of having elevated serum Tg showed a U-shaped curve with elevated Tg at low and high urinary iodine concentrations.Conclusion: Serum Tg may be a useful indicator of population iodine status and a non-specific biomarker of structural and functional thyroid abnormalities in epidemiological studies.

Strong evidence for the statistical association between radiation exposure and disease has been produced for thyroid cancer by epidemiological studies after the Chernobyl accident. However, limitations of the epidemiological approach in order to explore health risks especially at low doses of radiation appear obvious. Statistical fluctuations due to small case numbers dominate the uncertainty of risk estimates. Molecular radiation markers have been searched extensively to separate radiation-induced cancer cases from sporadic cases. The overexpression of the CLIP2 gene is the most promising of these markers. It was found in the majority of papillary thyroid cancers (PTCs) from young patients included in the Chernobyl tissue bank. Motivated by the CLIP2 findings we propose a mechanistic model which describes PTC development as a sequence of rate-limiting events in two distinct paths of CLIP2-associated and multistage carcinogenesis. It integrates molecular measurements of the dichotomous CLIP2 marker from 141 patients into the epidemiological risk analysis for about 13 000 subjects from the Ukrainian-American cohort which were exposed below age 19 years and were put under enhanced medical surveillance since 1998. For the first time, a radiation risk has been estimated solely from marker measurements. Cross checking with epidemiological estimates and model validation suggests that CLIP2 is a marker of high precision. CLIP2 leaves an imprint in the epidemiological incidence data which is typical for a driver gene. With the mechanistic model, we explore the impact of radiation on the molecular landscape of PTC. The model constitutes a unique interface between molecular biology and radiation epidemiology.

The Chernobyl nuclear power plant accident in Ukraine in 1986 led to widespread radioactive releases into the environment - primarily of radioiodines and cesium - heavily affecting the northern portions of the country, with settlement-averaged thyroid doses estimated to range from 10 mGy to more than 10 Gy. The increased risk of thyroid cancer among exposed children and adolescents is well established but the impact of radioactive contamination on the risk of other types of cancer is much less certain. To provide data on a public health issue of major importance, we have analyzed the incidence of nonthyroid cancers during the post-Chernobyl period in a well-defined cohort of 13,203 individuals who were < 18 years of age at the time of the accident. The report is based on standardized incidence ratio (SIR) analysis of 43 non-thyroid cancers identified through linkage with the National Cancer Registry of Ukraine for the period 1998 through 2009. We compared the observed and expected number of cases in three cancer groupings: all solid cancers excluding thyroid, leukemia, and lymphoma. Our analyses found no evidence of a statistically significant elevation in cancer risks in this cohort exposed at radiosensitive ages, although the cancer trends, particularly for leukemia (SIR = 1.92, 95% confidence interval: 0.69; 4.13), should continue to be monitored. (C) 2015 Elsevier Ltd. All rights reserved.

Background: There are limited data on the histopathology of papillary thyroid carcinomas (PTCs) diagnosed in irradiated populations. We evaluated the associations between iodine-131 dose and the histopathological characteristics of post-Chernobyl PTCs, the changes in these characteristics over time, and their associations with selected somatic mutations. Methods: This study included 115 PTCs diagnosed in a Ukrainian-American cohort ( n =13 243) during prescreening and four successive thyroid screenings. Of these PTCs, 65 were subjected to somatic mutation profiling. All individuals were <18 years at the time of the Chernobyl accident and had direct thyroid radioactivity measurements. Statistical analyses included multivariate linear and logistic regression. Results: We identified a borderline significant linear-quadratic association ( P =0.063) between iodine-131 dose and overall tumour invasiveness (presence of extrathyroidal extension, lymphatic/vascular invasion, and regional or distant metastases). Irrespective of dose, tumours with chromosomal rearrangements were more likely to have lymphatic/vascular invasion than tumours without chromosomal rearrangements ( P =0.020) or tumours with BRAF or RAS point mutations ( P =0.008). Controlling for age, there were significant time trends in decreasing tumour size ( P <0.001), the extent of lymphatic/vascular invasion ( P =0.005), and overall invasiveness ( P =0.026). Conclusions: We determined that the invasive properties of PTCs that develop in iodine-131-exposed children may be associated with radiation dose. In addition, based on a subset of cases, tumours with chromosomal rearrangements appear to have a more invasive phenotype. The increase in small, less invasive PTCs over time is a consequence of repeated screening examinations.

A previous study on papillary thyroid carcinomas (PTC) in young patients who were exposed to (131)iodine from the Chernobyl fallout revealed an exclusive gain of chromosomal band 7q11.23 in exposed cases compared to an age-matched control cohort. CLIP2, a gene located within band 7q11.23 was shown to be differentially expressed between exposed and non-exposed cases at messenger RNA and protein level. Therefore, a standardized procedure for CLIP2 typing of PTCs has been developed in a follow-up study. Here we used CLIP2 typing data on 117 post-Chernobyl PTCs from two cohorts of exposed patients with individual dose estimates and 24 non-exposed controls to investigate a possible quantitative dose-response relationship of the CLIP2 marker. The 'Genrisk-T' cohort consisted of 45 PTCs and the 'UkrAm' cohort of 72 PTCs. Both cohorts differed in mean dose (0.59 Gy Genrisk-T, 1.2 Gy UkrAm) and mean age at exposure (AaE) (2 years Genrisk-T, 8 years UkrAm), whilst the median latency (16 years Genrisk-T, 18 years UkrAm) was comparable. We analyzed the association between the binary CLIP2 typing and continuous thyroid dose with logistic regression. A clear positive dose-response relationship was found for young PTC cases [age at operation (AaO) < 20 years, AaE < 5 years]. In the elder age group a higher proportion of sporadic tumors is assumed due to a negligible dose response, suggesting different molecular mechanisms in sporadic and radiation-induced cases. This is further supported by the association of elder patients (AaO > 20 years) with positivity for BRAF V600E mutation.