Genomic characterization of cervical lymph node metastases in papillary thyroid carcinoma following the Chornobyl accident.

Childhood radioactive iodine exposure from the Chornobyl accident increased papillary thyroid carcinoma (PTC) risk. While cervical lymph node metastases (cLNM) are well-recognized in pediatric PTC, the PTC metastatic process and potential radiation association are poorly understood. Here, we analyze cLNM occurrence among 428 PTC with genomic landscape analyses and known drivers (131I-exposed = 349, unexposed = 79; mean age = 27.9 years). We show that cLNM are more frequent in PTC with fusion (55%) versus mutation (30%) drivers, although the proportion varies by specific driver gene (RET-fusion = 71%, BRAF-mutation = 38%, RAS-mutation = 5%). cLNM frequency is not associated with other characteristics, including radiation dose. cLNM molecular profiling (N = 47) demonstrates 100% driver concordance with matched primary PTCs and highly concordant mutational spectra. Transcriptome analysis reveals 17 differentially expressed genes, particularly in the HOXC cluster and BRINP3; the strongest differentially expressed microRNA also is near HOXC10. Our findings underscore the critical role of driver alterations and provide promising candidates for elucidating the biological underpinnings of PTC cLNM.

Prevalence of thyroid nodules in residents of Ukraine exposed as children or adolescents to iodine-131 from the Chornobyl accident.

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 (EOR/Gy) and 95% confidence intervals (95% CI) 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 subjects with non-neoplastic nodules. Among subjects with doses <5 Gy, the EOR/Gy for neoplastic nodules (5.35;95% CI:2.19,15.5) was significantly higher than for non-neoplastic nodules (0.24;95% 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.

Assessment of internal exposure to 131I and short-lived radioiodine isotopes and associated uncertainties in the Ukrainian cohort of persons exposed in utero.

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.

Impact of uncertainties in exposure assessment on thyroid cancer risk among cleanup workers in Ukraine exposed due to the Chornobyl accident.

A large excess risk of thyroid cancer was observed among Belarusian/Russian/Baltic Chornobyl cleanup workers. A more recent study of Ukraine cleanup workers found more modest excess risks of thyroid cancer. Dose errors in this data are substantial, associated with model uncertainties and questionnaire response. Regression calibration is often used for dose-error adjustment, but may not adequately account for the full error distribution. We aimed to examine the impact of exposure-assessment uncertainties on thyroid cancer among Ukrainian cleanup workers using Monte Carlo maximum likelihood, and compare with results derived using regression calibration. Analyses assessed the sensitivity of results to various components of internal and external dose. Regression calibration yielded an excess odds ratio per Gy (EOR/Gy) of 0.437 (95% CI - 0.042, 1.577, p = 0.100), compared with the EOR/Gy using Monte Carlo maximum likelihood of 0.517 (95% CI - 0.039, 2.035, p = 0.093). Trend risk estimates for follicular morphology tumors exhibited much more extreme effects of full-likelihood adjustment, the EOR/Gy using regression calibration of 3.224 (95% CI - 0.082, 30.615, p = 0.068) becoming ~ 50% larger, 4.708 (95% CI - 0.075, 85.143, p = 0.066) when using Monte Carlo maximum likelihood. Results were sensitive to omission of external components of dose. In summary, use of Monte Carlo maximum likelihood adjustment for dose error led to increases in trend risks, particularly for follicular morphology thyroid cancers, where risks increased by ~ 50%, and were borderline significant. The unexpected finding for follicular tumors needs to be replicated in other exposed groups.

Association between exposure to radioactive iodine after the Chernobyl accident and thyroid volume in Belarus 10-15 years later.

BACKGROUND: While there is a robust literature on environmental exposure to iodine-131 (131I) in childhood and adolescence and the risk of thyroid cancer and benign nodules, little is known about its effects on thyroid volume. METHODS: To assess the effect of 131I dose to the thyroid on the volume of the thyroid gland, we examined the data from the baseline screening of the Belarusian-American Cohort Study of residents of Belarus who were exposed to the Chernobyl fallout at ages ≤18 years. Thyroid dose estimates were based on individual thyroid activity measurements made shortly after the accident and dosimetric data from questionnaires obtained 10-15 years later at baseline screening. During baseline screening, thyroid gland volume was assessed from thyroid ultrasound measurements. The association between radiation dose and thyroid volume was modeled using linear regression where radiation dose was expressed with power terms to address non-linearity. The model was adjusted for attained age, sex, and place of residence, and their modifying effects were examined. RESULTS: The analysis was based on 10,703 subjects. We found a statistically significant positive association between radiation dose and thyroid volume (P < 0.001). Heterogeneity of association was observed by attained age (P < 0.001) with statistically significant association remaining only in the subgroup of ≥18 years at screening (P < 0.001). For this group, increase in dose from 0.0005 to 0.15 Gy was associated with a 1.27 ml (95% CI: 0.46, 2.07) increase in thyroid volume. The estimated effect did not change with increasing doses above 0.15 Gy. CONCLUSIONS: This is the first study to examine the association between 131I dose to the thyroid gland and thyroid volume in a population of individuals exposed during childhood and systematically screened 10-15 years later. It provides evidence for a moderate statistically significant increase in thyroid volume among those who were ≥ 18 years at screening. Given that this effect was observed at very low doses and was restricted to a narrow dose range, further studies are necessary to better understand the effect.

Risk of thyroid cancer in Ukrainian cleanup workers following the Chornobyl accident.

Although much is known about the radiation-related risk of thyroid cancer in those exposed at young ages, less is known about the risk due to adult exposure, particularly in men. We aimed to examine the association between thyroid radiation dose received during adulthood and thyroid cancer risk in men. We conducted a nested case-control study (149 cases; 458 controls) of male, Ukrainian cleanup workers who first worked in the Chornobyl zone between ages 18 and 59 years, with cases identified through linkage with the National Cancer Registry of Ukraine from 1988 to 2012. Individual thyroid doses due to external and internal exposure during the cleanup mission and during residence in contaminated settlements were estimated (total dose mean 199 mGy; range 0.15 mGy to 9.0 Gy). The excess odds ratio per gray (EOR/Gy) for overall thyroid cancer was 0.40 (95% CI: - 0.05, 1.48; p-value = 0.118). Time since exposure was borderline significant (p-value = 0.061) in modifying this association so that less time since exposure was associated with a stronger EOR/Gy. An elevated, but nonsignificant association was observed for follicular thyroid cancer (EOR/Gy = 1.72; 95% CI: - 0.25, 13.69; p-value = 0.155) based on a small number of cases (n = 24). Our findings for radiation-related overall thyroid cancer risk are consistent with evidence of increased risks observed in most of the other studies of adult exposure, though the magnitude of the effect in this study is lower than in the previous case-control study of Chornobyl cleanup workers.

Lack of transgenerational effects of ionizing radiation exposure from the Chernobyl accident.

Effects of radiation exposure from the Chernobyl nuclear accident remain a topic of interest. We investigated germline de novo mutations (DNMs) in children born to parents employed as cleanup workers or exposed to occupational and environmental ionizing radiation after the accident. Whole-genome sequencing of 130 children (born 1987-2002) and their parents did not reveal an increase in the rates, distributions, or types of DNMs relative to the results of previous studies. We find no elevation in total DNMs, regardless of cumulative preconception gonadal paternal [mean = 365 milligrays (mGy), range = 0 to 4080 mGy] or maternal (mean = 19 mGy, range = 0 to 550 mGy) exposure to ionizing radiation. Thus, we conclude that, over this exposure range, evidence is lacking for a substantial effect on germline DNMs in humans, suggesting minimal impact from transgenerational genetic effects.

Radiation-related genomic profile of papillary thyroid carcinoma after the Chernobyl accident.

The 1986 Chernobyl nuclear power plant accident increased papillary thyroid carcinoma (PTC) incidence in surrounding regions, particularly for radioactive iodine (131I)-exposed children. We analyzed genomic, transcriptomic, and epigenomic characteristics of 440 PTCs from Ukraine (from 359 individuals with estimated childhood 131I exposure and 81 unexposed children born after 1986). PTCs displayed radiation dose-dependent enrichment of fusion drivers, nearly all in the mitogen-activated protein kinase pathway, and increases in small deletions and simple/balanced structural variants that were clonal and bore hallmarks of nonhomologous end-joining repair. Radiation-related genomic alterations were more pronounced for individuals who were younger at exposure. Transcriptomic and epigenomic features were strongly associated with driver events but not radiation dose. Our results point to DNA double-strand breaks as early carcinogenic events that subsequently enable PTC growth after environmental radiation exposure.

Estimation of radiation gonadal doses for the American-Ukrainian trio study of parental irradiation in Chornobyl cleanup workers and evacuees and germline mutations in their offspring.

Radiation doses of parents exposed from the Chornobyl accident as cleanup workers or evacuees were estimated in the National Cancer Institute-National Research Center for Radiation Medicine trio (i.e. father, mother, offspring) study aimed at investigating the radiation effects on germlinede novomutations in children as well as other outcomes. Paternal (testes) and maternal (ovaries) gonadal doses were calculated along with associated uncertainty distributions for the following exposure pathways: (a) external irradiation during the cleanup mission, (b) external irradiation during residence in Pripyat, and (c) external irradiation and (d) ingestion of radiocesium isotopes, such as134Cs and137Cs, during residence in settlements other than Pripyat. Gonadal doses were reconstructed for 298 trios for the periods from the time of the accident on 26 April 1986 to two time points before the child's date of birth (DOB): 51 (DOB-51) and 38 (DOB-38) weeks. The two doses, DOB-51 and DOB-38 were equal (within 1 mGy) in most instances, except for 35 fathers where the conception of the child occurred within 3 months of exposure or during exposure. The arithmetic mean of gonadal DOB-38 doses was 227 mGy (median: 11 mGy, range 0-4080 mGy) and 8.5 mGy (median: 1.0 mGy, range 0-550 mGy) for fathers and mothers, respectively. Gonadal doses varied considerably depending on the exposure pathway, the highest gonadal DOB-38 doses being received during the cleanup mission (mean doses of 376 and 34 mGy, median of 144 and 7.4 mGy for fathers and mothers, respectively), followed by exposure during residence in Pripyat (7.7 and 13 mGy for mean, 7.2 and 6.2 mGy for median doses) and during residence in other settlements (2.0 and 2.1 mGy for mean, 0.91 and 0.81 mGy for median doses). Monte Carlo simulations were used to estimate the parental gonadal doses and associated uncertainties. The geometric standard deviations (GSDs) in the individual parental stochastic doses due to external irradiation during the cleanup mission varied from 1.2 to 4.7 (mean of 1.8), while during residence in Pripyat they varied from 1.4 to 2.8 (mean of 1.8), while the mean GSD in doses received during residence in settlements other than Pripyat was 1.3 and 1.4 for external irradiation and ingestion of radiocesium isotopes, respectively.

Chromosome Aberrations in a Group of People Exposed to Radioactive Releases from the Three Mile Island Nuclear Accident and Inferences for Radiation Effects.

Recently, it has been proposed that the doses received from 133Xe released during the accident in 1979 at the Three Mile Island (TMI) plant in Pennsylvania were much higher than has been conventionally assessed, due to a gross underestimation of the relative biological effectiveness of electrons from beta-particle-emitting radionuclides within the body. The central evidence cited in support of this proposal was the doses derived from cytogenetic analyses of blood sampled in the mid-1990s from people living near TMI at the time of the accident. However, the chromosome aberration data show a marked discrepancy in biodosimetric estimates evaluated from the frequencies of stable translocations and unstable dicentrics (corrected for temporal attenuation), strongly suggesting that exposures to clastogenic agents occurred long after the TMI accident. Few details have been reported on the people providing the blood samples and how they were selected for study. Crucially, this lack of information includes the distributions in the exposed and control groups of age at sampling, which is a critical factor in interpreting translocation data. Contrary to the recent claim, these cytogenetic data offer no support to the suggestion of a serious underestimation of internal doses from beta particles or from 133Xe discharged during the TMI accident.

Utility of gene expression studies in relation to radiation exposure and clinical outcomes: thyroid cancer in the Ukrainian-American cohort and late health effects in a MAYAK worker cohort.

PURPOSE: We herein report on changes in gene expression after radiation exposure to iodine-131 from the Chernobyl accident in the Ukrainian-American thyroid cohort and to external gamma ray or internal plutonium exposure in the Mayak Production Association radiation workers. MATERIALS AND METHODS: Taking advantage of access to tissue samples from the thyroid cancer cases in the Ukrainian-American cohort, our group tried to identify candidate genes to discriminate spontaneously occurring thyroid cancers from thyroid cancers caused by radiation exposure. We also examined gene expression changes in normal and cancerous thyroid tissue in relation to iodine-131 dose separately. Gene expression changes in the peripheral blood of radiation exposed Mayak workers were examined to elucidate the dose-to-gene and gene-to-health (e.g. cardiovascular disease) relationships. CONCLUSIONS: Results of both projects are discussed under the aspect of dose-response relationships (dose-to-gene) and clinical outcome relationships (gene-to-effect) in light of how mechanistic data can be translated into actionable knowledge for radiation protection or clinical purposes.

Field Study of the Possible Effect of Parental Irradiation on the Germline of Children Born to Cleanup Workers and Evacuees of the Chornobyl Nuclear Accident.

Although transgenerational effects of exposure to ionizing radiation have long been a concern, human research to date has been confined to studies of disease phenotypes in groups exposed to high doses and high dose rates, such as the Japanese atomic bomb survivors. Transgenerational effects of parental irradiation can be addressed using powerful new genomic technologies. In collaboration with the Ukrainian National Research Center for Radiation Medicine, the US National Cancer Institute, in 2014-2018, initiated a genomic alterations study among children born in selected regions of Ukraine to cleanup workers and/or evacuees exposed to low-dose-rate radiation after the 1986 Chornobyl (Chernobyl) nuclear accident. To investigate whether parental radiation exposure is associated with germline mutations and genomic alterations in the offspring, we are collecting biospecimens from father-mother-offspring constellations to study de novo mutations, minisatellite mutations, copy-number changes, structural variants, genomic insertions and deletions, methylation profiles, and telomere length. Genomic alterations are being examined in relation to parental gonadal dose, reconstructed using questionnaire and measurement data. Subjects are being recruited in exposure categories that will allow examination of parental origin, duration, and timing of exposure in relation to conception. Here we describe the study methodology and recruitment results and provide descriptive information on the first 150 families (mother-father-child(ren)) enrolled.

Belarusian in utero cohort: A new opportunity to evaluate the health effects of prenatal and early-life exposure to ionising radiation.

In April 1986, the Chernobyl nuclear accident resulted in wide-scale contamination of Belarus with significantly elevated levels of radioiodine isotopes, mainly iodine-131 (131I), and long-lived radiocaesium isotopes, mainly caesium-137 (137Cs). Various groups of the population were affected by exposure to ionising radiation, including pregnant women and their foetuses. This paper describes the methods and results related to the establishment of a cohort of 2965 Belarusian people exposed in utero due to Chernobyl fallout. The cohort consists of individuals whose mothers resided in the most radioactively contaminated areas in Belarus at the time of the accident. Prenatal and postnatal doses to the thyroid due to intake of 131I, external irradiation and ingestion of radiocaesium isotopes were estimated for all cohort members. Ongoing research on this unique cohort will provide important information on adverse health effects following prenatal and postnatal exposure to radioiodine and radiocaesium isotopes, for which available epidemiological data are scant.

Thyroid Dose Estimates for a Cohort of Belarusian Persons Exposed in Utero and During Early Life to Chernobyl Fallout.

Thyroid radiation doses were estimated for a cohort of 2,965 Belarusian persons who were exposed in utero and during early life to fallout from the Chernobyl nuclear power plant accident. Prenatal and postnatal doses to the thyroid due to intake of I, external irradiation from radionuclides deposited on the ground, and ingestion of cesium isotopes (Cs and Cs) were calculated for all cohort members. Dose estimation was based on personal interviews with subjects' mothers; the interviews collected data on subjects' residential history, consumption by mothers during time of pregnancy and breast-feeding, as well as consumption by subjects after birth. Direct instrumental measurements of radioactivity in mothers and the study subjects, if available, were also used for calculation of doses. Intake of I by mothers was found to be the predominant pathway for thyroid exposure for the study subjects. The average thyroid dose due to all exposure pathways was estimated to be 137 mGy (median dose of 25 mGy, maximal dose of 14.8 Gy), including 130 mGy (median dose of 17 mGy, maximal dose of 14.8 Gy) from I intake, 4.9 mGy (median dose of 3.0 mGy, maximal dose of 102 mGy) due to external irradiation, and 2.5 mGy (median dose of 1.7 mGy, maximal dose of 47 mGy) due to ingestion of Cs. The dose estimates will be used to evaluate the radiation-related risk of thyroid cancer and other thyroid diseases in this unique cohort.

Estimation of Radiation Doses for a Case-control Study of Thyroid Cancer Among Ukrainian Chernobyl Cleanup Workers.

Thyroid doses were estimated for 607 subjects of a case-control study of thyroid cancer nested in the cohort of 150,813 male Ukrainian cleanup workers who were exposed to radiation as a result of the 1986 Chernobyl nuclear power plant accident. Individual thyroid doses due to external irradiation, inhalation of I and short-lived radioiodine and radiotellurium isotopes (I, I, I, Te, and Te) during the cleanup mission, and intake of I during residence in contaminated settlements were calculated for all study subjects, along with associated uncertainty distributions. The average thyroid dose due to all exposure pathways combined was estimated to be 199 mGy (median: 47 mGy; range: 0.15 mGy to 9.0 Gy), with averages of 140 mGy (median: 20 mGy; range: 0.015 mGy to 3.6 Gy) from external irradiation during the cleanup mission, 44 mGy (median: 12 mGy; range: ~0 mGy to 1.7 Gy) due to I inhalation, 42 mGy (median: 7.3 mGy; range: 0.001 mGy to 3.4 Gy) due to I intake during residence, and 11 mGy (median: 1.6 mGy; range: ~0 mGy to 0.38 Gy) due to inhalation of short-lived radionuclides. Internal exposure of the thyroid gland to I contributed more than 50% of the total thyroid dose in 45% of the study subjects. The uncertainties in the individual stochastic doses were characterized by a mean geometric standard deviation of 2.0, 1.8, 2.0, and 2.6 for external irradiation, inhalation of I, inhalation of short-lived radionuclides, and residential exposure, respectively. The models used for dose calculations were validated against instrument measurements done shortly after the accident. Results of the validation showed that thyroid doses could be estimated retrospectively for Chernobyl cleanup workers two to three decades after the accident with a reasonable degree of reliability.

Epidemiology: Back to the Future.

In 2018, the Society for Epidemiologic Research and its partner journal, the American Journal of Epidemiology, assembled a working group to develop a set of papers devoted to the "future of epidemiology." These 14 papers covered a wide range of topic areas and perspectives, from thoughts on our profession, teaching, and methods to critical areas of substantive research. The authors of those papers considered current challenges and future opportunities for research and education. In light of past commentaries, 4 papers also include reflections on the discipline at present and in the future.

Thyroid Cancer and Benign Nodules After Exposure In Utero to Fallout From Chernobyl.

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.