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A growing body of evidence suggests a role of the von Hippel-Lindau (VHL) tumor suppressor gene in the progression of papillary thyroid carcinoma (PTC). Our previous study of VHL in PTCs showed that lower VHL expression was associated with aggressive tumor features, but we found no evidence for VHL downregulation through common genetic or epigenetic modifications. Several studies pointed to a role of microRNA-92a (miR-92a) in the regulation of VHL expression in different cancers. In the present study, we examined the expression levels of VHL mRNA and miR-92a in 42 pairs of PTCs and matched non-tumor thyroid tissues by means of quantitative RT-PCR. We explored the correlation between them and their association with clinicopathological parameters. The results revealed that both VHL and miR-92a were either up-or downregulated in PTCs compared to corresponding non-tumor tissues. On univariate analysis, lower VHL levels were significantly associated with extrathyroid spread (P = 0.022) and capsular invasion (P = 0.032). Multivariate analysis confirmed the association of low VHL with extrathyroid spread (OR 0.246, 95% CI 0.069-0.872, P = 0.038). Higher miR-92a among PTC tissues associated with the presence of nodal metastases (univariate analysis: P = 0.012; multivariate: OR 4.703, 95% CI 1.109-19.938, P = 0.036). A negative correlation between VHL and miR-92a was observed in a subgroup of PTCs having vascular invasion (P = 0.033, r = -0.673). The data here reported demonstrate that the expression of both VHL and miR-92a is deregulated in PTC tissues and that in some PTCs they may have opposite roles. These roles, as well as their diagnostic and/or prognostic utility, remain to be clarified.

The increase in risk for late-onset thyroid cancer due to radiation exposure is a potential health effect after a nuclear power plant accident mainly due to the release of radioiodine in fallout. The risk is particularly elevated in those exposed during infancy and adolescence. To estimate the possibility and extent of thyroid cancer occurrence after exposure, it is of utmost importance to collect and analyze epidemiological information providing the basis for evaluation of radiation risk, and to consider radiobiology and molecular genetics. In this regard, the dose-response of cancer risk, temporal changes in the rates of thyroid cancer, its histopathological types and subtypes, and frequency of underlying genetic abnormalities are important. At present, however, it is difficult or impossible to distinguish radiation-induced thyroid cancer from spontaneous/sporadic thyroid cancer because molecular radiation signatures, biomarkers of radiation exposure, or genetic factors specific to radiation-induced cancer have not yet been identified. The large-scale ultrasound screening in Fukushima Prefecture of Japan demonstrated a high detection rate of thyroid cancer in young individuals, revealing 116 and 71 cases in the first and second rounds, respectively, among the same cohort of approximately 300,000 subjects. These findings raised concerns among residents and the public that it might be due to putative exposure to radiation from the accident at Fukushima Daiichi Nuclear Power Plant. This review summarizes evaluations by international organizations and reviews scientific publications by the authors and others on childhood thyroid cancer, especially those relevant to radiation, including basic studies on molecular mechanisms of thyroid carcinogenesis. Clinical details are also provided on surgical cases in Fukushima Prefecture, and the effect of thyroid ultrasound screening is discussed. Correct understanding of issues relating to radiation and the thyroid are essential, Thyroid, 28 (1), pp.11-22; 2018

Background: Several functional single-nucleotide polymorphisms (SNPs) at the FOXE1 locus on chromosome 9q22.33 have been associated with the risk for papillary thyroid carcinoma (PTC). This study set out to elucidate whether their effects are independent, using genotyping results in populations of Asian and European descent. Methods: SNPs rs965513 and rs1867277 and a polymorphic region determining the length of the FOXE1 polyalanine (poly-Ala) tract were genotyped in 501 patients with PTC and 748 healthy individuals from Japan, and in 660 patients and 820 population controls from Belarus. Functional analysis of transactivation activities of FOXE1 isoforms with varying number of alanine repeats was performed by a Dual-LuciferaseR Assay. Results: All three polymorphisms were significantly associated with PTC in both populations on univariate analysis. However, conditional analysis revealed independent effects of rs965513 and rs1867277 SNPs but not of the FOXE1 poly-Ala polymorphism. The independent effect of the lead rs965513 SNP was observed in both populations, while that of rs1867277 was only identified in the Japanese population, in which linkage disequilibrium between the three polymorphisms is markedly weaker. Despite the strong decrease in transcriptional activity with increasing FOXE1 poly-Ala tract length, no difference in transactivation potential of the FOXE1 poly-Ala isoforms could be seen after adjustment for the minimal promoter activity in the reporter vectors. Plasmids encoding FOXE1 isoforms of increasing poly-Ala tract length were also found to produce less FOXE1 protein after cell transfection. Conclusions: The functional variants rs965513 and rs1867277 independently contribute to genetic predisposition to PTC, while a contributing role of the FOXE1 poly-Ala polymorphism could not be confirmed., Thyroid, 27(2), pp.224-235; 2017

Background: The symposium entitled “Chernobyl +30, Fukushima +5: Lessons and Solutions for Fukushima’s Thyroid Question” was held in September, 2016 in Fukushima. The aim of the Symposium was to revisit and recapitulate evidence from the studies in Chernobyl in order to share multidisciplinary opinions and views on the likely reason for the high rate of thyroid cancer detected by the Thyroid Ultrasound Examination program in Fukushima Prefecture. Participants and matters discussed: The high prevalence of thyroid cancer in young individuals causes concerns among Fukushima residents and the general public that it might be due to putative radiation exposure from the Fukushima Daiichi Nuclear Power Plant accident. Twenty-six experts from Japan and abroad, including participants affiliated with international organizations, reviewed the results of radiation epidemiology investigations in Chernobyl, presented clinical experience of diagnosis, treatment and follow-up of patients with radiation-related thyroid cancer, and scrutinized the findings on thyroid cancer in Fukushima. Conclusion: Conclusions drawn at the symposium included understanding that in contrast to Chernobyl, doses to the public from the accident in Fukushima were too low to give rise to a discernible excess risk for thyroid cancer. The high detection rate of thyroid cancer and benign abnormalities resulted from the use of highly sensitive ultrasound equipment and sophisticated protocol of examination used in the Thyroid Ultrasound Examination, and therefore not attributable to radiation. Coordinated efforts will be necessary to avoid overdiagnosis and overtreatment, which may carry its own health disbenefits. Clear communication to the screening participants and their families is recommended in regard to why the examination is being conducted and to explain the likely outcomes and risks, including the means and options for treatment if a thyroid disorder is detected., Environmental Health, 16, 3; 2017

Although most papillary thyroid carcinomas (PTCs) have a good prognosis, a small but certain fraction shows aggressive behavior. Therefore, a novel and well-performing molecular marker is needed. In the present study, we assessed the impact of the combination of the TERT promoter/BRAF mutations and Ki-67 labeling index (LI) as a prognostic marker in PTC patients. Of 400 PTC samples, 354 were successfully genotyped for both TERT promoter/BRAF and analyzed for Ki-67 LI. Based on the combination of the mutational status and Ki-67 LI, the cases were categorized into three groups: high-, middle-, and low-risk. The recurrence rates of low-, middle-, and high-risk group were 1.9% (6 of 323), 18.2% (4 of 22), and 44.4% (4 of 9), respectively. The Kaplan-Meier curve and log-rank analyses demonstrated that there were statistical differences between any two groups. The hazard ratios for recurrence remained significant after adjustment for age, sex, tumor size, and extrathyroidal extension (low vs. middle: 8.80, 95% CI: 2.35-32.92, p = 0.001; middle vs. high: 6.255, 95% CI: 1.13-34.51, p = 0.035). In conclusion, the combination of the TERT promoter/BRAF V600E mutations and Ki-67 LI performed excellent in predicting PTC recurrence and may be clinically useful., Scientific Reports, 7, 41752; 2017

Background: Several single nucleotide polymorphisms (SNP) have been identified to be associated with the risk for differentiated thyroid cancer in populations of distinct ethnic background. The relationship of these genetic markers to a benign tumor of the thyroid, follicular adenoma (FA), is not well established. Methods: In a multicenter retrospective case-control study, five thyroid cancer-related SNPs - rs966513 (9q22.33, FOXE1), rs944289 (14q13.3, PTCSC3), rs2439302 (8p12, NRG1), rs1867277 (9q22.23, FOXE1), and rs6983267 (8q24, POU5F1B) - were genotyped in 959 cases of histologically verified FA, 535 papillary thyroid carcinomas (PTC), and 2766 population controls. Results: A significant association was found between FA and rs944289 (p=0.002; OR 1.176 [CI 1.064-1.316]), and suggestively with rs2439302 (p=0.033; OR 1.149 [CI 1.010-1.315]). In PTC, significant associations were confirmed for rs965513 (p=4.21E-04; OR 1.587 [CI 1.235-2.000]) and rs944289 (p=0.003; OR 1.234 [CI 1.075-1.408]), newly found for rs2439302 (p=0.003; OR 1.266 [CI 1.087-1.493]) and rs1867277 (p=1.17E-04; OR 1.492 [CI 1.235-1.818]), and was not replicated for rs6983267 (p=0.082; OR 1.136 [CI 0.980-1.316]) in this series. A significant correlation between rs2439302 genotype and relative expression of NRG1 was detected in normal and tumor counterparts of PTC (about 10% decrease per each risk allele). NRG1 expression also significantly correlated with that of PTCSC3. Conclusions: Association of rs944289, which was previously known to confer risk for thyroid cancer, with FA, and the correlation between PTCSC3 and NRG1 expression demonstrates that predisposing genetic factors are partly common for benign and malignant thyroid tumors, and imply broader roles of the pathways they underlie in thyroid tumorigenesis, not limited to carcinogenesis., Thyroid, 25(3), pp.333-340; 2015

One of the major health consequences of the Chernobyl Nuclear Power Plant accident in 1986 was a dramatic increase in incidence of thyroid cancer among those who were aged less than 18 years at the time of the accident. This increase has been directly linked in several analytic epidemiological studies to iodine-131 (131I) thyroid doses received from the accident. However, there remains limited understanding of factors that modify the 131Irelated risk. Focusing on post-Chernobyl pediatric thyroid cancer in Belarus, we reviewed evidence of the effects of radiation, thyroid screening, and iodine deficiency on regional differences in incidence rates of thyroid cancer. We also reviewed current evidence on content of nitrate in groundwater and thyroid cancer risk drawing attention to high levels of nitrates in open well water in several contaminated regions of Belarus, i.e. Gomel and Brest, related to the usage of nitrogen fertilizers. In this hypothesis generating study, based on ecological data and biological plausibility, we suggest that nitrate pollution may modify the radiationrelated risk of thyroid cancer contributing to regional differences in rates of pediatric thyroid cancer in Belarus. Analytic epidemiological studies designed to evaluate joint effect of nitrate content in groundwater and radiation present a promising avenue of research and may provide useful insights into etiology of thyroid cancer., PLOS ONE, 10(9), e0137226; 2015

After the accident at the Fukushima Daiichi Nuclear Power Plant, the thyroid ultrasound screening program for children aged 0-18 at the time of the accident was started from October 2011. The prevalence of thyroid carcinomas in that population has appeared to be very high (84 cases per 296,253). To clarify the pathogenesis, we investigated the presence of driver mutations in these tumours. 61 classic papillary thyroid carcinomas (PTCs), two follicular variant PTCs, four cribriform-morular variant PTCs and one poorly-differentiated thyroid carcinoma were analysed. We detected BRAF V600E in 43 cases (63.2%), RET/PTC1 in six (8.8%), RET/PTC3 in one (1.5%) and ETV6/NTRK3 in four (5.9%). Among classic and follicular variant PTCs, BRAF V600E was significantly associated with the smaller size. The genetic pattern was completely different from post-Chernobyl PTCs, suggesting non-radiogenic etiology of these cancers. This is the first study demonstrating the oncogene profile in the thyroid cancers discovered by large mass screening, which probably reflects genetic status of all sporadic and latent tumours in the young Japanese population. It is assumed that BRAF V600E may not confer growth advantage on paediatric PTCs, and many of these cases grow slowly, suggesting that additional factors may be important for tumour progression in paediatric PTCs., Scientific Reports, 5, 16976; 2015

Background: Neuroendocrine tumor (NET) of the thyroid other than medullary carcinoma is extremely rare. We describe here a case of calcitonin-negative small cell neuroendocrine carcinoma (SCNEC), which occurred in a thyroid gland that had previously been irradiated at high dose (60Gy) for pharyngeal cancer, with molecular analyses for follicular cell origin. Patient Findings: The tumor cells were small with fine chromatin, inconspicuous nucleoli, and inapparent cytoplasm, and showed neuroendocrine architectures such as palisading, rosettes, and trabeculae. Mitotic figures were numerous exceeding 10 mitoses per 10 high-power fields. The tumor cells invaded into several vessels and metastasized to regional lymph nodes. Immunohistochemically, the tumor cells were strongly positive for neuroendocrine markers and thyroglobulin (Tg), a marker of thyroid follicular cells but negative for calcitonin and carcinoembryonic antigen (CEA). Expression of Tg and thyrotropin receptor (TSHR) were confirmed by quantitative real-time polymerase chain reaction (RT-PCR). Ki-67 labeling index was more than 70% in the tumor cells. Taken together, the tumor was diagnosed as SCNEC of the thyroid. Genetic analyses also revealed microsatellite abnormalities of the phosphatase and tensin homolog (PTEN) gene, suggesting that functional loss of PTEN contributes to carcinogenesis. Conclusions: This is the first report describing a SCNEC of the thyroid with molecular analyses that provide evidence for a follicular epithelial origin.

Alterations of the von Hippel-Lindau (VHL) tumor suppressor gene can cause different hereditary tumors associated with VHL syndrome, but the potential role of the VHL gene in papillary thyroid carcinoma (PTC) has not been characterized. This study set out to investigate the relationship of VHL expression level with clinicopathological features of PTC in an ethnically and geographically homogenous group of 264 patients from Serbia, for the first time. Multivariate logistic regression analysis showed a strong correlation between low level of VHL expression and advanced clinical stage (OR=5.78, 95% CI 3.17-10.53, P LT 0.0001), classical papillary morphology of the tumor (OR=2.92, 95% CI 1.33-6.44, P=0.008) and multifocality (OR=1.96, 95% CI 1.06-3.62, P=0.031). In disease-free survival analysis, low VHL expression had marginal significance (P=0.0502 by the log-rank test) but did not appear to be an independent predictor of the risk for chance of faster recurrence in a proportion hazards model. No somatic mutations or evidence of VHL downregulation via promoter hypermethylation in PTC were found. The results indicate that the decrease of VHL expression associates with tumor progression but the mechanism of downregulation remains to be elucidated.

THYROID CANCER IN UKRAINE AFTER CHERNOBYL dosimetry, epidemiology, pathology, molecular biology, pp.1-17; 2014

THYROID CANCER IN UKRAINE AFTER CHERNOBYL dosimetry, epidemiology, pathology, molecular biology, p.viii; 2014

THYROID CANCER IN UKRAINE AFTER CHERNOBYL dosimetry, epidemiology, pathology, molecular biology, pp.39-64; 2014

Thyroid, 24(10), pp.1547-1548; 2014