Radiation-associated Thyroid Cancer Research Articles

Оценка радиационных рисков злокачественных новообразований среди населения регионов России, загрязнённых радионуклидами вследствие аварии на Чернобыльской АЭС

Some areas of the Russian Federation were contaminated with radionuclides released as a re-sult of the Chernobyl accident. The current paper clarifies some items of the previously published study based on NRER (National Radiation-Epidemiological Registry, the Registry) data. The pre-vious issue presented estimates of radiation risks of cancer incidence among the population of four the most contaminated regions of the Russian Federation: Bryansk, Kaluga, Oryol and Tula oblasts. Risks of thyroid cancer are estimated with account of screening effect. The cohort con-sisted of more than 327 thousand people resided in the contaminated areas. The average dose to the thyroid of children and adolescents was 0.174 Gy, the average dose to the thyroid of adults was 0.035 Gy. Thyroid cancer was diagnosed in 1549 members of the cohort during the follow-up period from 1991 over 2019, among them 423 cases were children and adolescents at the accident and 1126 cases were adults. Significant increase in thyroid cancer incidence was ob-served in adults exposed internally through the intake of iodine-131 at a young age. The statisti-cally significant radiation risk of thyroid cancer persists over 30 years after exposure. The risk de-creases with increasing the attained age. In people exposed to radiation before the age of 1 year and reaching the age of 20 years, the coefficient of excess relative risk of thyroid cancer (ERR/Gy) was 4.61. Radiation associated thyroid cancer is attributed to 20.6% of the cohort mem-bers exposed internally through the intake of radioiodine isotopes in their childhood and adoles-cence, and thyroid cancer from intake of radioiodine is attributed to 58% of cases exposed to ra-diation under 4 years of age. Marked screening effect (ES) was found during the disease diag-nosing, screening coefficient was 5.6 for children and 2.1 for adults. There were not attributed to radiation statistically significant risks of solid cancers, including radiation induced breast cancer in females, in the cohort of people resided in the areas contaminated with radionuclides. Radia-tion risk of leukemia was also not identified, although the average value of excess relative risk in men exceeded zero. Further observations of the cohort of persons resided in areas contaminated with radionuclides will increase the statistical power of radiation-epidemiological studies and clarify the assessment of radiation risks of human for chronic exposure at low doses.

Radiation-Associated Thyroid Cancer Surveillance and Management in a Cohort of Late Effects Patients.

Compared to the general population, the incidence of thyroid cancer in childhood and adolescent and young adult malignancy survivors is increased 14.0-18.0 times (CI 11.7-23.8). The cumulative incidence is variably reported as 0.5% by age 45 with 30-year incidence of 1.3% in women and 0.6% in men. This study aims to evaluate the incidence of radiation-associated thyroid cancer amongst patients treated with prior radiation to the thyroid followed up in a late effects service. A secondary aim was to assess screening compliance in this cohort. The medical records of all patients attending the late effects service from 1 January 2000 to 20 February 2013 were interrogated to identify patients exposed to thyroid irradiation. The screening compliance and incidence of thyroid cancer were assessed for the duration whilst under the guidance of the late effect service. Mode of diagnosis, all imaging and cytology were retrieved from the institutional electronic record. Cytology was categorized according to Bethesda. Four hundred and sixty-five patients were exposed to direct or scatter neck irradiation. Compliance with thyroid surveillance was observed in 76.9%. Ultrasound features of microcalcification and increased internal vascularity had a low sensitivity (62.5%) for predicting a malignant nodule, which improved when used in conjunction with a Bethesda IV-VI result (91.7%). However, cytological assessment was not performed in 45.6% of operative cases. Thirty-three patients had thyroid carcinoma of which 45.4% (n = 15) were incidental. The majority were papillary thyroid cancers (88.9%); of which 12.5% were node positive and 34.4% were multifocal. The incidence of thyroid cancer was elevated 57.6 times compared to the Australian general population (p < 0.001). Due to the high incidence of thyroid cancer, this study supports screening in this cohort. However, due to the risk of overtreatment, we endorse further investigation of thyroid nodules with ultrasound-guided fine-needle aspiration cytology based on sonographic criteria as for the general population and American Thyroid Association guidelines.

NTRK1-3 point mutations in poor prognosis thyroid cancers.

6087 Background: NTRK1-3 fusions, identified in pediatric radiation-associated thyroid cancers, are low frequency oncogenic drivers that can trigger constitutive activation of TrK1-3 tyrosine kinase domains with responsively heightened downstream signaling through RAS-MAPK, PI3K-AKT, and/or PLCγ-PKC. NTRK point mutations are rare and of largely uninvestigated oncogenic potential, but some appear oncogenic. Methods: Advanced thyroid cancer (TC) patients (pts) requiring systemic therapy at Mayo Clinic sites underwent tumor genetic interrogation using Foundation One analyses with the goal of informing salvage therapeutic strategies. In this IRB-approved study, data from pts with TCs bearing NTRK point mutations were retrospectively analyzed, as this occurrence was unexpected but potentially of prognostic and/or therapeutic relevance. Results: Five of 55 pts (9%) with advanced TCs subject to Foundation One tumor interrogation had NTRK1-3 point mutations (allele frequency, AF, 15-49%); none had fusions. All 5 tumors had microsatellite stability; 4/5 had low tumor mutation burden (2-5 mutations/megabase). NTRK mutations in 3 anaplastic TC (ATC) pts (15% prevalence) were: NTRK3 I749M (AF 15%; overall survival, OS, 15 mos), NTRK1 R744H (AF not available; OS 9.5 mos), and NTRK1 R583H (AF 20.1%; OS &gt; 4.9 mos); NTRK2 S167Y (AF 49%; OS &gt; 51 mos) or NTRK1 R6W (AF 42%; OS &gt; 60 mos) were found in one papillary (PTC) and one Hürthle cell (HCC) TC pt respectively (summary table below). Conclusions: NTRK point mutations, but not fusions, were unexpectedly identified in 9% of assessed advanced TCs - but remarkably in 15% of ATCs. Mutated NTRKs, along with oncogenic p53 and TERT, may contribute to TC progression, especially in ATC, consequent to downstream activation of MAPK and PI3K-AKT pathways. We posit that NTRK point mutations may have therapeutic implications for treatment of refractory disease. [Table: see text]

A Perspective on the New Pooled Analysis of Radiation-Associated Thyroid Cancer

A Perspective on the New Pooled Analysis of Radiation-Associated Thyroid Cancer

Research of DNA repair genes polymorphism XRCC1 and XPD and the risks of thyroid cancer development in persons exposed to ionizing radiation after Chornobyl disaster

The objective of this work was to determine and compare the features of DNA repair gene XRCC1 Arg399Gln and XPD Lys751Gln polymorphisms in patients with thyroid cancer (TC), who were exposed to ionizing radiation (IR) as a result of the Chornobyl disaster, and in patients without exposure to ionizing radiation in history. Determination of gene XRCC1 Arg399Gln and XPD Lys751Gln polymorphisms was performed by polymerase chain reaction (PCR) in 102 patients with thyroid cancer: 38 people, who were exposed to ionizing radiation due to Chornobyl disaster (members of the accident, and evacuees and residents from controlled areas contaminated with radionuclides), 64 individuals without exposure to ionizing radiation in history and 41 persons residents of Ukraine without cancer pathology in the control group. For comparison of the data on spontaneous and radiation-associated thyroid cancer and settlement of allele frequencies differences and risk of cancer pathology were used the literature data on control groups of populations of Russia, Belarus and Poland. Comparing to the literature data on XRCC1 Arg399Gln polymorphisms in radiation-exposed individuals without cancer pathology, the risk of thyroid cancer in homozygous minor allele XRCC1 Gln399Gln carriers, who were exposed to ionizing radiation was significantly increased: OR = 4,14, p = 0,001 (CI95 % 1,72-9,93). In homozygous carriers of the minor allele of the gene XPD Lys751Gln, exposed to IR, revealed increased risk of thyroid cancer: OR = 3,30, p = 0,05 (CI 95 % 0,82-14,14), when compared with the control group of Ukrainian population. The carriage of homozygous minor allele Gln399Gln XRCC1 and XPD Gln751Gln of DNA repair genes is a risk factor for thyroid cancer under the influence of ionizing radiation in research group of Ukrainian population.

Thyroid Cancer: Molecular Characteristics of Radiation-Associated Papillary Thyroid Cancer, with a Special Reference to of Atomic Radiation Exposure

Among atomic-bomb (A-bomb) survivors of Hiroshima and , incidence of thyroid cancer significantly increased after exposure to nuclear radiation. This review will focus on the initiating gene alterations in the development of adult-onset papillary thyroid cancer (PTC) among A-bomb survivors. The effects of A-bomb radiation on chromosomal rearrangements (RET and NTRK1 rearrangements) and point mutations (BRAF and RAS mutations) after exposure were different. In contrast to PTC cases with point mutations, PTC cases with chromosomal rearrangements were observed more frequently among those exposed to high radiation doses compared to low doses, and these cases developed cancer earlier after exposure than did cases with point mutations. Interestingly, PTC cases with non-detected gene alterations were found more frequently among patients who were exposed to high radiation doses and who developed cancer earlier after radiation exposure than did the cases with BRAF point mutation. This suggests that heretofore non-detected gene alterations may also be involved in adult-onset PTC among A-bomb survivors.

Formation of carcinogenic chromosomal rearrangements in human thyroid cells after induction of double-strand DNA breaks by restriction endonucleases

Ionizing radiation (IR) exposure increases the risk of thyroid cancer and other cancer types. Chromosomal rearrangements, such as RET/PTC, are characteristic features of radiation-associated thyroid cancer and can be induced by radiation in vitro. IR causes double-strand breaks (DSBs), suggesting that such damage leads to RET/PTC, but the rearrangement mechanism has not been established. To study the mechanism, we explored the possibility of inducing RET/PTC by electroporation of restriction endonucleases (REs) into HTori-3 human thyroid cells. We used five REs, which induced DSB in a dose-dependent manner similar to that seen with IR. Although all but one RE caused DSB in one or more of the three genes involved in RET/PTC, rearrangement was detected only in cells electroporated with either PvuII (25 and 100 U) or StuI (100 and 250 U). The predominant rearrangement type was RET/PTC3, which is characteristic of human thyroid cancer arising early after Chernobyl-related radioactive iodine exposure. Both enzymes that produced RET/PTC had restriction sites only in one of the two fusion partner genes. Moreover, the two enzymes that produced RET/PTC had restriction sites present in clusters, which was not the case for RE that failed to induce RET/PTC. In summary, we establish a model of DSB induction by RE and report for the first time the formation of carcinogenic chromosomal rearrangements, predominantly RET/PTC3, as a result of DSB produced by RE. Our data also raise a possibility that RET/PTC rearrangement can be initiated by a complex DSB that is induced in one of the fusion partner genes.

The Chernobyl Accident and its Consequences

The accident at the Chernobyl nuclear power plant was the worst industrial accident of the last century that involved radiation. The unprecedented release of multiple different radioisotopes led to radioactive contamination of large areas surrounding the accident site. The exposure of the residents of these areas was varied and therefore the consequences for health and radioecology could not be reliably estimated quickly. Even though some studies have now been ongoing for 25 years and have provided a better understanding of the situation, these are yet neither complete nor comprehensive enough to determine the long-term risk. A true assessment can only be provided after following the observed population for their natural lifespan. Here we review the technical aspects of the accident and provide relevant information on radioactive releases that resulted in exposure of this large population to radiation. A number of different groups of people were exposed to radiation: workers involved in the initial clean-up response, and members of the general population who were either evacuated from the settlements in the Chernobyl nuclear power plant vicinity shortly after the accident, or continued to live in the affected territories of Belarus, Russia and Ukraine. Through domestic efforts and extensive international co-operation, essential information on radiation dose and health status for this population has been collected. This has permitted the identification of high-risk groups and the use of more specialised means of collecting information, diagnosis, treatment and follow-up. Because radiation-associated thyroid cancer is one of the major health consequences of the Chernobyl accident, a particular emphasis is placed on this malignancy. The initial epidemiological studies are reviewed, as are the most significant studies and/or aid programmes in the three affected countries.

THYROID CANCER INCIDENCE AMONG PEOPLE LIVING IN AREAS CONTAMINATED BY RADIATION FROM THE CHERNOBYL ACCIDENT

As a result of the Chernobyl nuclear power plant accident, massive amounts of radioactive materials were released into the environment and large numbers of individuals living in Belarus, Russia, and Ukraine were exposed to radioactive iodines, primarily 131I. Iodine-131 concentrated in the thyroid gland of residents of the contaminated areas, with children and adolescents being particularly affected. In the decade after the accident, a substantial increase in thyroid cancer incidence was observed among exposed children in the three affected countries, and compelling evidence of an association between pediatric thyroid cancer incidence and radiation exposure to the thyroid gland accumulated. The data currently available suggest that both the magnitude and patterns of thyroid cancer risk are generally consistent with those reported following external exposure. Based on data from case-control studies, iodine deficiency appeared to enhance the risk of developing thyroid cancer following exposure from Chernobyl. Results from a recent large cohort study, however, did not support these findings. Data on adult exposure are limited and not entirely consistent. Similarly, information on thyroid cancer risks associated with in utero exposure is insufficient to draw conclusions. The lack of information on these two population groups indicates an important gap that needs to be filled. Twenty years after the accident, excess thyroid cancers are still occurring among persons exposed as children or adolescents, and, if external radiation can be used as a guide, we can expect an excess of radiation-associated thyroid cancers for several more decades. Since considerable uncertainties about the long-term health effects from Chernobyl remain, continued follow-up of the exposed populations should provide valuable information.

RET oncogene amplification in thyroid cancer: correlations with radiation-associated and high-grade malignancy

A radiation etiology is well known in thyroid carcinogenesis. RET oncogene rearrangement is the most common oncogenic alteration in Chernobyl-related papillary thyroid cancer (PTC). To find the characteristic alteration associated with RET rearrangements in radiation-induced thyroid cancers, we analyzed the RET oncogene by fluorescence in situ hybridization. The fluorescence in situ hybridization technique has the possibility of detecting RET rearrangements at a single-cell level regardless of the specific fusion partner involved and directly reveals RET copy number on a per-cell basis. Our study demonstrated RET amplification in all 3 cases of radiation-associated thyroid cancers but not in sporadic well-differentiated PTC (n = 11). Furthermore, RET amplification was observed in all 6 cases of sporadic anaplastic thyroid cancers (ATCs). The frequency of RET amplification-positive cells was higher in ATC (7.2%-24.1%) than in PTC (1.5%-2.7%). The highest frequency of RET amplification-positive cells was observed among ATC cases with a strong p53 immunoreactivity. In conclusion, we found RET amplification, which is a rare oncogenic aberration, in thyroid cancer. This report is the first one to suggest the presence of RET amplification in PTC and ATC. RET amplification was correlated with radiation-associated, high-grade malignant potency, and p53 accumulation, suggesting genomic instability. RET amplification might be induced by a high level of genomic instability in connection with progression of thyroid carcinogenesis and, subsequently, be associated with radiation-induced and/or high-grade malignant cases.

Childhood Thyroid Cancers and Radioactive Iodine Therapy: Necessity of Precautious Radiation Health Risk Management

One of the lessons from Chernobyl's legacy on health impact beyond 20 years is not only how to detect and treat the patients with radiation-associated thyroid cancers but how to follow up those who received radioactive iodine treatment repetitively after surgery in order to monitor any recurrence/worsening and also how to predict the risk of secondary primary cancers for their lifetime period. To evaluate the possibility of second primary tumors after radioactive iodine treatment, we reviewed the reports on risks from both external and internal radiation exposure, especially at high doses during childhood through an internet service of the National Library of Medicine and the National Institutes of Health, PubMed by the end of June, 2007, together with our own experience of Chernobyl childhood thyroid cancers. Children who were internally exposed after Chernobyl accident have a long-term risk of well differentiated thyroid cancers. Once they have disease, ironically radioactive iodine ablation is one of the useful therapies after surgical treatment. Elevated risks of solid cancers and leukemia have been found in radioiodine-treated patients, however, so far precious few reports from Chernobyl thyroid cancer patient were published. To reduce the adverse effects of radioactive iodine therapy on non-target tissues, recombinant human TSH has been applied and proved effective. Period of latency of second primary cancers may be very long. Therefore patients treated with high activities of radioactive iodine, especially children cases, should be carefully followed up during their whole lifespan.

Microarray Comparative Genomic Hybridization Reveals Genome-Wide Patterns of DNA Gains and Losses in Post-Chernobyl Thyroid Cancer

Genetic gains and losses resulting from DNA strand breakage by ionizing radiation have been demonstrated in vitro and suspected in radiation-associated thyroid cancer. We hypothesized that copy number deviations might be more prevalent, and/or occur in genomic patterns, in tumors associated with presumptive DNA strand breakage from radiation exposure than in their spontaneous counterparts. We used cDNA microarray-based comparative genome hybridization to obtain genome-wide, high-resolution copy number profiles at 14,573 genomic loci in 23 post-Chernobyl and 20 spontaneous thyroid cancers. The prevalence of DNA gains in tumors from cases in exposed individuals was two- to fourfold higher than for cases in unexposed individuals and up to 10-fold higher for the subset of recurrent gains. DNA losses for all cases were low and more prevalent in spontaneous cases. We identified unique patterns of copy variation (mostly gains) that depended on a history of radiation exposure. Exposed cases, especially the young, harbored more recurrent gains that covered more of the genome. The largest regions, spanning 1.2 to 4.9 Mbp, were located at 1p36.32-.33, 2p23.2-.3, 3p21.1-.31, 6p22.1-.2, 7q36.1, 8q24.3, 9q34.11, 9q34.3, 11p15.5, 11q13.2-12.3, 14q32.33, 16p13.3, 16p11.2, 16q21-q12.2, 17q25.1, 19p13.31-qter, 22q11.21 and 22q13.2. Copy number changes, particularly gains, in post-Chernobyl thyroid cancer are influenced by radiation exposure and age at exposure, in addition to the neoplastic process.

Segmental Jumping Translocation of Ret Oncogene in Radiation-associated Thyroid Cancer

Segmental Jumping Translocation of Ret Oncogene in Radiation-associated Thyroid Cancer

Investigation of Loss of Heterozygosity and SNP Frequencies in the RET Gene in Papillary Thyroid Carcinoma

In both medullary carcinoma and papillary carcinoma of the thyroid, altered expression of the RET gene is implicated in tumorigenesis. Recent studies suggest that loss of heterozygosity (LOH) at the G691S SNP may be associated with tumors from patients with a history of radiation exposure. We investigated LOH for three RET SNPs (G691S, S904S, and L769L) in tumor and normal tissue from 46 patients from Ukraine and Belarus who were exposed to radioactive fallout following the Chernobyl nuclear accident and were operated for papillary thyroid carcinoma between 1995 and 2000. Normal tissue from 28 patients was heterozygous for at least one SNP; DNA from the corresponding tumor samples was also heterozygous, indicating that no LOH had taken place. To assess SNP frequencies in a radiation-associated thyroid cancer cohort, we investigated a further 68 unpaired post-Chernobyl samples. For G691S, there was considerable deviation from Hardy-Weinberg equilibrium; more detailed analysis showed that this was linked to age at onset of disease. Among younger patients, the distribution of genotypes conformed to Hardy-Weinberg equilibrium; among older patients, we observed marked deviation (p = 0.0072), with significant over-representation of the rare S allele relative to the younger groups (Fisher's exact, p = 0.0233). This suggests that SNPs in the RET oncogene may play a role in sporadic papillary thyroid carcinoma.

The Chernobyl accident and its consequences: Update at the millennium

A marked increase in the incidence of papillary thyroid cancer in children has been documented in regions of the former Soviet Union most heavily contaminated by radioactive fallout from the Chernobyl nuclear power plant accident in April 1986. Accumulation of radioactive iodines by normal iodine trapping mechanisms resulted in significant radiation doses to the thyroid gland. Although it has long been known that thyroidal radiation resulted in nuclear and chromosomal abnormalities visible by light microscopy, modern molecular biology techniques are beginning to identify much smaller alterations in chromosomal coding sequences that are associated with malignant transformation. Although stable chromosomal abnormalities can be detected in Chernobyl-associated thyroid cancers, they are much less prevalent than in thyroid cancers developing after external beam irradiation. However, several unique chromosomal breakpoints have been described in radiation-associated thyroid cancers that are not commonly found in spontaneously occurring thyroid cancer. Furthermore, activation of specific subtypes of the ret/PTC tyrosine kinase oncogene appears to be more common in radiation-associated thyroid cancers than in spontaneous thyroid cancers. In summary, thyroid cancers developing in the aftermath of the Chernobyl accident provide a unique opportunity to search for chromosomal abnormalities that may be specific for radiation-induced thyroid cancer.

Radiation-Associated Thyroid Cancer - Facts and Fiction

Thyroid cancer is a rare and complex disease and the thyroid contains various cell types from which specific diseases arise. The malignancies range from indolent to extremely aggressive. Several risk factors for thyroid cancers have been suggested, but only ionizing radiation has been found to have a causative effect. With the exception of tobacco, ionizing radiation is probably the most studied carcinogen there is. It is not yet possible to determine whether or not a specific cancer was induced by radiation and epidemiological studies therefore provide the primary data on cancer risk in man after exposure to ionizing radiation. The current epidemiological knowledge on radiation-associated thyroid cancer is reviewed, focusing on the sharply increased risks recently found among children in the Chernobyl area.

9 Radiation associated thyroid cancer: Katsutaro Shimaoka, M.D. Radiation Effects Research Foundation, Nagasaki, Japan

9 Radiation associated thyroid cancer: Katsutaro Shimaoka, M.D. Radiation Effects Research Foundation, Nagasaki, Japan

Association of differentiated thyroid carcinoma with HLA-DR7.

Seventy-four American white thyroid cancer patients were typed for HLA-A, B, and DR antigens. A significant increase in HLA-DR7 was found in the nonradiation-associated thyroid cancer patients (42.5%, 20/47 cases), compared to 22.8% of 979 normal controls. The association is stronger in the follicular and mixed papillary-follicular subgroup (52.0%, 13/25 cases, P corrected less than 0.01). The occurrence of various malignancies in family members was found in 57.9% of HLA-DR7 positive patients, versus 20% of HLA-DR7 negative patients, in a retrospective record review. Although the frequency of HLA-DR7 was not increased in the radiation-associated thyroid cancer patients (22.2%, 6/27 cases), the interval from the irradiation date to the onset date of thyroid cancer was shorter in HLA-DR7 positive cases (17.3 +/- 6.2 years) than in HLA-DR7 negative patients (29.4 +/- 11.5 years). This data suggest that HLA-DR7 is associated with and may influence development of thyroid cancer.

Natural History of Radiation-Associated Thyroid Cancer

The clinical courses of 91 patients with radiation-associated thyroid cancer were compared with courses in a control population. Radiation-associated carcinoma appears to be a disease of younger persons, and 90% of the tumors are papillary. No anaplastic or medullary tumors were observed. Ninety percent of the tumors were larger than those found in an autopsy series that surveyed for "biologically benign" thyroid tumors. There was a higher incidence of multicentric disease, locally invasive disease, and distant metastases in the population that had had x-ray exposure. Although the population with x-ray exposure had had more aggressive treatment, more recurrences were present in patients who had had radiation therapy. The death rate was similar in both groups. Parathyroid adenoma occurred more frequently in the population that had radiation exposure than in controls and appears to be a radiation-associated illness.

Natural history of radiation-associated thyroid cancer

Natural history of radiation-associated thyroid cancer