Radiation-related genomic profile of papillary thyroid carcinoma after the Chernobyl accident
Genomics of radiation-induced damage
The potential adverse effects of exposures to radioactivity from nuclear accidents can include acute consequences such as radiation sickness, as well as long-term sequelae such as increased risk of cancer. There have been a few studies examining transgenerational risks of radiation exposure but the results have been inconclusive. Morton et al. analyzed papillary thyroid tumors, normal thyroid tissue, and blood from hundreds of survivors of the Chernobyl nuclear accident and compared them against those of unexposed patients. The findings offer insight into the process of radiation-induced carcinogenesis and characteristic patterns of DNA damage associated with environmental radiation exposure. In a separate study, Yeager et al. analyzed the genomes of 130 children and parents from families in which one or both parents had experienced gonadal radiation exposure related to the Chernobyl accident and the children were conceived between 1987 and 2002. Reassuringly, the authors did not find an increase in new germline mutations in this population.
Structured Abstract
INTRODUCTION
The 1986 Chernobyl (Chornobyl in Ukrainian) nuclear power plant accident exposed millions of individuals in the surrounding region to radioactive contaminants, resulting in increased papillary thyroid carcinoma (PTC) incidence in radioactive iodine (131I)–exposed children. Currently, no reliable biomarkers for radiation-induced cancers have been identified, and large-scale genomic characterizations of human tumors after radiation exposure are lacking.
RATIONALE
To investigate the contribution of environmental radiation to the genomic characteristics of PTC and gain further insight into radiation-induced carcinogenesis, we analyzed 440 pathologically confirmed fresh-frozen PTCs from Ukraine (359 with estimated childhood or in utero 131I exposure, 81 from unexposed children born after March 1987; mean age at PTC = 28.0 years, range 10.0 to 45.6) and matched normal tissue (nontumor thyroid tissue and/or blood). Our genomic characterization included whole-genome, mRNA, and microRNA sequencing; DNA methylation profiling; and genotyping arrays.
RESULTS
The mean estimated radiation dose among 131I-exposed individuals was 250 mGy (range, 11.0 to 8800). In multivariable models adjusted for age at PTC and sex, we observed radiation dose–dependent increases in small deletions (P = 8.0 × 10–9) and simple/balanced structural variants (P = 1.2 × 10–14) but no association with single-nucleotide variants or insertions. Further analyses demonstrated stronger radiation-related associations for clonal—but not subclonal—small deletions and simple/balanced structural variants that bore hallmarks of nonhomologous end-joining repair (deletions, P = 4.9 × 10–31; simple/balanced structural variants, P = 5.5 × 10–19). In contrast, radiation dose was not associated with locally templated insertions characteristic of alternative end-joining repair.
Candidate drivers were identified for 433 tumors (98.4%), of which 401 had only a single candidate driver, illustrating the parsimonious nature of PTC carcinogenesis. More than half of the drivers (n = 253) were mutations, occurring commonly (n = 194) in BRAF. Fusions accounted for the remaining drivers, frequently involving RET (n = 73) or other receptor tyrosine kinase genes (n = 64). In total, 401 PTCs had drivers in the mitogen-activated protein kinase (MAPK) pathway. In multivariable models adjusted for age at PTC and sex, we observed radiation dose–dependent enrichment of fusion versus mutation drivers (P = 6.6 × 10–8), whereas the radiation dose distribution did not differ substantially by driver.
The effects of radiation on genomic alterations (fusion drivers, deletions, or structural variants) were more pronounced for individuals who were younger at exposure. Analyses were consistent with a linear dose response for most radiation-associated molecular characteristics. Individuals with PTC who were unexposed to 131I or had lower doses had higher genetic risk (P = 4.7 × 10–4) according to a 12-locus polygenic risk score. Analyses of transcriptomic and epigenomic features demonstrated strong associations with the PTC driver gene but not with radiation dose.
CONCLUSION
Our large-scale integrated genomic landscape analysis of PTCs after the Chernobyl accident with detailed dose estimation points to DNA double-strand breaks as early carcinogenic events that subsequently enable PTC growth after environmental radiation exposure. Tumor epigenomic and transcriptomic profiles reflected the PTC driver and did not identify a reliable set of biomarkers for radiation-induced carcinogenesis. Nonhomologous end-joining was consistently implicated as the key repair mechanism for the observed radiation dose–associated DNA double-strand breaks, leading to more fusion drivers as a result of increasing radiation dose. Linear increases in radiation-associated damage, especially for exposure at younger ages, underscore the potential deleterious consequences of ionizing radiation exposure.
Genomic profiling of post-Chernobyl thyroid cancers reveals clonal DNA double-strand breaks repaired by nonhomologous end-joining.
Radioactive iodine deposited on surrounding pastures after the Chernobyl nuclear power plant explosion increased thyroid cancer risk, particularly for childhood exposure. Comprehensive genomic profiling of post-Chernobyl thyroid tumors revealed radiation dose–dependent increases in clonal DNA double-strand breaks but no dose relationship with transcriptomic or epigenomic characteristics, highlighting environmental radiation exposure as an early carcinogenic event.
Abstract
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.
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Supplementary Material
Summary
Materials and Methods
Figs. S1 to S32
Tables S1 to S22
Data S1 to S3
MDAR Reproducibility Checklist
Resources
File (pap.pdf)
File (abg2538-data-dictionary.pdf)
File (abg2538-data-s1.txt)
File (abg2538-data-s2.zip)
File (abg2538-data-s3.txt)
File (abg2538-tables-s13-s14-s17.xlsx)
File (abg2538_morton_sm.pdf)
File (abg2538_reproducibility-checklist.pdf)
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Volume 372 • Issue 6543 • 14 May 2021
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Received: 22 December 2020
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22 April 2021
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http://dx.doi.org/10.13039/100000054National Cancer Institute: U24CA082102
RE: Genomic profile of papillary thyroid carcinoma after the Chernobyl accident
A tendency to overestimate health risks from low doses of ionizing radiation has been discussed previously [1-5]. Apparently, certain scientists exaggerating medical and ecological consequences of the anthropogenic increase in the radiation background contribute to a strangulation of the atomic energy, which would agree with the interests of fossil fuel producers. Nuclear power has returned to the agenda because of the concerns about increasing global energy demand and climate changes. Health burdens are greatest for power stations based on lignite, coal, and oil. The health burdens are smaller for natural gas and still lower for nuclear power. The same ranking applies also to the greenhouse gas emissions and thus probably to climate changes [6].
The research [7] makes a comparison between 359 papillary thyroid cancers (TCs) from patients who underwent radiation exposure from the Chernobyl accident (CA) and the control group - TCs from 81 patients born >9 months after CA. The "study population included a substantial number of papillary TCs occurring after <100 mGy", where development of radiogenic cancers from 131I exposure would be improbable [3]. In fact, doses <100 mGy at low rates may induce adaptive response against neoplastic transformation [8]. As discussed previously [2-5], the distinction between the "exposed" and control groups can be caused not by radiation but by the difference, on average, in the tumor grade. The incidence of TC among people younger than 15 years in the North of Ukraine (overlapping with the contaminated area) was reported to be 0.1 and in Belarus - 0.3 cases/million/year from 1981 through 1985 [9]. The detection rate of pediatric TC in the former Soviet Union prior to CA was lower than in other developed countries [4,10]. This indicates that there were undiagnosed cases in the population. Neglected cancers, detected by the screening and improved diagnostics, self-reported in conditions of increased public awareness after CA, or brought from other areas and registered as Chernobyl victims, were misinterpreted as rapidly growing radiogenic malignancies [2-5]. Some people were eager to be recognized as Chernobyl victims to gain access to health care provisions [11]. Cases from non-contaminated areas must have been averagely more advanced as there was no extensive screening there. Pediatric TCs found during first 10 years after CA were described as relatively aggressive, invasive and metastatic [12]. The proposed "aggressivity" apparently resulted from the detection of old neglected malignancies, interpreted as radiogenic tumors with the "rapid onset and aggressive development" [13]. The screening detected not only small nodules but also advanced TC, neglected because of the incomplete coverage of the population by medical checkups prior to CA. This predictable phenomenon was confirmed by the fact that the "first wave" TCs after CA were on average larger and higher-grade than those diagnosed later [14]. In this connection, the following phrase should be commented: "… the increased detection of pre-existing papillary TCs in the population that may not become clinically evident until later, if at all, due to intensive screening and heightened awareness of thyroid cancer risk in Ukraine" [7]. This concept has been propagated since 2011 and earlier [1-5]. As for individuals born after CA (the control group in [7]), the data pertaining to them originated from a later period, when the quality of diagnostics improved while the reservoir of advanced neglected cancers was largely exhausted by the screening. Therefore, the average stage and grade of TCs in the exposed group must have been higher than among the controls in [7].
As discussed previously, certain molecular-genetic characteristics of post-Chernobyl TCs are probably associated with a later stage of the tumor progression [2-5]. The study under discussion reported "…radiation dose-related increases in DNA double-strand breaks in human TCs developing after the CA… Non-homologous end-joining (NHEJ) [was] the most important repair mechanism… increased likelihood of fusion versus point mutation drivers" etc. [7]. These findings are not surprising: the DNA damage tends to accumulate along with the tumor progression. Double-strand breaks with error-prone repair drive genome diversity in cancer cells [15]. The NHEJ repair pathway is potentially mutagenic [16]. Some aberrant gene fusions drive the tumor progression as well [17]. At the same time, no association of the radiation dose with transcriptomic and epigenomic features was found [7]. This indicates that some transcriptomic and epigenomic markers are to a lesser extent associated with the neoplastic progression than the DNA lesions. The causative role of low-dose radiation e.g. "a dose-dependent carcinogenic effect of radiation derived primarily from DNA double-strand breaks" [7] is in fact unproven. The authors should think about re-interpretation of their valuable results. Associations of certain markers with the tumor progression (disease duration, tumor size, stage and grade, metastases etc.) are a potential field for the future research and re-interpretation of the data already obtained. The medical surveillance of populations exposed to low-dose radiation is important; but more consideration should be given to potential bias e.g. screening effect, dose-dependent selection and self-selection discussed in [2,3]. It can be reasonably assumed that the screening effect and increased attention of exposed people to their own health will result in new reports on the elevated cancer and other health risks in the areas with enhanced natural and anthropogenic radiation background. In the author's opinion, the epidemiological research of populations exposed to the Chernobyl fallout would hardly add much reliable information, among others, because of inexact dose reconstructions and probable registration of unexposed individuals as exposed. "Uncertainties in radiation dose estimates" were acknowledged in [7]. Indeed, "for 53 individuals, doses were estimated using detailed information derived from individual direct thyroid radioactivity measurements taken within 8 weeks of the accident" [7], whereas the half-life of 131I is ~8 days. Furthermore, dose-effect correlations can be explained by a recall bias: it is known that patients with TC tend to recollect circumstances related to radiation exposures better than healthy people [18]. It can be reasonably assumed that patients with advanced cancers would recollect such circumstances better than practically healthy individuals having small nodules. The higher the average dose estimate and/or radiocontamination in the area of residence, the greater would be the probability to undergo the screening. Apparently, some non-radiation-related features of post-Chernobyl TC are more prevalent in populations with higher average dose estimates. One of such features is the relatively high percentage of advanced neglected cancers detected after CA and misinterpreted as aggressive radiogenic malignancies [2-5].
In conclusion, some dose-effect correlations discussed in [7] and elsewhere can be explained by mechanisms unrelated to radiation. A promising approach to the study of dose-response relationships are lifelong animal experiments. The life duration is known to be a sensitive endpoint attributable to radiation exposures [19] that can reveal the net harm or potential benefit (within a certain range according to the concept of hormesis [20]) from low-dose exposures. Last but not least, the suppositions about enhanced aggressiveness of cancers from radiocontaminated areas may be conductive to the overtreatment [5,21,22].
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