Research Article

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

See allHide authors and affiliations

Science  14 May 2021:
Vol. 372, Issue 6543, eabg2538
DOI: 10.1126/science.abg2538

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

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.

Science, this issue p. eabg2538, p. 725

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.

View Full Text

Stay Connected to Science