Papillary Thyroid Carcinoma in Ukraine After Chernobyl and in Japan After Fukushima: Different Histopathological Scenarios

Bogdanova, Tetiana; Saenko, Vladimir; Hashimoto, Yuko; Hirokawa, Mitsuyoshi; Zurnadzhy, Liudmyla; Hayashi, Toshitetsu; Ito, Masahiro; Iwadate, Manabu; Mitsutake, Norisato; Rogounovitch, Tatiana; Sakamoto, Atsuhiko; Naganuma, Hiroshi; Miyauchi, Akira; Тronko, М.D.; Thomas, Geraldine; Yamashita, Shunichi; Suzuki, Shinichi

doi:10.1089/thy.2020.0308

Cited by 19 publications

(22 citation statements)

References 37 publications

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“…The relationship of a number of molecular characteristics, particularly total mutational burden and driver type, with age at PTC warrants further investigation across a broader age range (10). Additional research with detailed dose data are needed to understand whether our findings extend across a broader dose range, to other types of radiation, as well as to other tumor types, and whether radiation-related genomic characteristics have an impact on histopathological parameters (46)(47)(48). It has been hypothesized that ionizing radiation exposure could accelerate tumor development, and substantial evidence demonstrates that cancer survivors exposed to high-dose radiotherapy exhibit an aging phenotype (36,37).…”

Section: Discussionmentioning

confidence: 91%

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

Morton

Karyadi

Stewart

et al. 2021

Science

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108

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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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Section: Discussionmentioning

confidence: 91%

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

Morton

Karyadi

Stewart

et al. 2021

Science

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108

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“…In addition to conventional clinicopathological characteristics, we introduced a synthetic variable termed "invasiveness score". The invasiveness score is the arithmetic sum of every instance of N1, M1, intrathyroid spread, extrathyroidal extension, multifocality or lymphatic/vascular invasion (encoded 0 for the absence and 1 for the presence of a given feature in a given tumor), either isolated or in combination with other(s), for each tumor [56]. Thus defined, the invasiveness score ranged from 0 to 4; the latter was the maximum observed in this childhood PTC series.…”

Section: Discussionmentioning

confidence: 98%

Major Oncogenic Drivers and Their Clinicopathological Correlations in Sporadic Childhood Papillary Thyroid Carcinoma in Belarus

Rogounovitch

Mankovskaya

Fridman

et al. 2021

Cancers

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Childhood papillary thyroid carcinoma (PTC) diagnosed after the Chernobyl accident in Belarus displayed a high frequency of gene rearrangements and low frequency of point mutations. Since 2001, only sporadic thyroid cancer occurs in children aged up to 14 years but its molecular characteristics have not been reported. Here, we determine the major oncogenic events in PTC from non-exposed Belarusian children and assess their clinicopathological correlations. Among the 34 tumors, 23 (67.6%) harbored one of the mutually exclusive oncogenes: 5 (14.7%) BRAFV600E, 4 (11.8%) RET/PTC1, 6 (17.6%) RET/PTC3, 2 (5.9%) rare fusion genes, and 6 (17.6%) ETV6ex4/NTRK3. No mutations in codons 12, 13, and 61 of K-, N- and H-RAS, BRAFK601E, or ETV6ex5/NTRK3 or AKAP9/BRAF were detected. Fusion genes were significantly more frequent than BRAFV600E (p = 0.002). Clinicopathologically, RET/PTC3 was associated with solid growth pattern and higher tumor aggressiveness, BRAFV600E and RET/PTC1 with classic papillary morphology and mild clinical phenotype, and ETV6ex4/NTRK3 with follicular-patterned PTC and reduced aggressiveness. The spectrum of driver mutations in sporadic childhood PTC in Belarus largely parallels that in Chernobyl PTC, yet the frequencies of some oncogenes may likely differ from those in the early-onset Chernobyl PTC; clinicopathological features correlate with the oncogene type.

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“…The relationship of a number of molecular characteristics, particularly total mutational burden and driver type, with age at PTC warrants further investigation across a broader age range (10). Additional research with detailed dose data is needed to understand whether our findings extend across a broader dose range, to other types of radiation, as well as to other tumor types, and whether radiation-related genomic characteristics have an impact on histopathological parameters (46)(47)(48). It has been hypothesized that ionizing radiation exposure could accelerate tumor development, and substantial evidence demonstrates that cancer survivors exposed to high-dose radiotherapy exhibit an aging phenotype (36,37).…”

Section: Discussionmentioning

confidence: 92%

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

Lm¹,

Dm²,

Stewart³

et al. 2021

ESPE

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The 1986 Chernobyl nuclear power plant accident increased papillary thyroid cancer (PTC) incidence in surrounding regions, particularly for 131 I-exposed children. We analyzed genomic, transcriptomic, and epigenomic characteristics of 440 PTCs from Ukraine (359 with estimated childhood 131 I exposure and 81 unexposed children born after 1986). PTCs displayed radiation 5 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 non-homologous end-joining repair. Radiation-related genomic alterations were more pronounced for those younger at exposure. Transcriptomic and epigenomic features were strongly associated with driver events but not radiation dose. Our results point to 10 DNA double-strand breaks as early carcinogenic events that subsequently enable PTC growth following environmental radiation exposure.1The accidental explosion in reactor 4 at the Chernobyl nuclear power plant in April 1986 resulted in the exposure of millions of inhabitants of the surrounding areas of Ukraine, Belarus, and the Russian Federation to radioactive contaminants (1). Epidemiologic and clinical research in the ensuing decades has demonstrated increased risk of papillary thyroid carcinoma (PTC) with increasing thyroid gland exposure to radioactive iodine ( 131 I) from fallout, which was deposited on pastures with grazing cows and ingested through milk, particularly during early childhood (2). Together with data from populations exposed to other types of radiation, compelling evidence indicates that PTC risk increases following childhood exposure to ionizing radiation, a recognized carcinogen (2-5).Currently, there are no established molecular biomarkers for cancers induced by radiation, nor have there been large-scale analyses of the genomic landscape of human cancers occurring after a well-quantified radiation exposure. Classical cytogenetic studies have demonstrated radiation dose-associated increases in large chromosomal aberrations (such as inversions and translocations) that reflect DNA double-strand breaks and are the current standard for biodosimetry; however, these assays are typically performed in peripheral blood lymphocytes from individuals exposed to whole body irradiation and have not been directly linked to tumor characteristics (6, 7). Next-generation sequencing of 12 second primary tumors of various types that occurred within the field of previous therapeutic ionizing radiation suggested an excess of small deletions and balanced inversions (8), but radiation dose estimates were not available.RNA sequencing (RNA-seq) analyses of 65 PTCs (mean age at diagnosis=24.7 years) occurring after the Chernobyl accident identified that higher doses were associated with an increased likelihood of gene fusion drivers (9). In a genomic landscape analysis of 496 primarily unexposed PTCs (mean age at diagnosis=46.8 years; 16 patients with known prior radiation 2 exposure),...

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Papillary Thyroid Carcinoma in Ukraine After Chernobyl and in Japan After Fukushima: Different Histopathological Scenarios

Cited by 19 publications

References 37 publications

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

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

Major Oncogenic Drivers and Their Clinicopathological Correlations in Sporadic Childhood Papillary Thyroid Carcinoma in Belarus

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

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