Newly discovered genomic mutation patterns in radiation-induced small intestinal tumors of ApcMin/+ mice.

Among the small intestinal tumors that occur in irradiated mice of the established mouse model B6/B6-Chr18MSM-F1 ApcMin/+, loss of heterozygosity analysis can be utilized to estimate whether a deletion in the wild-type allele containing the Adenomatous polyposis coli (Apc) region (hereafter referred to as Deletion), a duplication in the mutant allele with a nonsense mutation at codon 850 of Apc (Duplication), or no aberration (Unidentified) has occurred. Previous research has revealed that the number of Unidentified tumors tends to increase with the radiation dose. In the present study, we investigated the molecular mechanisms underlying the development of an Unidentified tumor type in response to radiation exposure. The mRNA expression levels of Apc were significantly lower in Unidentified tumors than in normal tissues. We focused on epigenetic suppression as the mechanism underlying this decreased expression; however, hypermethylation of the Apc promoter region was not observed. To investigate whether deletions occur that cannot be captured by loss of heterozygosity analysis, we analyzed chromosome 18 using a customized array comparative genomic hybridization approach designed to detect copy-number changes in chromosome 18. However, the copy number of the Apc region was not altered in Unidentified tumors. Finally, gene mutation analysis of the Apc region using next-generation sequencing suggested the existence of a small deletion (approximately 3.5 kbp) in an Unidentified tumor from a mouse in the irradiated group. Furthermore, nonsense and frameshift mutations in Apc were found in approximately 30% of the Unidentified tumors analyzed. These results suggest that radiation-induced Unidentified tumors arise mainly due to decreased Apc expression of an unknown regulatory mechanism that does not depend on promoter hypermethylation, and that some tumors may result from nonsense mutations which are as-yet undefined point mutations.

Background radiation and cancer risks: A major intellectual confrontation within the domain of radiation genetics with multiple converging biological disciplines.

This paper assesses the judgments of leading radiation geneticists and cancer risk assessment scientists from the mid-1950s to mid-1970s that background radiation has a significant effect on human genetic disease and cancer incidence. This assumption was adopted by the National Academy of Sciences (NAS) Biological Effects of Atomic Radiation (BEAR) I Genetics Panel for genetic diseases and subsequently applied to cancer risk assessment by other leading individuals/advisory groups (e.g., International Commission on Radiation Protection-ICRP). These recommendations assumed that a sizeable proportion of human mutations originated from background radiation due to cumulative exposure over prolonged reproductive periods and the linear nature of the dose-response. This paper shows that the assumption that background radiation is a significant cause of spontaneous mutation, genetic diseases, and cancer incidence is not supported by experimental and epidemiological findings, and discredits erroneous risk assessments that improperly influenced the recommendations of national and international advisory committees, risk assessment policies, and beliefs worldwide.

Contemporary diagnostic approach to atypical vascular lesion and angiosarcoma.

Vascular neoplasms account for a substantial fraction of cutaneous mesenchymal tumors, spanning from clinically indolent benign lesions to highly aggressive malignancies. These neoplasms present a distinctive challenge in terms of their diagnostic histopathology, both because of the breadth of their morphological manifestations and because of the significant histological overlap between different entities, even benign and malignant ones. The post-radiotherapy setting is particularly problematic diagnostically, insofar as radiation exposure predisposes not only to secondary angiosarcoma, but also to atypical vascular lesion, a largely benign proliferation of cutaneous blood vessels typically affecting the breast. To address these challenges, we explore the clinical, histological, and molecular features of malignant vascular neoplasia, including primary and secondary subtypes, through the comparative lens of atypical vascular lesion. In addition to highlighting the key morphological indicators of malignancy in superficial vasoformative tumors, we offer an approach that integrates clinical characteristics and molecular genetic profiling to facilitate accurate classification. With this current knowledge as our foundation, we also look ahead in an effort to frame some of the key unanswered questions regarding superficial vascular malignancies and their natural history, clinical management, and molecular underpinnings.

Interstitial deletion of the Apc locus in ß-catenin-overexpressing cells is a signature of radiation-induced intestinal tumors in C3B6F1 ApcMin/+ mice†.

Recent studies have identified interstitial deletions in the cancer genome as a radiation-related mutational signature, although most of them do not fall on cancer driver genes. Pioneering studies in the field have indicated the presence of loss of heterozygosity (LOH) spanning Apc in a subset of sporadic and radiation-induced intestinal tumors of ApcMin/+ mice, albeit with a substantial subset in which LOH was not detected; whether copy number losses accompany such LOH has also been unclear. Herein, we analyzed intestinal tumors of C3B6F1 ApcMin/+ mice that were either left untreated or irradiated with 2 Gy of γ-rays. We observed intratumor mosaicism with respect to the nuclear/cytoplasmic accumulation of immunohistochemically detectable ß-catenin, which is a hallmark of Apc+ allele loss. An immunoguided laser microdissection approach enabled the detection of LOH involving the Apc+ allele in ß-catenin-overexpressing cells; in contrast, the LOH was not observed in the non-overexpressing cells. With this improvement, LOH involving Apc+ was detected in all 22 tumors analyzed, in contrast to what has been reported previously. The use of a formalin-free fixative facilitated the LOH and microarray-based DNA copy number analyses, enabling the classification of the aberrations as nondisjunction/mitotic recombination type or interstitial deletion type. Of note, the latter was observed only in radiation-induced tumors (nonirradiated, 0 of 8; irradiated, 11 of 14). Thus, an analysis considering intratumor heterogeneity identifies interstitial deletion involving the Apc+ allele as a causative radiation-related event in intestinal tumors of ApcMin/+ mice, providing an accurate approach for attributing individual tumors to radiation exposure.

Preleukemic Fusion Genes Induced via Ionizing Radiation.

Although the prevalence of leukemia is increasing, the agents responsible for this increase are not definitely known. While ionizing radiation (IR) was classified as a group one carcinogen by the IARC, the IR-induced cancers, including leukemia, are indistinguishable from those that are caused by other factors, so the risk estimation relies on epidemiological data. Several epidemiological studies on atomic bomb survivors and persons undergoing IR exposure during medical investigations or radiotherapy showed an association between radiation and leukemia. IR is also known to induce chromosomal translocations. Specific chromosomal translocations resulting in preleukemic fusion genes (PFGs) are generally accepted to be the first hit in the onset of many leukemias. Several studies indicated that incidence of PFGs in healthy newborns is up to 100-times higher than childhood leukemia with the same chromosomal aberrations. Because of this fact, it has been suggested that PFGs are not able to induce leukemia alone, but secondary mutations are necessary. PFGs also have to occur in specific cell populations of hematopoetic stem cells with higher leukemogenic potential. In this review, we describe the connection between IR, PFGs, and cancer, focusing on recurrent PFGs where an association with IR has been established.

Establishment and characterization of the first patient-derived radiation-induced angiosarcoma xenograft model (RT-AS5).

Angiosarcomas are a heterogeneous group of rare endothelial malignancies with a complex, not completely unravelled biology. They encompass primary (sporadically occurring) angiosarcomas of several origins and secondary angiosarcomas, which often arise due to DNA damaging factors including radiotherapy or ultraviolet light exposure. The optimal treatment of metastatic angiosarcomas is unclear and the prognosis is poor. In order to discover novel treatment strategies for angiosarcomas it is important to take the heterogeneity of these tumors into account. For this reason it is also important to have preclinical models available for the different clinical subtypes. Owing to the rarity of angiosarcomas, models are scarce. So far, only five human cell lines of angiosarcomas (all of the scalp after UV exposure) are available worldwide. In this paper we describe a novel established patient-derived xenograft model of a radiotherapy-induced angiosarcoma of the breast. The tumor was characterized by a MYC amplification, CD31 and ERG immunohistochemical positivity and was further characterized by using next generation sequencing (TruSight Oncology 500) in combination with the R-package XenofilteR to separate mouse from human sequence reads.

The Gofman-Tamplin Cancer Risk Controversy and Its Impact on the Creation of BEIR I and the Acceptance of LNT.

BACKGROUND:  The major public dispute between John Gofman and his colleague Arthur Tamplin and the United States (US) Atomic Energy Commission (AEC) at the end of the 1960s and during the early 1970s significantly impacted the course of cancer risk assessment in the US and worldwide. The challenging and provocative testimony of Gofman to the US Senate in early 1970 lead to the formation of the US National Academy of Sciences (NAS) Biological Effects of Ionizing Radiation (BEIR) I Committee in order to evaluate the accuracy of claims by Gofman and Tamplin that emissions from nuclear power plants would significantly increase the occurrence of genetic defects and cancers. BEIR I recommended the adoption of the linear non-threshold (LNT) dose response model for the assessment of cancer risks from radiation exposures. The US EPA adopted this recommendation and generalized it to incorporate chemical carcinogens, thereby affecting cancer risk assessments over the next decades. Despite the scientific limitations and ideological framework of their perspectives, Gofman and Tamplin are of considerable historical importance since they had essential roles in affecting the adoption of LNT by regulatory agencies.

Calorie restriction alters the mechanisms of radiation-induced mouse thymic lymphomagenesis.

Calorie restriction (CR) suppresses not only spontaneous but also chemical- and radiation-induced carcinogenesis. Our previous study revealed that the cancer-preventive effect of CR is tissue dependent and that CR does not effectively prevent the development of thymic lymphoma (TL). We investigated the association between CR and the genomic alterations of resulting TLs to clarify the underlying resistance mechanism. TLs were obtained from previous and new experiments, in which B6C3F1 mice were exposed to radiation at 1 week of age and fed with a CR or standard (non-CR) diet from 7 weeks throughout their lifetimes. All available TLs were used for analysis of genomic DNA. In contrast to the TLs of the non-CR group, those of the CR group displayed suppression of copy-neutral loss of heterozygosity (LOH) involving relevant tumor suppressor genes (Cdkn2a, Ikzf1, Trp53, Pten), an event regarded as cell division-associated. However, CR did not affect interstitial deletions of those genes, which were observed in both groups. In addition, CR affected the mechanism of Ikzf1 inactivation in TLs: the non-CR group exhibited copy-neutral LOH with duplicated inactive alleles, whereas the CR group showed expression of dominant-negative isoforms accompanying a point mutation or an intragenic deletion. These results suggest that, even though CR reduces cell division-related genomic rearrangements by suppressing cell proliferation, tumors arise via diverse carcinogenic pathways including inactivation of tumor suppressors via interstitial deletions and other mutations. These findings provide a molecular basis for improved prevention strategies that overcome the CR resistance of lymphomagenesis.

Radiation-induced sarcoma of head and neck: Clinical characteristics and molecular signatures.

BACKGROUND: Radiation-induced sarcoma of the head and neck (RISHN) is a rare yet devastating potential complication of radiotherapy treatment. We aimed to evaluate the clinicopathological characteristics and molecular signatures of RISHN in patients who underwent radiotherapy for head and neck cancer (HNC) to identify high-risk patients and enable earlier cancer detection. METHODS: This study retrospectively evaluated 24 sarcoma patients who received radiotherapy for HNC between 1994 and 2019. Patients were divided into two groups based on RISHN latency period. Patient demographics, initial tumor staging, risk factors, and survival between groups were analyzed, and whole-exome sequencing (WES) of selected samples was performed. RESULTS: The median age at diagnosis of RISHN was 54 years, and the male-to-female ratio was 2:1. The latency period ranged from 0.8 to 64.4 years (median 6.5 years), with a median survival of 21.5 months. Primary cancer in the oral cavity, treatment with alkylating agents, alcohol consumption, betel nut chewing, and smoking were identified as risk factors for short (<5 years) latency periods. The majority of RISHN cases occurred in the oral cavity (58.3%). WES analysis showed that tumor necrosis factor and cell cycle checkpoint pathways were differentially involved in both patient groups. CONCLUSIONS: Although case numbers were small, our cohort represents the largest case series of RISHN from a single institution to date. Clinicians must be aware of factors affecting RISHN development and latency, and risk factor identification may lead to earlier detection and prevention in the future.

Heavy-ion radiation-induced colitis and colorectal carcinogenesis in Il10-/- mice display co-activation of ß-catenin and NF-κB signaling.

Space radiation-induced gastrointestinal (GI) cancer risk models for future interplanetary astronauts are being developed that primarily rely on quantitative animal model studies to assess radiation-quality effects of heavy-ion space radiation exposure in relation to γ-rays. While current GI-cancer risk estimation efforts are focused on sporadic GI-cancer mouse models, emerging in-vivo data on heavy-ion radiation-induced long-term GI-inflammation are indicative of a higher but undetermined risk of GI-inflammation associated cancers, such as colitis-associated cancer (CAC). Therefore, we aimed to assess radiation quality effects on colonic inflammation, colon cancer incidence, and associated signaling events using an in-vivo CAC model i.e., Il10-/- mice. Male Il10-/- mice (8-10 weeks, n = 12/group) were irradiated with either sham, γ-rays or heavy-ions (28Si or 56Fe), and histopathological assessments for colitis and CAC were conducted at 2.5 months post-exposure. qPCR analysis for inflammation associated gene transcripts (Ptges and Tgfb1), and in-situ staining for markers of cell-proliferation (phospho-histone H3), oncogenesis (active-ß-catenin, and cyclin D1), and inflammation (phospho-p65NF-κB, iNOS, and COX2) were performed. Significantly higher colitis and CAC frequency were noted after heavy-ion exposure, relative to γ and control mice. Higher CAC incidence after heavy-ion exposure was associated with greater activation of ß-catenin and NF-κB signaling marked by induced expression of common downstream inflammatory (iNOS and COX2) and pro-proliferative (Cyclin D1) targets. In summary, IR-induced colitis and CAC incidence in Il10-/- mice depends on radiation quality and display co-activation of ß-catenin and NF-κB signaling.

Lung-Cancer Risk in Mice after Exposure to Gamma Rays, Carbon Ions or Neutrons: Egfr Pathway Activation and Frequent Nuclear Abnormality.

Lung is one of the high-risk organs for radiation-induced carcinogenesis, but the risk of secondary lung-cancer development after particle-beam therapy and the underlying mechanism(s) remain to be elucidated. To investigate the effects of particle-beam radiation on adjacent normal tissues during cancer therapy, 7-week-old male and female B6C3F1 mice were irradiated with 0.2-4 Gy of gamma rays (for comparison), carbon ions (290 MeV/u, linear energy transfer 13 keV/µm), or fast neutrons (0.05-1 Gy, mean energy, ∼2 MeV), and lung-tumor development was assessed by histopathology. Mice irradiated with ≥2 Gy of carbon ions or ≥0.2 Gy of neutrons developed lung adenocarcinoma (AC) significantly sooner than did non-irradiated mice. The relative biological effectiveness values for carbon ions for lung AC development were 1.07 for male mice and 2.59 for females, and the corresponding values for neutrons were 4.63 and 4.57. Genomic analysis of lung ACs revealed alterations in genes involved in Egfr signaling. Hyperphosphorylation of Erk and a frequent nuclear abnormality (i.e., nuclear groove) were observed in lung ACs of mice irradiated with carbon ions or neutrons compared with ACs from non-irradiated or gamma-ray-irradiated groups. Our data indicate that the induction of lung AC by carbon ions occurred at a rate similar to that for gamma rays in males and approximately 2-to 3-fold greater than that for gamma rays in females. In contrast, the effect of neutrons on lung AC development was approximately 4- to 5-fold greater than that of gamma rays. Our results provide valuable information concerning risk assessment of radiation-induced lung tumors after particle-beam therapy and increase our understanding of the molecular basis of tumor development.

Ionizing radiation protection and the linear No-threshold controversy: Extent of support or counter to the prevailing paradigm.

This study has developed a relationship that categorized radiation protection and allows for a proper, clear, and concise review of the different classifications in terms of principles of protection, dose criteria, categories, fundamental tools, exposure situations, applications and control measures. With the groundwork laid, advances of the linear no-threshold (LNT) model which has attracted attention in the field of radiobiology and epidemiology were examined in detail. Various plausible dose-response relationship scenarios were x-rayed under low-dose extrapolation. Intensive review of factors opposing the LNT model involving radiophobia (including misdiagnosis, alternative surgery/imaging, suppression of ionizing radiation (IR) research); radiobiology (including DNA damage repair, apoptosis/necrosis, senescence protection) and cost issues (including-high operating cost of LNT, incorrect prioritization, exaggeration of LNT impact, risk-to-benefit analysis) were performed. On the other hand, factors supporting the use of LNT were equally examined, they include regulatory bodies' endorsement, insufficient statistical significance, partial DNA repair, variability of irradiated bodies, different latency periods for cancer, dynamic nature of threshold and conflicting interests. After considering the gaps in the scientific investigations that either support or counter the scientific paradigm on the use of LNT model, further research and advocacy is recommended that will ultimately lead to the acceptance of an alternative paradigm by the international regulators.

Cancer Effects of Low to Moderate Doses of Ionizing Radiation in Young People with Cancer-Predisposing Conditions: A Systematic Review.

Moderate to high doses of ionizing radiation (IR) are known to increase the risk of cancer, particularly following childhood exposure. Concerns remain regarding risks from lower doses and the role of cancer-predisposing factors (CPF; genetic disorders, immunodeficiency, mutations/variants in DNA damage detection or repair genes) on radiation-induced cancer (RIC) risk. We conducted a systematic review of evidence that CPFs modify RIC risk in young people. Searches were performed in PubMed, Scopus, Web of Science, and EMBASE for epidemiologic studies of cancer risk in humans (<25 years) with a CPF, exposed to low-moderate IR. Risk of bias was considered. Fifteen articles focusing on leukemia, lymphoma, breast, brain, and thyroid cancers were included. We found inadequate evidence that CPFs modify the risk of radiation-induced leukemia, lymphoma, brain/central nervous system, and thyroid cancers and limited evidence that BRCA mutations modify radiation-induced breast cancer risk. Heterogeneity was observed across studies regarding exposure measures, and the numbers of subjects with CPFs other than BRCA mutations were very small. Further studies with more appropriate study designs are needed to elucidate the impact of CPFs on RIC. They should focus either on populations of carriers of specific gene mutations or on common susceptible variants using polygenic risk scores.

Brca1L63X /+ rat is a novel model of human BRCA1 deficiency displaying susceptibility to radiation-induced mammary cancer.

Women who are heterozygous for deleterious BRCA1 germline mutations harbor a high risk of hereditary breast cancer. Previous Brca1-heterozygous animal models do not recapitulate the breast cancer phenotype, and thus all currently used knockout models adopt conditional, mammary-specific homozygous Brca1 loss or addition of Trp53 deficiency. Herein, we report the creation and characterization of a novel Brca1 mutant rat model harboring the germline L63X mutation, which mimics a founder mutation in Japan, through CRISPR-Cas9-based genome editing. Homozygotes (Brca1L63X/L63X ) were embryonic lethal, whereas heterozygotes (Brca1L63X/+ ) showed apparently normal development. Without carcinogen exposure, heterozygotes developed mammary carcinoma at a comparable incidence rate with their wild-type (WT) littermates during their lifetime. Intraperitoneal injection of 1-methyl-1-nitrosourea (25 or 50 mg/kg) at 7 weeks of age induced mammary carcinogenesis at comparable levels among the heterozygotes and their littermates. After exposure to ionizing radiation (0.1-2 Gy) at 7 weeks of age, the heterozygotes, but not WT littermates, displayed dose-dependent mammary carcinogenesis with 0.8 Gy-1 excess in hazard ratio during their middle age; the relative susceptibility of the heterozygotes was more prominent when rats were irradiated at 3 weeks of age. The heterozygotes had tumors with a lower estrogen receptor α immunopositivity and no evidence of somatic mutations of the WT allele. The Brca1L63X/+ rats thus offer the first single-mutation, heterozygous model of BRCA1-associated breast cancer, especially with exposure to a DNA break-inducing carcinogen. This implies that such carcinogens are causative and a key to breast cancer prevention in individuals who carry high-risk BRCA1 mutations.

Clinical and Molecular Insights of Radiation-Induced Breast Sarcomas: Is There Hope on the Horizon for Effective Treatment of This Aggressive Disease?

Radiation-induced breast sarcomas (RIBS) are rare entities representing <1% of all primary breast malignancies, limiting most reports to small retrospective case series. They constitute a heterogeneous group of neoplasms, with high-grade angiosarcoma being the most common subtype. Other sarcoma histotypes, such as undifferentiated pleomorphic sarcoma and leiomyosarcoma, can also be identified. Radiation-induced breast angiosarcoma (RIBA) has an incidence of approximately 0.1% after breast-conserving therapy and arises mainly from the dermis of the irradiated breast. MYC gene amplification is highly indicative of secondary breast angiosarcomas. Their clinical presentation often mimics benign port-radiation lesions, leading to a delay in diagnosis and a lost window of opportunity for cure. Surgery with negative margins is the mainstay of treatment of localized RIBS. In the case of angiosarcoma, technical difficulties, including multifocality, infiltrative margins, and difficulty in assessing tumor margins, render surgical treatment quite challenging. A limited number of studies showed that adjuvant radiation therapy reduces local recurrences; therefore, it is proposed by many groups for large, high-grade tumors. Chemotherapy has been evaluated retrospectively in a small subset of patients, with some evidence supporting its use in angiosarcoma patients. Approximately half of patients with RIBA will show local recurrence. In the advanced setting, different therapeutic options are discussed in the review, including chemotherapy, antiangiogenic therapy, and immunotherapy, whereas the need for further research on molecular therapeutic targets is pointed out.

[Radiation Carcinogenesis in Animal Models: Part 1].

Exposure to ionizing radiation (IR) increases the risk of cancers, as epidemiology studies of atomic bomb survivors and patients who have received radiotherapy show. The carcinogenic effects of IR are well-documented, although the effects of radiation carcinogenesis change in each organ. The mammary gland is known to be highly susceptible to radiation-induced cancer. We have previously reported that (i) differential DNA methylation patterns in rat mammary carcinomas induced by pre-and post-pubertal IR; (ii) the effect of parity on rat mammary carcinogenesis varies between pre-and post-pubertal IR. In this review, we summarize our radiation researches as well as related with other radiation researches in rodent models.

High Relative Biological Effectiveness of 2 MeV Fast Neutrons for Induction of Medulloblastoma in Ptch1+/- Mice with Radiation-specific Deletion on Chromosome 13.

Neutron radiation, a high-linear energy transfer radiation, has a high relative biological effectiveness (RBE) for various end points. The age at exposure is an important modifier of the effects of radiation, including carcinogenesis, with infants being generally more radiosensitive. Ptch1+/- mice offer a unique experimental system for assessing radiation carcinogenesis. Spontaneous development of medulloblastoma tumors occurs in nonirradiated animals that lose their Ptch1+ allele, most frequently by a loss of heterozygosity (LOH) of chromosome 13 via recombination or non-disjunction (referred to as S-type tumors). In contrast, tumors occur in irradiated Ptch1+/- mice as a result of chromosome 13 LOH with an interstitial deletion (R-type), making spontaneous and radiation-induced tumors discernible. To elucidate the influence of age on the effect of fast neutrons, we irradiated Ptch1+/- mice with neutrons (mean energy, ∼2 MeV) or γ rays on embryonic day (E)14 and E17 and on postnatal day (P)1, 4 or 10 and classified the resulting medulloblastomas based on chromosome 13 aberrations. Instead of LOH, some tumors harbored mutations in their Ptch1+ gene via a nonirradiation-associated mechanism such as duplication, insertion, base substitution or deletion with microhomology-mediated end joining; thus, these tumors were classified as S-type. The RBE regarding the induction of R-type tumors was 12.9 (8.6, 17.2), 9.6 (6.9, 12.3), 21.5 (17.2, 25.8), and 7.1 (4.7, 9.5) (mean and 95% confidence interval) for mice irradiated on E14, E17, P1 and P4, respectively, with the highest value seen during the most active development of the tissue and P10 being completely resistant. These results indicate that the developmental stage at exposure of the tissue influences the RBE of neutrons.

Comprehensive analysis for detecting radiation-specific molecules expressed during radiation-induced rat thyroid carcinogenesis.

Although the association between radiation exposure and thyroid carcinogenesis is epidemiologically evident, 'true' radiation-induced cancers cannot be identified from biological evidence of radiation-associated cases. To assess the individual risk for thyroid cancer due to radiation exposure, we aimed to identify biomarkers that are specifically altered during thyroid carcinogenesis after irradiation in a time-dependent manner in an animal model. Thyroid glands were obtained from rats (n = 175) at 6-16 months after local X-ray (0.1-4 Gy) irradiation of the neck at 7 weeks of age. The gene expression profile in thyroid glands was comprehensively analyzed using RNA microarray. Subsequently, the expression levels of the genes of interest were verified using droplet digital PCR (ddPCR). The expression level of candidate genes as biomarkers for irradiated thyroid was examined in a randomized, controlled, double-blind validation study (n = 19) using ddPCR. The incidence of thyroid cancer increased in a dose- and time-dependent manner and was 33% at 16 months after irradiation with 4 Gy. The Ki-67 labeling index in non-tumorous thyroid was significantly higher in the exposed group than in the control. Comprehensive analysis identified radiation-dependent alteration in 3329 genes. Among them, ddPCR revealed a stepwise increase in CDKN1A expression from early pre-cancerous phase in irradiated thyroid compared to that in the control. The irradiated thyroids were accurately distinguished (positive predictive value 100%, negative predictive value 69%) using 11.69 as the cut-off value for CDKN1A/ß-actin. Thus, CDKN1A expression can be used as a biomarker for irradiated thyroid glands at the pre-cancerous phase.

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

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.

Role of DNA Repair Variants and Diagnostic Radiology Exams in Differentiated Thyroid Cancer Risk: A Pooled Analysis of Two Case-Control Studies.

BACKGROUND: Given the increased use and diversity of diagnostic procedures, it is important to understand genetic susceptibility to radiation-induced thyroid cancer. METHODS: On the basis of self-declared diagnostic radiology examination records in addition to existing literature, we estimated the radiation dose delivered to the thyroid gland from diagnostic procedures during childhood and adulthood in two case-control studies conducted in France. A total of 1,071 differentiated thyroid cancer (DTC) cases and 1,188 controls from the combined studies were genotyped using a custom-made Illumina OncoArray DNA chip. We focused our analysis on variants in genes involved in DNA damage response and repair pathways, representing a total of 5,817 SNPs in 571 genes. We estimated the OR per milli-Gray (OR/mGy) of the radiation dose delivered to the thyroid gland using conditional logistic regression. We then used an unconditional logistic regression model to assess the association between DNA repair gene variants and DTC risk. We performed a meta-analysis of the two studies. RESULTS: The OR/mGy was 1.02 (95% confidence interval, 1.00-1.03). We found significant associations between DTC and rs7164173 in CHD2 (P = 5.79 × 10-5), rs6067822 in NFATc2 (P = 9.26 × 10-5), rs1059394 and rs699517 both in ENOSF1/THYS, rs12702628 in RPA3, and an interaction between rs7068306 in MGMT and thyroid radiation doses (P = 3.40 × 10-4). CONCLUSIONS: Our results suggest a role for variants in CDH2, NFATc2, ENOSF1/THYS, RPA3, and MGMT in DTC risk. IMPACT: CDH2, NFATc2, ENOSF1/THYS, and RPA3 have not previously been shown to be associated with DTC risk.