Atomic Bomb Radiation Research Articles

Abstract 5133: Lifetime Risk of Stroke in Atomic-bomb Survivors-Adult Health Study in Hiroshima and Nagasaki, Japan

Background : It is suggested that Atomic-bomb radiation may cause increase in stroke mortality. The objective of this study was to estimate the radiation effect on lifetime risk (LTR) of stroke among Atomic-bomb survivors. Our hypothesis is that even low-dose radiation may cause stroke incidence in different mechanism of high-dose irradiation. Methods : We evaluated radiation effect on stroke incidence by dose and age at time of bombing (ATB) groups: < 0.005 Gy (n=2607), 0.005– 0.5 Gy (n=2051), 0.5–1.0 Gy (n=939), 1.0+Gy (n=824) and < 10 y.o. (younger) vs. ≥ 10 y.o. (older) ATB. Adult Health Study (AHS) subjects were Atomic-bomb survivors and unexposed controls. Participants have been followed biennially by RERF since 1958. Eligible subjects were alive and stroke-free at baseline age (55–56 y.o.) and had corresponding blood pressure data available. Stroke events were all reviewed by WHO MONICA methods using health exam and death certificate information. Cumulative incidence and LTR analyses accounted for the competing risk of non-stroke death with consideration of blood pressure levels. Results : Median follow-up for the 7487 subjects was 16.1 years (range: 1 day to 44.3 years), where 3788 subjects had died, 868 had a documented first-ever stroke event (356 male, 512 female). These stroke events were classified as hemorrhagic (n=231), thromboembolic (n=542), and unspecified (n=95). A minority of subjects (11%) was <10 y.o. ATB, and dose was unknown in 1066 subjects. There was no significant difference among 4 dose-groups in cumulative incidence rates of any stroke as well as hemorrhagic or thromboembolic stroke. However, there was a significant difference when we considered age ATB within dose groups (p=0.0003). Ten-years risk estimates for any stroke were 3.0% in 0 – 0.005 Gy, 2.0% in 0.005– 0.5 Gy, 5.0% in 0.5–1.0 Gy, 11.1% in 1.0+ Gy (p<0.0001), even within subtypes (hemorrhagic stroke; p=0.053, thromboembolic stroke; p=0.0034). Conclusion : Our results suggest that Atomic-bomb radiation in young subjects increases risk of stroke. Continued observation is needed due to the limited follow-up time in AHS subjects <10 y.o. ATB. This is the first report on the LTR of stroke incidence supporting the long-term radiation related increase in stroke mortality.

Genomic instability in the epidermis induced by atomic bomb (A‐bomb) radiation

Radiation etiology is suggested in the occurrence of basal cell carcinoma (BCC) of the skin among atomic bomb (A-bomb) survivors. Any genotoxicity, including ionizing radiation, can induce a DNA damage response (DDR), leading to genomic instability (GIN), which allows the accumulation of mutations during tumorigenesis. In this study, the authors evaluated the presence of GIN in the epidermis of survivors as a late effect of A-bomb radiation. In total, 146 BCCs, including 23 cases arising from nonexposed skin, were identified in survivors from 1968 to 1999. The incidence rate (IR) of BCC was calculated with stratification by distance in kilometers from the hypocenter (< or =1.5 km, 1.6-2.9 km, and > or =3 km). Nineteen epidermal samples surrounding BCC at the nonexposed sites were collected and tested for p53 binding protein 1 (53BP1) expression with immunofluorescence. 53BP1 rapidly forms nuclear foci at the sites of DNA double strand breaks (DSBs). Because 1 manifestation of GIN is the induction of endogenous DSBs, the level of 53BP1-focus formation (DDR type) can be considered as a marker for GIN. : The incidence rate of BCC increased significantly as exposure distance approached the hypocenter. Of the 7 epidermal samples from the proximal group (< or =1.5 km), 5 samples predominantly expressed DDR and an abnormal type of 53BP1 expression. In contrast, 4 of 5 samples from the distal group (> or =3 km) and all samples from the control group predominantly expressed the stable type of 53BP1 expression in the epidermis. : The current results demonstrated the endogenous activation of DDR in the epidermis surrounding BCC in the proximal group, suggesting the presence of a GIN in the survivors as a late effect of A-bomb radiation, which may indicate a predisposition to cancer.

Cancer and non-cancer effects in Japanese atomic bomb survivors**Presented as an invited paper at the 21st LH Gray Conference ‘The Radiobiology—RadiationProtection Interface’, Royal College of Physicians, Edinburgh 4–6 June 2008.

The survivors of the atomic bombings in Hiroshima and Nagasaki are a general populationof all ages and sexes and, because of the wide and well characterised range of dosesreceived, have been used by many scientific committees (International Commission onRadiological Protection (ICRP), United Nations Scientific Committee on the Effects ofAtomic Radiation (UNSCEAR), Biological Effects of Ionizing Radiations (BEIR)) as thebasis of population cancer risk estimates following radiation exposure. Leukaemia was thefirst cancer to be associated with atomic bomb radiation exposure, with preliminaryindications of an excess among the survivors within the first five years after the bombings.An excess of solid cancers became apparent approximately ten years after radiationexposure. With increasing follow-up, excess risks of most cancer types have beenobserved, the major exceptions being chronic lymphocytic leukaemia, and pancreatic,prostate and uterine cancer. For most solid cancer sites a linear dose response isobserved, although in the latest follow-up of the mortality data there is evidence (p = 0.10) for an upward curvature in the dose response for all solid cancers. The only cancer siteswhich exhibit (upward) curvature in the dose response are leukaemia, and non-melanomaskin and bone cancer. For leukaemia the dose response is very markedly upwardcurving, indeed largely describable as a pure quadratic dose response, particularlyin the low dose (0–2 Sv) range. Even 55 years after the bombings over 40% ofthe Life Span Study cohort remain alive, so continued follow-up of this group isvital for completing our understanding of long-term radiation effects in people.In general, the relative risks per unit dose among the Japanese atomic bomb survivors aregreater than those among comparable subsets in studies of medically exposed individuals.Cell sterilisation largely accounts for the discrepancy in relative risks between these twopopulations, although other factors may contribute, such as the generally higher underlyingcancer risks in the medical series than in the Japanese atomic bomb survivors. Risks amongoccupationally exposed groups such as nuclear workforces and underground miners aregenerally consistent with those observed in the Japanese atomic bomb survivors. Ingeneral, consistent patterns of variation of risk with age at exposure are also seen inall studies—risks for all cancer types diminish with increasing age at exposure.There are also excess risks of various types of non-malignant disease in the Japanese atomicbomb survivors, in particular cardiovascular, respiratory and digestive diseases. Indeed,risks are elevated to much the same degree for a number of non-malignant diseaseendpoints, suggestive of bias. However, in contrast with the cancer data, there is much lessconsistency in the pattern of risk between the atomic bomb survivors and other exposedgroups; for example, radiation-associated respiratory and digestive diseases have not beenseen in these other groups. Although cardiovascular risks have been seen elsewhere,particularly in medically exposed groups, in contrast with the cancer data there is muchless consistency in risk between studies: risks per unit dose in epidemiological studiesvary over at least two orders of magnitude, possibly as a result of confoundingfactors. In the absence of a convincing mechanistic explanation of epidemiologicalevidence, at present a cause-and-effect interpretation of the reported statisticalassociations for cardiovascular disease is unreliable but cannot be excluded. Furtherepidemiological and biological evidence will allow a firmer conclusion to be drawn.

Answer to the comments by Eric J. Grant et al. in “Radiation unlikely to be responsible for high cancer rates among distal Hiroshima A-bomb survivors”

Eric J. Grant et al. raised three issues concerning our paper “Hiroshima survivors exposed to very low doses of A-bomb primary radiation showed a high risk for cancers” [1]. Their proposed title was “Radiation unlikely responsible for high cancer rates among distal Hiroshima A-bomb survivors”. However, in response, we suggest that a better title would be “Risk analysis in LSS without using an unexposed group is responsible for the apparent low cancer rates among distal Hiroshima A-bomb survivors”. We discuss the reasons for this proposal here.

P09: Elevated levels of plasma-reactive oxygen species and inflammatory markers among atomic-bomb survivors

Even after more than 60 years have passed, exposure to atomic-bomb (A-bomb) radiation continues to have long-term health effects in survivors, whose risks of inflammation-related diseases increase with increasing radiation dose. It is known that persistent inflammation underlies several cancers through increased production of reactive oxygen species (ROS) and endogenous tumor promoters (e.g., TNF-α). In our previous study, plasma levels of inflammatory cytokines and biomarkers, IL-6, TNF-α, CRP, IFN-γ, Igs, and erythrocyte sedimentation rate (ESR), increased significantly with radiation dose. We have recently developed an automated plasma ROS assay system based on use of a clinical chemistry analyzer. In this study we investigated association between radiation dose, plasma ROS levels, and sub-clinical inflammatory status in A-bomb survivors in Hiroshima. Excluding patients with history of cancer, rheumatoid arthritis, chronic bronchitis, or myocardial infarction, we randomly selected 442 study subjects from the Adult Health Study population, consisting of A-bomb survivors and unexposed people. We observed statistically significant radiation-associated increase in plasma ROS levels. ROS levels were positively associated with the inflammatory biomarkers IL-6, TNF-α, CRP, and ESR ( P It is evident that total ROS production increased with enhanced inflammatory status, suggesting a plausible mechanistic pathway between radiation-induced persistent inflammation and cancer.

P08: Effects of inflammation-related cytokine gene polymorphisms on gastric cancer risk among atomic bomb survivors

RERF epidemiology studies found that risks of certain cancers among atomic-bomb (A-bomb) survivors, including gastric cancer, increased with past exposure dose to atomic radiation, and that these risks remain high even today. RERF immunology studies implied that radiation exposure greatly affected host immune systems of A-bomb survivors, further providing for the possibility that altered immune response in this population, specifically inflammatory response and immunological host defense, might be involved in the development of various cancers. In fact, we have reported that the enhancement of persistent inflammation with increased age was further accelerated among people exposed to A-bomb radiation. In this study, we examined relationship between gastric cancer risk and radiation dose based on 43 SNPs of inflammation-related genes ( IL1B, IL6, IL8, IL10, BAT1, NFKBIL1, LTA, TNF, and LST1 ), in a case-control study of 238 cases and 1757 controls within a subcohort of the RERF Adult Health Study. We found statistically significant association between IL10 , LTA , and TNF SNPs and risk of gastric cancer, but not between other SNPs and risk of gastric cancer. Three SNPs on the LTA-TNF loci were associated with elevated risk of gastric cancer. Additionally, our genome analysis identified a single haplotype block within the IL10 gene locus, which was indicated by four htSNPs (generating two major alleles, IL10-ATTA and IL10-GGCG ). We found that risk of gastric cancer significantly varied by IL-10 haplotype in both non-exposed and exposed individuals, and that risk-enhancing effects of radiation were evident in all the haplotypes. Our findings offer further evidence that variation in the IL10 and TNF loci affects gastric cancer risk.

P07: Gastric cancer risks among atomic-bomb survivors differ by HLA class I genotype

Since radiation exposure affects the immune system as well as risk of various cancers, we have commenced an “immunogenome” study to look at genetic susceptibility to radiation-associated cancers. HLA class I molecules are known to regulate various immune and inflammatory responses. In this study, we examined effects of radiation exposure on individual susceptibility to gastric cancer based on HLA Class I ( HLA-A, -B, -C ) polymorphisms. This study comprised 150 gastric cancer patients and 300 controls. HLA genotype distribution among the controls not exposed to atomic-bomb radiation was almost identical to that in the general Japanese population. Comparison between non-exposed gastric cancer patients and non-exposed controls showed no statistically significant relationship between gastric cancer risk and HLA-B or HLA-C genotypes. However, frequency of HLA-A*2601 , one of the HLA-A genotypes, was significantly lower among cases (3.7%) than controls (18.3%), with P HLA-A*2601 among the gastric cancer patients (average radiation dose: 0.8 Gy) (18.8%) was almost the same as frequency among the controls (15.8%). Risk elevation by radiation was most prominent in HLA-A*2601 , compared with other genotypes. These results suggest that HLA-A*2601 may be involved in decreased gastric cancer risk among non-exposed people and that, among those with the HLA-A*2601 allele, radiation exposure may increase gastric cancer risk. On the basis of this finding, we conducted further analysis of association between the HLA-A*2601 allele and plasma levels of various inflammatory markers along with analyses of pathological typing and H. pylori infection.

Hiroshima survivors exposed to very low doses of A-bomb primary radiation showed a high risk for cancers

Hiroshima survivors exposed to very low doses of A-bomb primary radiation showed a high risk for cancers

Incidence of dementia among atomic-bomb survivors — Radiation Effects Research Foundation Adult Health Study

Radiotherapy has been reported to cause neuropsychological dysfunction. Here we examined whether exposure to atomic bomb radiation affected the incidence of dementia among 2286 atomic bomb survivors and controls — all members of the Adult Health Study cohort. Study subjects were non-demented and aged ≥ 60 years at baseline examination and had been exposed in 1945 at ≥ 13 years of age to a relatively low dose (≤ 4 Gy), compared with total dose from radiotherapy. Dementia diagnoses were made during biennial health examinations with a two-phase procedure. DSM IV criteria were used for diagnosing dementia, NINCDS-ADRDA for Alzheimer disease, and NINDS-AIREN for vascular disease. To estimate the effect of radiation on the dementia incidence rate, we applied Poisson regression analysis. Incidence per 1000 person–years was 16.3 in the < 5 mGy group, 17.0 in the 5–499 mGy group, and 15.2 in the ≥ 500 mGy group. Alzheimer disease was the predominant type of dementia in each dose category. After adjustment for potential risk factors, radiation exposure did not affect the incidence rate of either all dementia or any of its subtypes. No case of dementia had a history of therapeutic cranial irradiation. Although we found no relationship between radiation exposure and the development of dementia among atomic bomb survivors exposed at ≥ 13 years old in this longitudinal study, effects on increased risk of early death among atomic bomb survivors will be considered.

Answer to the comment by Yoshisada Shibata on “Hiroshima survivors exposed to very low doses of A-bomb primary radiation showed a high risk for cancers”

The SMR is an indirect method based on the age structure of the target population. It is a ratio of the observed (O) to the expected (E) number of deaths, where E is the number of individuals of the target population multiplied by the ageand sex-specific mortality rates of the standard population. In his commentary, Shibata wrote that ‘‘The authors should have compared the mortality directly between the target population and a common standard population,...’’. We are unclear what is meant by this statement. If we were to compare age-period specific mortality rates for each age group (seven classes) and calendar year (five periods), we would need to analyze 35fold (seven age-classes times five periods) more data than that analyzed in the reported study. The result of such a mega-analysis would be to diffuse the focus of our study, with the reader ultimately having great difficulty understanding the results. A comparison using SMR may not have been the best approach, but we could not have achieved the aim of our study if we did not use summary rates. Shibata said that ‘‘the effects of the age distribution in the target population on the power of the hypothesis test are considerably large’’. The test of significance was performed appropriately in our paper. Therefore, his comment is unrelated to the validity of the analysis in our study. If, as pointed out by Shibata, ‘‘a relatively large portion of LSS subjects have been living in areas other than Hiroshima or Okayama prefecture,’’ the results may have been the same—even if other prefectures were used as the standard population. Therefore, we also believe that if information were to be provided on the percentage of the LSS group living in areas other than Hiroshima and Okayama prefectures, this would be valuable data for discussion and future research.

Atomic Bomb Radiation Dosimetry in Hiroshima and Nagasaki and its Meanings

Atomic Bomb Radiation Dosimetry in Hiroshima and Nagasaki and its Meanings

Study of trans-generational effects of atomic-bomb radiation

Study of trans-generational effects of atomic-bomb radiation

Rates of Postcancer Parenthood

Rates of Postcancer Parenthood

Prevalence and Cause of Death in Patients with Monoclonal Gammopathy in Atomic Bomb Survivors in Hiroshima

Purpose: To examine the effect of Atomic bomb (A-bomb) radiation exposure condition on the development M-proteinemia in A-bomb survivors in Hiroshima.Back ground: The influence of radiation exposure on the development of M-proteinemia remained unclear. The screening test for monoclonal gammopathy in A- bomb survivors in Hiroshima was started from Sep. 1988 at the Hiroshima Atomic Bomb Casualty Council Health management center to challenge this problem with the free access policy.Materials: The peak year of the examined population was 1989, which was examined 42915 survivors. This population was designed as study population. This population consisted of five groups of irradiated conditions as follows, 60% was exposed directly in all over the Hiroshima city at A- bombing, 27% entered to center of Hiroshima city within 14 days after A-bombing, 9% helped the victims of A- bombing at the suburbs and 1% was exposed in prenatal state.Examination study: Each participant was examined one test yearly. Routine laboratory tests, such as complete blood cell counts, serum biochemical examination and serum protein electrophoresis on cellulose acetate were performed for the first step screening. M-protein or low level of gammaglobulin was subsequently assessed in a detailed analysis by immunoelectrophoresis of serum and urine, and measurement of serum concentration of immunoglobulin andβ2-Microglobulin.Results: One thousand and hundred eighty two cases of M-proteinemia were detected for 18 years. The over all prevalence rate was 2.75%, and 4.1% in males and 2.1% in females. Nine hundred twenty nigh cases of MGUS(78.6%), 147 cases of MM(12.4%), 80 cases of IgM Macroglobulinemia(6.8%) and 26 cases of two clone M-proteinemia(2.2%) were detected. Of these M-proteinemia, 669cases(2.6%) were developed in directly exposed population, 368cases(3.1%) were in entered population and 133 cases(3.4%) were in helper population. The prevalence rate of these M-proteinemia was increased depend on aging. Forty three cases (4.6%) of MGUS moved to overt MM for 18 years. The mean duration time from MGUS to overt MM was 8.9 years (2~18 years). Four hundred sixteen cases (35.2%) were died with MM or lymphoproliferative diseases (99cases,23.8%), cancer (93cases,22.3%), infection (50cases,12%), cardio or cerebral vascular diseases (89 cases,21.4%) and others (85cases,21%). The 101 cases (13.2%) of 766 living cases combined some cancer throughout the follow up. No significant differences in the prevalence rate of M-proteinemia and death from MM or combination with cancer were observed among any A-bomb irradiated conditions.Conclusions: There were no clear correlations between the development or disease state of M-proteinemia and the irradiated conditions. We are now starting to analyze the individual radiation dose effects longitudinally on the development of M-proteinemia.

Cardiovascular Disease Risk among Atomic Bomb Survivors ExposedIn Utero, 1978–2003

Given the well-documented association of in utero radiation exposure with childhood cancer and developmental impairments, the possibility of effects on adult onset diseases is an important issue. The objectives of the present study were to examine the effects of atomic bomb radiation dose on the incidence of hypertension, hypercholesterolemia and cardiovascular disease (myocardial infarction and stroke) among survivors exposed in utero and to compare their risk estimates with those of survivors exposed in childhood (<10 years old) at the time of the bombing. A total of 506 participants exposed in utero and 1,053 participants exposed in childhood were followed during 1978-2003 with biennial clinical examinations. There were no significant radiation dose effects for any diseases in the entire in utero-exposed cohort or in trimester-of-exposure subgroups, though there was a suggestion of an increased risk when fatal and nonfatal cardiovascular disease cases were combined. Positive radiation dose effects were found for hypertension and cardiovascular disease in the childhood-exposure cohort, but there were no statistically significant differences in the relative risks when we compared the two cohorts. Since the in utero cohort was under age 60 at the latest examination, continued follow-up is needed to document cardiovascular disease risk more fully.

RET/PTC Rearrangements Preferentially Occurred in Papillary Thyroid Cancer among Atomic Bomb Survivors Exposed to High Radiation Dose

A major early event in papillary thyroid carcinogenesis is constitutive activation of the mitogen-activated protein kinase signaling pathway caused by alterations of a single gene, typically rearrangements of the RET and NTRK1 genes or point mutations in the BRAF and RAS genes. In childhood papillary thyroid cancer, regardless of history of radiation exposure, RET/PTC rearrangements are a major event. Conversely, in adult-onset papillary thyroid cancer among the general population, the most common molecular event is BRAF(V600E) point mutation, not RET/PTC rearrangements. To clarify which gene alteration, chromosome aberration, or point mutation preferentially occurs in radiation-associated adult-onset papillary thyroid cancer, we have performed molecular analyses on RET/PTC rearrangements and BRAF(V600E) mutation in 71 papillary thyroid cancer cases among atomic bomb survivors (including 21 cases not exposed to atomic bomb radiation), in relation to radiation dose as well as time elapsed since atomic bomb radiation exposure. RET/PTC rearrangements showed significantly increased frequency with increased radiation dose (P(trend) = 0.002). In contrast, BRAF(V600E) mutation was less frequent in cases exposed to higher radiation dose (P(trend) < 0.001). Papillary thyroid cancer subjects harboring RET/PTC rearrangements developed this cancer earlier than did cases with BRAF(V600E) mutation (P = 0.03). These findings were confirmed by multivariate logistic regression analysis. These results suggest that RET/PTC rearrangements play an important role in radiation-associated thyroid carcinogenesis.

Genome-wide identification of functional polymorphisms modulating individual risk of lung cancer

Accumulated DNA damage in hematopoietic stem cells is a primary mechanism of aging-associated dysfunction in human hematopoiesis. About 70 years ago, atomic-bomb (A-bomb) radiation induced DNA damage and functional decreases in the hematopoietic system of A-bomb survivors in a radiation dose-dependent manner. The peripheral blood cell populations then recovered to a normal range, but accompanying cells derived from hematopoietic stem cells still remain that bear molecular changes possibly caused by past radiation exposure and aging. In the present study, we evaluated radiation-related changes in the frequency of phosphorylated (Ser-139) H2AX (γH2AX) foci formation in circulating CD34-positive/lineage marker-negative (CD34 + Lin-) hematopoietic stem and progenitor cells (HSPCs) among 226Hiroshima A-bomb survivors. An association between the frequency of γH2AX foci formation in HSPCs and the radiation dose was observed, but the γH2AX foci frequency was not significantly elevated by past radiation. We found a negative correlation between the frequency of γH2AX foci formation and the length of granulocyte telomeres. A negative interaction effect between the radiation dose and the frequency of γH2AX foci was suggested in a proportion of a subset of HSPCs as assessed by the cobblestone area-forming cell assay (CAFC), indicating that the self-renewability of HSPCs may decrease in survivors who were exposed to a higher radiation dose and who had more DNA damage in their HSPCs. Thus, although many years after radiation exposure and with advancing age, the effect of DNA damage on the self-renewability of HSPCs may be modified by A-bomb radiation exposure.

Experimental Derivation of Relative Biological Effectiveness of A-Bomb Neutrons in Hiroshima and Nagasaki and Implications for Risk Assessment

Epidemiological data on the health effects of A-bomb radiation in Hiroshima and Nagasaki provide the framework for setting limits for radiation risk and radiological protection. However, uncertainty remains in the equivalent dose, because it is generally believed that direct derivation of the relative biological effectiveness (RBE) of neutrons from the epidemiological data on the survivors is difficult. To solve this problem, an alternative approach has been taken. The RBE of polyenergetic neutrons was determined for chromosome aberration formation in human lymphocytes irradiated in vitro, compared with published data for tumor induction in experimental animals, and validated using epidemiological data from A-bomb survivors. The RBE of fission neutrons was dependent on dose but was independent of the energy spectrum. The same RBE regimen was observed for lymphocyte chromosome aberrations and tumors in mice and rats. Used as a weighting factor for A-bomb survivors, this RBE system was superior in eliminating the city difference in chromosome aberration frequencies and cancer mortality. The revision of the equivalent dose of A-bomb radiation using DS02 weighted by this RBE system reduces the cancer risk by a factor of 0.7 compared with the current estimates using DS86, with neutrons weighted by a constant RBE of 10.

Effects of IL-10 and IL-6 Gene Polymorphisms and Atomic-bomb Radiation Exposure on Gastric Cancer Risk

Cells repair DNA double-strand breaks (DSBs) through a complex set of pathways critical for maintaining genomic integrity. To systematically map these pathways, we developed a high-throughput screening approach called Repair-seq that measures the effects of thousands of genetic perturbations on mutations introduced at targeted DNA lesions. Using Repair-seq, we profiled DSB repair products induced by two programmable nucleases (Cas9 and Cas12a) in the presence or absence of oligonucleotides for homology-directed repair (HDR) after knockdown of 476 genes involved in DSB repair or associated processes. The resulting data enabled principled, data-driven inference of DSB end joining and HDR pathways. Systematic interrogation of this data uncovered unexpected relationships among DSB repair genes and demonstrated that repair outcomes with superficially similar sequence architectures can have markedly different genetic dependencies. This work provides a foundation for mapping DNA repair pathways and for optimizing genome editing across diverse modalities.

Significance of HER2 and C‐MYC oncogene amplifications in breast cancer in atomic bomb survivors

It has been postulated that radiation induces breast cancers in atomic bomb (A-bomb) survivors. Oncogene amplification is an important mechanism during breast carcinogenesis and also serves as an indicator of genomic instability (GIN). The objective of this study was to clarify the association of oncogene amplification in breast cancer in A-bomb survivors with radiation exposure. In total, 593 breast cancers were identified in A-bomb survivors from 1968 to 1999, and the association between breast cancer incidence and A-bomb radiation exposure was evaluated. Invasive ductal cancers from 67 survivors and 30 nonsurvivors were analyzed for amplification of the HER2 and C-MYC genes by fluorescence in situ hybridization, and expression levels of hormone receptors were analyzed by immunostaining. The incidence rate increased significantly as exposure distance decreased from the hypocenter (hazard ratio per 1-km decrement, 1.47; 95% confidence interval [95% CI], 1.30-1.66). The incidence of HER2 and C-MYC amplification was increased significantly in the order of the control group, the distal group (P = .0238), and the proximal group (P = .0128). Multivariate analyses revealed that distance was a risk factor for the coamplification of C-MYC and HER2 in breast cancer in survivors (odds ratio per 1-km increment, 0.17; 95% CI, 0.01-0.63). The histologic grade of breast cancers became significantly higher in the order of the control group, the distal group, and the proximal group and was associated with oncogene amplifications. The current results suggested that A-bomb radiation may affect the development of oncogene amplification by inducing GIN and may be associated with a higher histologic grade in breast cancer among A-bomb survivors.