Atomic Bomb Radiation Research Articles

Radiation effects on cancer risks in the life span study cohort

To determine late health effects of radiation in atomic bomb survivors, the Radiation Effects Research Foundation has been conducting studies on the Life Span Study (LSS) population, which consists of 93,000 atomic bomb survivors and 27,000 controls. A recent report on the incidence of solid cancers estimates that at the age of 70 y, after exposure at the age of 30 y, solid-cancer rates increase by about 35% per Gy for men and 58% per Gy for women. The age-at-exposure is an important risk modifier. Furthermore, it seems that radiation-associated increases in cancer rates persist throughout life. In addition, radiation has similar effects upon first-primary and second-primary cancer risks. A recent report on leukemia mortality suggested that the effect of radiation on leukemia mortality persisted for more than five decades. In addition, a significant dose-response for myelodysplastic syndrome is found in Nagasaki LSS members 40-60 y after radiation exposure. In view of the nature of the continuing increase in solid cancers, the LSS should continue to provide important new information on cancer risks, as most survivors still alive today were exposed to the atomic bomb radiation under the age of 20 y and are now entering their cancer-prone years.

Evaluation of systemic markers of inflammation in atomic‐bomb survivors with special reference to radiation and age effects

Past exposure to atomic bomb (A-bomb) radiation has exerted various long-lasting deleterious effects on the health of survivors. Some of these effects are seen even after >60 yr. In this study, we evaluated the subclinical inflammatory status of 442 A-bomb survivors, in terms of 8 inflammation-related cytokines or markers, comprised of plasma levels of reactive oxygen species (ROS), interleukin (IL)-6, tumor necrosis factor α (TNF-α), C-reactive protein (CRP), IL-4, IL-10, and immunoglobulins, and erythrocyte sedimentation rate (ESR). The effects of past radiation exposure and natural aging on these markers were individually assessed and compared. Next, to assess the biologically significant relationship between inflammation and radiation exposure or aging, which was masked by the interrelationship of those cytokines/markers, we used multivariate statistical analyses and evaluated the systemic markers of inflammation as scores being calculated by linear combinations of selected cytokines and markers. Our results indicate that a linear combination of ROS, IL-6, CRP, and ESR generated a score that was the most indicative of inflammation and revealed clear dependences on radiation dose and aging that were found to be statistically significant. The results suggest that collectively, radiation exposure, in conjunction with natural aging, may enhance the persistent inflammatory status of A-bomb survivors.

Evaluation of Demographic Factors That Influence Acute Radiation Response

Casualty estimation tools are critical in planning for nuclear event scenarios. Current consequence assessment models based on healthy adult males may not adequately represent the population. To develop an understanding of the impact of demographic variables on casualty estimates, human data was surveyed to identify key demographic factors that affect acute radiation response. Information on in utero exposures, gender, age, and comorbidity status was collected from atomic bomb survivors, radiation accidents, and clinical oncology. Burn and trauma studies were also examined to gain insight into the impact of demographic variables on acute injury outcomes. Fetal radiation sensitivity is well documented; increased mortality or malformations are observed depending on gestational age. A greater incidence of radiation syndrome was observed among male atomic bomb survivors. Trauma data show increased mortality in males, apparently due to immunological differences between genders. Limited data suggest vulnerability in the very young and old due to immunological status and comorbidities, respectively. Certain genetically susceptible subpopulations demonstrate marked increased sensitivity to radiation exposure. Interaction of radiation and comorbid conditions has not been well studied; however, burn and trauma data indicate that comorbidities negatively impact response to acute injury. Key factors evaluated together with their prevalence indicate the importance of modeling demographic variability in casualty estimations. Also they can help identify vulnerable subpopulations and provide insight on treatment requirements.

Rearranged Anaplastic Lymphoma Kinase (ALK) Gene in Adult-Onset Papillary Thyroid Cancer Amongst Atomic Bomb Survivors

We previously noted that among atomic bomb survivors (ABS), the relative frequency of cases of adult papillary thyroid cancer (PTC) with chromosomal rearrangements (mainly RET/PTC) was significantly greater in those with relatively higher radiation exposure than those with lower radiation exposure. In contrast, the frequency of PTC cases with point mutations (mainly BRAF(V600E)) was significantly lower in patients with relatively higher radiation exposure than those with lower radiation exposure. We also found that among ABS, the frequency of PTC cases with no detectable gene alterations in RET, neurotrophic tyrosine kinase receptor 1 (NTRK1), BRAF, or RAS was significantly higher in patients with relatively higher radiation exposure than those with lower radiation exposure. However, in ABS with PTC, the relationship between the presence of the anaplastic lymphoma kinase (ALK) gene fused with other gene partners and radiation exposure has received little study. In this study, we tested the hypothesis that the relative frequency of rearranged ALK in ABS with PTC, and with no detectable gene alterations in RET, NTRK1, BRAF, or RAS, would be greater in those having relatively higher radiation exposures. The 105 subjects in the study were drawn from the Life Span Study cohort of ABS of Hiroshima and Nagasaki who were diagnosed with PTC between 1956 and 1993. Seventy-nine were exposed (>0 mGy), and 26 were not exposed to A-bomb radiation. In the 25 ABS with PTC, and with no detectable gene alterations in RET, NTRK1, BRAF, or RAS, we examined archival, formalin-fixed, paraffin-embedded PTC specimens for rearrangement of ALK using reverse transcription-polymerase chain reaction and 5' rapid amplification of cDNA ends (5' RACE). We found rearranged ALK in 10 of 19 radiation-exposed PTC cases, but none among 6 patients with PTC with no radiation exposure. In addition, solid/trabecular-like architecture in PTC was closely associated with ALK rearrangements, being observed in 6 of 10 PTC cases with ALK rearrangements versus 2 of 15 cases with no ALK rearrangements. The six radiation-exposed cases of PTC harboring both ALK rearrangements and solid/trabecular-like architecture were associated with higher radiation doses and younger ages at the time of the A-bombing and at diagnosis compared to the other 19 PTC with no detectable gene alterations. Our findings suggest that ALK rearrangements are involved in the development of radiation-induced adult-onset PTC.

The acute effects of sub-lethal gamma irradiation on the thymus and T cells were directly affected by age, sex and radiation exposure dose (115.8)

Abstract To study the effects of A-bomb radiation on immunosenescence, we developed a mouse model to evaluate the effects of sub-lethal gamma irradiation, varying exposure dose and analysis time points in males and females. The current data report the effects on 2 and 6-month old mice exposed at 0, 0.5, 1, 2, or 4 Gray (Gy), analyzed 1.5 months after irradiation. We saw a dose dependent reduction of DN1 thymocytes, especially of DN1a,b subsets. Although DN cells were reduced, the DP subset was increased, with a dose dependent restoration of total thymocyte numbers at all but the highest exposures. Significantly, there was a dose dependent increase of CD4 and decrease of CD8 SP cells, resulting in an increased CD4/CD8 ratio. Thymic NK cell numbers were increased at low doses, but decreased at the 4Gy dose. In males, total peripheral T cell numbers showed a dose-dependent decline while thymocyte numbers showed the opposite effect. In contrast, peripheral T cells showed the same increased CD4/CD8 ratio as thymocytes. Newly produced thymocytes contributed more to restoration of peripheral T cells at low doses, but peripheral homeostasis appeared to have more effect at 4Gy. Thymic epithelial cells (TECs) were also affected, with an increase of total TEC number at low doses followed by a dose dependent reduction at higher doses. These results suggest that age, sex and exposure dose all affect the restoration of the immune system during early recovery period after sub-lethal irradiation.

712 CATAMNESTIC FOLLOW-UP OF RENAL CELL CARCINOMAS AMONG ATOMIC BOMB SURVIVORS ACCORDING TO RADIATION EXPOSURE STATUS

INTRODUCTION AND OBJECTIVES: Over 65 years have passed since exposure to the atomic bomb (A-bomb) in Hiroshima. Many reports exist on radiation carcinogenesis in many carcinomas, and several prospective cohort studies were conducted. So far, however, there are few reports on the prognosis of A-bomb survivors versus patients not exposed to A-bomb radiation (non-exposed). We evaluated differences in prognosis of primary renal malignancies in A-bomb survivors and the non-exposed. METHODS: Of 479 patients who underwent nephrectomy at our hospital from March 1991 to December 2011, with renal cell carcinoma diagnosed in the resected specimen, 255 patients with evaluable cases in the postoperative course and birth month before June 1946, which included prenatal exposure to A-bomb radiation, were included. We retrospectively evaluated overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS) rates and analyzed patient clinicopathological findings. RESULTS: Of these 255 patients, 35 (13.7%) were A-bomb survivors. Mean age, sex, stage groupings, and histological classification and grade were similar between the A-bomb survivors and the non-exposed. Clinical T1 (cT1) patients were observed significantly more frequently among A-bomb survivors (32/35, 91.4%) than among the non-exposed (125/220, 56.8%; p 0.001). At a median follow-up of 47 months, OS rates at 5 and 10 years were 92.8% and 87.7%, respectively, in the A-bomb survivors and 74.6% and 69.3%, respectively, in the non-exposed (p 0.053). CSS rates at 5 and 10 years were 92.8% and 92.8%, respectively, in A-bomb survivors and 81.9% and 80.3%, respectively, in the non-exposed (p 0.137). DFS rates at 5 and 10 years were 92.7% and 92.7%, respectively, in A-bomb survivors and 86.7% and 83.7%, respectively, in the non-exposed (p 0.192). OS rates compared in cT1 patients showed no significant difference between A-bomb survivors and the non-exposed (p 0.690). In multivariate analysis, pT1 but not exposure of A-bomb was independent predictor for favorable prognosis. CONCLUSIONS: There was no difference in the prognosis of primary renal malignancies in A-bomb survivors and the non-exposed. Thus, the A-bomb does not seem to affect the prognosis of patients with renal cell carcinoma. Source of Funding: None

Late effect of Atomic bomb radiation on myeloid disorders: leukemia and myelodysplastic syndromes

Leukemia was the first malignancy linked to radiation exposure in atomic bomb survivors. Clear evidence of the dose-dependent excess risk of three major types of leukemia (acute lymphocytic leukemia, acute myeloid leukemia [AML], and chronic myeloid leukemia) was found, especially in people exposed at young ages. Such leukemia risks were at their highest in the late 1950s, and declined gradually thereafter over the past 50years. Findings from recent risk analyses, however, suggest the persistence of AML risk even after 1990, and evidence of increased risk of myelodysplastic syndromes (MDS) due to atomic bomb radiation has recently been shown. High-risk MDS and forms involving complex chromosomal aberrations were found to be much more frequent in people exposed to higher radiation doses. These lines of epidemiological evidence suggest that the risk of radiation-induced hematological malignancies has persisted for six decades since the initial exposure.

P2-06-01: Genomic Instability in Breast Cancers from Atomic Bomb Survivors: An Analysis of Microarray-Comparative Genomic Hybridization with Old Archival Tissues.

Abstract Background: Sixty-six years after two atomic bombs (A-bombs) explosion on Hiroshima and Nagasaki, the incidence of breast cancer in A-bomb survivors still higher than that in controlled populations. We have reported a higher incidence of HER2 and C-MYC oncogene amplification in breast cancers from A-bomb survivors, which suggested genomic instability (GIN) induced by A-bomb radiation exposure might promote breast carcinogenesis in A-bomb survivors. The purpose of this study was to clarify the effect of A-bomb radiation exposure on GIN in breast cancer using microarray-comparative genomic hybridization (aCGH). Materials and Methods: DNA was extracted from the paraffin-embedded tissues of invasive ductal cancers from 11 survivors exposed at 1.5km from the hypocenter and 9 calendar year-matched non-exposed patients followed by aCGH analysis using a high-density oligonucleotide microarray (Agilent® SurePrint G3 8×60k microarray). The total length of chromosomal aberrant region was used as an indicator of GIN, and correlation with clinicopathological factors were statistically tested. Results: The mean of the derivative log ratio spread (DLRSpread), which estimates the log ratio noise by calculating the spread of log ratio differences between consecutive probes along all chromosomes, was 0.60 (range, 0.30 to 1.05). The concordance of aCGH results with FISH results for HER2 gene amplification was 90%. Samples from A-bomb survivors had significantly more copy number aberrations (CNA) than samples from control patients (P= 0.040). Samples with C-MYC gene amplification determined by aCGH analysis tended to harbor more CNA (P= 0.20), and age at the time of diagnosis tended to be inversely associated with the total length of chromosomal aberrant regions (P= 0.13). The multivariate analysis with covariance revealed that the status of A-bomb exposure was the only independent factor which was significantly associated the total length of chromosomal aberrant regions (P= 0.0324). Conclusions: This study suggested that A-bomb radiation may affect the development of chromosomal aberrant regions including oncogene amplification by inducing GIN and may be associated with a higher histological grade in breast cancer found in A-bomb survivors. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-06-01.

Significance of genomic instability in breast cancer in atomic bomb survivors: analysis of microarray-comparative genomic hybridization

BackgroundIt has been postulated that ionizing radiation induces breast cancers among atomic bomb (A-bomb) survivors. We have reported a higher incidence of HER2 and C-MYC oncogene amplification in breast cancers from A-bomb survivors. The purpose of this study was to clarify the effect of A-bomb radiation exposure on genomic instability (GIN), which is an important hallmark of carcinogenesis, in archival formalin-fixed paraffin-embedded (FFPE) tissues of breast cancer by using microarray-comparative genomic hybridization (aCGH).MethodsTumor DNA was extracted from FFPE tissues of invasive ductal cancers from 15 survivors who were exposed at 1.5 km or less from the hypocenter and 13 calendar year-matched non-exposed patients followed by aCGH analysis using a high-density oligonucleotide microarray. The total length of copy number aberrations (CNA) was used as an indicator of GIN, and correlation with clinicopathological factors were statistically tested.ResultsThe mean of the derivative log ratio spread (DLRSpread), which estimates the noise by calculating the spread of log ratio differences between consecutive probes for all chromosomes, was 0.54 (range, 0.26 to 1.05). The concordance of results between aCGH and fluorescence in situ hybridization (FISH) for HER2 gene amplification was 88%. The incidence of HER2 amplification and histological grade was significantly higher in the A-bomb survivors than control group (P = 0.04, respectively). The total length of CNA tended to be larger in the A-bomb survivors (P = 0.15). Correlation analysis of CNA and clinicopathological factors revealed that DLRSpread was negatively correlated with that significantly (P = 0.034, r = -0.40). Multivariate analysis with covariance revealed that the exposure to A-bomb was a significant (P = 0.005) independent factor which was associated with larger total length of CNA of breast cancers.ConclusionsThus, archival FFPE tissues from A-bomb survivors are useful for genome-wide aCGH analysis. Our results suggested that A-bomb radiation may affect the increased amount of CNA as a hallmark of GIN and, subsequently, be associated with a higher histologic grade in breast cancer found in A-bomb survivors.

Low-Dose-Rate, Low-Dose Irradiation Delays Neurodegeneration in a Model of Retinitis Pigmentosa

The existence of radiation hormesis is controversial. Several stimulatory effects of low-dose (LD) radiation have been reported to date; however, the effects on neural tissue or neurodegeneration remain unknown. Here, we show that LD radiation has a neuroprotective effect in mouse models of retinitis pigmentosa, a hereditary, progressive neurodegenerative disease that leads to blindness. Various LD radiation doses were administered to the eyes in a retinal degeneration mouse model, and their pathological and physiological effects were analyzed. LD gamma radiation in a low-dose-rate (LDR) condition rescues photoreceptor cell apoptosis both morphologically and functionally. The greatest effect was observed in a condition using 650 mGy irradiation and a 26 mGy/minute dose rate. Multiple rounds of irradiation strengthened this neuroprotective effect. A characteristic up-regulation (563%) of antioxidative gene peroxiredoxin-2 (Prdx2) in the LDR-LD-irradiated retina was observed compared to the sham-treated control retina. Silencing the Prdx2 using small-interfering RNA administration reduced the LDR-LD rescue effect on the photoreceptors. Our results demonstrate for the first time that LDR-LD irradiation has a biological effect in neural cells of living animals. The results support that radiation exhibits hormesis, and this effect may be applied as a novel therapeutic concept for retinitis pigmentosa and for other progressive neurodegenerative diseases regardless of the mechanism of degeneration involved.

Effect of Radiation on Age at Menopause among Atomic Bomb Survivors

Exposure to ionizing radiation has been thought to induce ovarian failure and premature menopause. Proximally exposed female atomic bomb survivors were reported to experience menopause immediately after the exposure more often than those who were distally exposed. However, it remains unclear whether such effects were caused by physical injury and psychological trauma or by direct effects of radiation on the ovaries. The objective of this study was to see if there are any late health effects associated with the exposure to atomic bomb radiation in terms of age at menopause in a cohort of 21,259 Life Span Study female A-bomb survivors. Excess absolute rates (EAR) of natural and artificial menopause were estimated using Poisson regression. A linear threshold model with a knot at 0.40 Gy [95% confidence interval (CI): 0.13, 0.62] was the best fit for a dose response of natural menopause (EAR at 1 Gy at age of 50 years = 19.4/1,000 person-years, 95% CI: 10.4, 30.8) and a linear threshold model with a knot at 0.22 Gy (95% CI: 0.14, 0.34) was the best fit for artificial menopause (EAR at 1 Gy at age of 50 years for females who were exposed at age of 20 years = 14.5/1,000 person-years, 95% CI: 10.2, 20.1). Effect modification by attained age indicated that EARs peaked around 50 years of age for both natural and artificial menopause. Although effect modification by age at exposure was not significant for natural menopause, the EAR for artificial menopause tended to be larger in females exposed at young ages. On the cumulative incidence curve of natural menopause, the median age at menopause was 0.3 years younger in females exposed to radiation of 1 Gy compared with unexposed females. The median age was 1 year younger for combined natural and artificial menopause in the same comparison. In conclusion, age at menopause was thought to decrease with increasing radiation dose for both natural and artificial menopause occurring at least 5 years after the exposure.

Height loss starting in middle age predicts increased mortality in the elderly

The purpose of this study was to determine the mortality risk among Japanese men and women with height loss starting in middle age, taking into account lifestyle and physical factors. A total of 2498 subjects (755 men and 1743 women) aged 47 to 91 years old underwent physical examinations during the period 1994 to 1995. Those individuals were followed for mortality status through 2003. Mortality risk was estimated using an age-stratified Cox proportional hazards model. In addition to sex, adjustment factors such as radiation dose, lifestyle, and physical factors measured at the baseline--including smoking status, alcohol intake, total cholesterol, blood pressure, and diagnosed diseases--were used for analysis of total mortality and mortality from each cause of death. There were a total of 302 all-cause deaths, 46 coronary heart disease and stroke deaths, 58 respiratory deaths including 45 pneumonia deaths, and 132 cancer deaths during the follow-up period. Participants were followed for 20,787 person-years after baseline. Prior history of vertebral deformity and hip fracture were not associated with mortality risk. However, more than 2 cm of height loss starting in middle age showed a significant association with all-cause mortality among the study participants (HR = 1.76, 95% CI 1.31 to 2.38, p = 0.0002), after adjustment was made for sex, attained age, atomic-bomb radiation exposure, and lifestyle and physical factors. Such height loss also was significantly associated with death due to coronary heart disease or stroke (HR = 3.35, 95% CI 1.63 to 6.86, p = 0.0010), as well as respiratory-disease death (HR = 2.52, 95% CI 1.25 to 5.22, p = 0.0130), but not cancer death. Continuous HL also was associated with all-cause mortality and CHD- or stroke-caused mortality. Association between height loss and mortality was still significant, even after excluding persons with vertebral deformity. Height loss of more than 2 cm starting in middle age was an independent risk factor for cardiovascular and respiratory-disease mortality among the elderly, even after adjusting for potential risk factors.

Risk for Progression to Overt Hypothyroidism in an Elderly Japanese Population with Subclinical Hypothyroidism

Few population-based studies report the changes with time in thyroid function tests in patients with subclinical hypothyroidism. We compared the risk for developing overt hypothyroidism in patients with subclinical hypothyroidism and euthyroid controls from the same population of elderly Japanese. We also sought associations of selected parameters with the development of overt hypothyroidism in the subclinical hypothyroid and euthyroid groups. We measured thyrotropin (TSH) and free thyroxine (T4) levels at baseline examinations performed from 2000 to 2003 in the cohort of Japanese atomic-bomb survivors and identified 71 patients with spontaneous subclinical hypothyroidism (normal free T4 and TSH >4.5 mIU/L without a history of thyroid treatment, mean age 70 year) and 562 euthyroid controls. We re-examined TSH and free T4 levels an average of 4.2 years later (range, 1.9-6.9). The risk for progression to overt hypothyroidism was significantly increased in subclinical hypothyroid patients (7.0%) compared with control subjects (1.6%) after adjusting for age and sex (odds ratio, 4.56; p=0.009). Higher baseline TSH levels were associated with progression from subclinical to overt hypothyroidism (p=0.02) in the multivariate analysis, including age, sex, antithyroid peroxidase antibody, and ultrasonography (US) findings. The analysis using binary TSH data suggested that a TSH level >8 mIU/L was a predictive value for development of overt hypothyroidism (p=0.005). On the other hand, serum TSH levels spontaneously normalized in 38 (53.5%) of the patients with subclinical hypothyroidism. In the multivariate analysis, normalization of TSH levels was associated with lower baseline TSH levels (p=0.004) and normal and homogenous thyroid US findings (p=0.04). Atomic-bomb radiation dose was not associated with subclinical hypothyroidism or its course. Subclinical hypothyroidism was four times more likely to be associated with development of overt hypothyroidism than euthyroid controls in the sample population of Japanese elderly. TSH levels in half of the patients normalized spontaneously when assessed after an average follow-up period of 4.2 years. Baseline TSH level and thyroid US findings are potential predictors of future thyroid function in subclinical hypothyroidism.

Risk of cancer and non-cancer diseases in the atomic bomb survivors

Late health effects of exposure to atomic bomb radiation have been evaluated in survivors. A cohort of 120 321 people has been followed since 1950 for mortality, including the cause of death using the Japanese population registry system (Life Span Study), and for cancer incidence using population-based cancer registries. Findings have included a markedly increased risk of leukaemia several years after the exposure, increased risk of various malignant tumours several decades after the exposure and, more recently, findings of increased rates of non-cancer diseases such as cardiovascular diseases.

Hepatocellular Carcinoma in Non-cirrhotic Liver Without Evidence of Iron Overload in a Patient with Primary Hemochromatosis. Review

We report a case of a 70-year-old male with hepatocellular carcinoma (HCC) with a history of hemochromatosis but with no evidence of cirrhosis or iron overload and with a history of exposure to atomic bomb radiation. It is very rare to see hepatocellular carcinoma in the absence of evidence of liver injury. We did an extensive review of current English medical literature through Pubmed from 1980 to 2009 and found 14 case reports of patient with hepatocellular cancer in absence of cirrhosis. The details of these cases were reanalyzed as reported and documented for review. There are 14 previous case reports of HCC developing in hemochromatosis in absence of cirrhosis but ten of them had evidence of iron overload in the non-tumorous livers. Our case is the fifth case of Hepatocellular cancer in hemochromatosis in absence of cirrhosis and iron overload. Hepatocellular carcinoma is a very rare in absence of cirrhosis but patient with other risk factors like hemochromatosis, viral infections, radiation, and toxin exposure should be monitored closely for any sign and symptoms suggestive of malignancy.

T-Cell Immunosenescence and Inflammatory Response in Atomic Bomb Survivors

In this paper we summarize the long-term effects of A-bomb radiation on the T-cell system and discuss the possible involvement of attenuated T-cell immunity in the disease development observed in A-bomb survivors. Our previous observations on such effects include impaired mitogen-dependent proliferation and IL-2 production, decreases in naive T-cell populations, and increased proportions of anergic and functionally weak memory CD4 T-cell subsets. In addition, we recently found a radiation dose-dependent increase in the percentages of CD25(+)/CD127(-) regulatory T cells in the CD4 T-cell population of the survivors. All these effects of radiation on T-cell immunity resemble effects of aging on the immune system, suggesting that ionizing radiation might direct the T-cell system toward a compromised phenotype and thereby might contribute to an enhanced immunosenescence. Furthermore, there are inverse, significant associations between plasma levels of inflammatory cytokines and the relative number of naïve CD4 T cells, also suggesting that the elevated levels of inflammatory markers found in A-bomb survivors can be ascribed in part to T-cell immunosenescence. We suggest that radiation-induced T-cell immunosenescence may result in activation of inflammatory responses and may be partly involved in the development of aging-associated and inflammation-related diseases frequently observed in A-bomb survivors.

Abstract 4715: Genetic susceptibility to radiation-associated colon and rectum cancers among atomic-bomb survivors with special reference to the CD14 gene

Abstract Past epidemiology studies reported that atomic-bomb (A-bomb) radiation exposure enhanced risk of colon cancer, but not rectum cancer, among the survivors. The reason for this different sensitivity to radiation remains to be elucidated. Colorectal cancer is a multi-factorial disease, the onset of which is attributed to both environmental and genetic factors, with animal experiments showing that intestinal bacterial toxins accelerate carcinogenesis. It was recently reported that single nucleotide polymorphisms (SNPs) identified in the promoter region of CD14, encoding a receptor for the lipopolysaccharide component of the outer membrane of Gram-negative bacteria, regulate CD14 gene expression and thereby affect susceptibility to inflammatory diseases such as atopic dermatitis, coronary artery disease, and hepatic diseases. This study investigated relationship between a novel CD14 gene polymorphism and the development of radiation-associated colon and rectum cancers among an A-bomb survivor cohort, in terms of a case-cohort study. On the basis of this T/G polymorphism, we determined CD14 genotypes with 210 colorectal cancer cases and with a subcohort of 2,160 individuals who were randomly selected from the cohort. Our results showed that the individuals exposed to A-bomb radiation (≥5 mGy) were at an increased risk of colon cancer, but not rectum cancer, with relative risk (RR) of 1.19/Gy (95%CI: 1.04-1.36). When we divided the study subjects into three groups for radiation dose and into two groups for CD14 genotypes, significantly high risk of colon cancer was found with RR of 2.40 (95%CI: 1.37-4.23) for the combined category of CD14-T/T homozygote and the highest dose (≥0.7Gy), compared with the baseline category (CD14-T/G or G/G and no dose). These results suggest that CD14-related inflammatory response might be involved in the development of radiation-associated colon cancer, not rectum cancer, among A-bomb survivors, and that the CD14 genotyping might be involved in individual risk of colon cancer together with radiation dose. To find a functional significance of this polymorphism, we are currently working on ELISA-based assay to measure serum levels of soluble CD14 among healthy individuals in relation to the CD14 genotyping. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4715.

Metabolic cardiovascular disease risk factors and their clustering in subclinical hypothyroidism

A possible association between subclinical hypothyroidism and cardiovascular disease (CVD) has been reported. Monitoring of atomic-bomb survivors for late effects of radiation exposure at the Radiation Effects Research Foundation has provided the opportunity to examine associations between subclinical hypothyroidism and metabolic CVD risk factors. The objective of the study was to evaluate associations between subclinical hypothyroidism and metabolic CVD risk factors, and a cluster of these factors. This was a cross-sectional study of 3549 subjects (mean age 70 years; 1221 men and 2328 women) between 2000 and 2003 comprising 306 subjects with subclinical hypothyroidism and 3243 control euthyroid subjects in Japan. We investigated associations between subclinical hypothyroidism and metabolic CVD risk factors such as hypertension, diabetes mellitus, dyslipidaemia and hyperuricaemia, and a cluster of these factors. Subclinical hypothyroidism was not significantly associated with either hypertension, diabetes mellitus or hyperuricaemia defined by taking into account the use of medications in both men and women, but in men it was associated with dyslipidaemia (P = 0.02). We observed a significantly increased odds ratio (OR) for the presence of three or more metabolic CVD risk factors in men with subclinical hypothyroidism after adjusting for age, body mass index (BMI), and smoking status [OR: 1.83, 95% confidence interval (CI): 1.13-2.94, P = 0.01]. The significant associations remained after an additional adjustment for atomic-bomb radiation dose. There appears to be a significant increase in a cluster of metabolic CVD risk factors among people with subclinical hypothyroidism.

No Evidence of Increased Mutation Rates at Microsatellite Loci in Offspring of A-Bomb Survivors

To evaluate the genetic effects of A-bomb radiation, we examined mutations at 40 microsatellite loci in exposed families (father-mother-offspring, mostly uni-parental exposures), which consisted of 66 offspring having a mean paternal dose of 1.87 Gy and a mean maternal dose of 1.27 Gy. The control families consisted of 63 offspring whose parents either were exposed to low doses of radiation (< 0.01 Gy) or were not in the cities of Hiroshima or Nagasaki at the time of the bombs. We found seven mutations in the exposed alleles (7/2,789; mutation rate 0.25 x 10(-2)/locus/generation) and 26 in the unexposed alleles (26/7,465; 0.35 x 10(-2)/locus/generation), which does not indicate an effect from parental exposure to radiation. Although we could not assign the parental origins of four mutations, the conclusion may hold since even if we assume that these four mutations had occurred in the exposed alleles, the estimated mean mutation rate would be 0.39 x 10(-2) in the exposed group [(7 + 4)/2,789)], which is slightly higher than 0.35 x 10(-2) in the control group, but the difference is not statistically significant.

Longitudinal Trends of Total White Blood Cell and Differential White Blood Cell Counts of Atomic Bomb Survivors

In studying the late health effects of atomic-bomb (A-bomb) survivors, earlier findings were that white blood cell (WBC) count increased with radiation dose in cross-sectional studies. However, a persistent effect of radiation on WBC count and other risk factors has yet to be confirmed. The objectives of the present study were 1) to examine the longitudinal relationship between A-bomb radiation dose and WBC and differential WBC counts among A-bomb survivors and 2) to investigate the potential confounding risk factors (such as age at exposure and smoking status) as well as modification of the radiation dose-response. A total of 7,562 A-bomb survivors in Hiroshima and Nagasaki were included in this study from 1964-2004. A linear mixed model was applied using the repeated WBC measurements. During the study period, a secular downward trend of WBC count was observed. Radiation exposure was a significant risk factor for elevated WBC and differential WBC counts over time. A significant increase of WBC counts among survivors with high radiation dose (> 2 Gy) was detected in men exposed below the age of 20 and in women regardless of age at exposure. Effects on WBC of low dose radiation remain unclear, however. Cigarette smoking produced the most pronounced effect on WBC counts and its impact was much larger than that of radiation exposure.