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Keywords:

  • atomic bomb;
  • genomic instability;
  • p53 binding protein 1;
  • radiation;
  • basal cell carcinoma

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. Conflict of Interest Disclosures
  8. References

BACKGROUND:

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.

METHODS:

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 (≤1.5 km, 1.6-2.9 km, and ≥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.

RESULTS:

The incidence rate of BCC increased significantly as exposure distance approached the hypocenter. Of the 7 epidermal samples from the proximal group (≤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 (≥3 km) and all samples from the control group predominantly expressed the stable type of 53BP1 expression in the epidermis.

CONCLUSIONS:

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 2009. © 2009 American Cancer Society.

Sixty-three years have elapsed since 2 atomic bombs (A-bombs) were exploded on Hiroshima and Nagasaki, Japan in August 1945. The survivors who were exposed at young ages already have reached the cancer-prone age. The incidence of several types of leukemia peaked during the period from 5 years to 10 years after the A-bomb explosions. Meanwhile, an increased risk of cancer has continued for decades, and the incidence of certain types of cancer has remained higher in survivors than in controlled populations.1-3 We recently described a higher IR of multiple primary cancers (MPCs) in A-bomb survivors, particularly for those who were exposed at a younger age and at a closer distance to the hypocenter.4 The occurrence of MPCs is considered a reflection of systematic exposure to carcinogens or a predisposition to cancer that serves as an indicator of genomic instability (GIN). These results provide evidence for the involvement of A-bomb radiation in the occurrence of MPCs among the survivors. Thus, a higher risk of cancer still persists in survivors. Although a long-lasting radiation effect is considered to be a contributing factor in tumorigenesis in A-bomb survivors, to date, the molecular mechanisms involved are not fully understood.

It has been postulated that ionizing radiation induces breast cancers among A-bomb survivors.3 Our recent study demonstrated the association of human epidermal growth factor receptor 2 or HER-2 and cellular myelocytomatosis or C-MYC oncogene amplification in breast cancers among A-bomb survivors with radiation exposure.5 It is believed that oncogene amplification is associated with GIN and with the main characteristic of solid tumors.6 It is conceivable that radiation from the A-bomb 63 years ago may have induced a higher level of GIN in A-bomb survivors as a long-lasting health effect associated with the development of oncogene amplifications and subsequent carcinogenesis.

Ionizing radiation effectively induces DNA double strand breaks (DSBs) in normal cells and activates DNA damage response (DDR) pathways to maintain genomic integrity. Thus, defective DDR can result in GIN, which generally is considered central to any carcinogenic process.7, 8 Alternatively, the presence of activated DDR can be a hallmark of an enhanced carcinogenic process. P53-binding protein 1 (53BP1) belongs to a family of evolutionarily conserved DDR proteins with C-terminal breast cancer 1 (BRCA1) C-terminus domains.9, 10 53BP1 is a nuclear protein that rapidly localizes at the sites of DSBs and activates p53 along with other kinases.11-16 Subsequently, activated p53 plays a critical role in cellular responses to genomic injury, such as cell cycle arrest, DNA repair, and apoptosis.17, 18 It has been well documented in vitro with immunofluorescence that 53BP1 exhibits diffuse nuclear staining in untreated primary cells. However, after exposure to radiation, 53BP1 localizes at the sites of DSBs and forms discrete nuclear foci.11, 12, 19, 20 We recently demonstrated in formalin-fixed, paraffin-embedded mouse intestine that immunofluorescence analysis specifically detected the 53BP1 nuclear foci as a state of DDR induced by radiation.21 Because 1 manifestation of GIN is the induction of endogenous DDR,22 the level of 53BP1-focus formation can be considered a cytologic marker for GIN.

Skin cancers are relatively rare in Japan. The age-adjusted IR of approximately 1.0 to 5.5 per 100,000 person-years (PY) for nonmelanoma skin cancer in Japan are much lower than the rates among US white of approximately 250 per 100,000 PY.23, 24 A previous study indicated that the crude IR of basal cell carcinoma (BCC) of the skin among residents in Nagasaki city who were not exposed to A-bomb radiation was 3.1 per 100,000 PY.25 In addition to breast cancer, the incidence of BCC also reportedly was elevated in A-bomb survivors, suggesting a radiation etiology in skin carcinogenesis as well.26 The skin is the primary barrier for humans against the external environment. Therefore, epidermal cells are the first cells to be exposed to physical and chemical genotoxic agents, such as ultraviolet (UV) radiation, ionizing radiation, and superoxide. In the current study, by using immunofluorescence staining for 53BP1, we demonstrated the sporadic activation of DDR in the epidermis surrounding BCC resected from survivors who were exposed to A-bomb radiation proximal to the hypocenter. The results suggest that the presence of increased GIN as a late effect of radiation from the A-bomb can predispose survivors to the development of cancer.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. Conflict of Interest Disclosures
  8. References

Identification of Basal Cell Carcinoma in Atomic Bomb Survivors

Clinical data were available on 91,890 A-bomb survivors who were registered after 1968 at the Division of Scientific Data Registry, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences. The population that was used in this study was confined to residents if Nagasaki city who were exposed directly to the A-bomb. To identify cases of skin BCC in survivors, we used a database compiled by the Nagasaki Tumor Tissue Registries. This database contains 301,673 pathologic reports of patients living in south Nagasaki prefecture, including Nagasaki city, that were collected from 1961 to 1999. The database includes patient age, sex, tumor site, histologic diagnosis, and date of diagnosis.

Association Between Basal Cell Carcinoma and Atom Bomb Radiation

An event of BCC in each survivor was considered to occur with a pathologic diagnosis. PY of observation were cumulated from the date on which an individual survivor's data were registered in our database, beginning in 1968 and continuing until there was either a diagnosis of BCC, time of death, termination of follow-up (emigration from Nagasaki city), or the end of study (December 31, 1999). These BCC cases were divided into 3 different distance groups: individuals who were exposed at a distance ≤1.5 km from the hypocenter (proximal group), individuals who were exposed at a distance >1.5 km but <3 km from the hypocenter (intermediate group), and individuals who were exposed at a distance ≥3 km from the hypocenter (distal). Then, the IR of BCC per 100,000 PY among A-bomb survivors was calculated with stratification by distance in kilometers from the hypocenter (≤1.5 km, 1.6-2.9 km, ≥3 km).

The exposure distance was used as a measure of the estimated irradiated dose, as documented previously in several unique epidemiological studies on Nagasaki survivors.4, 26-29 The estimated doses in Nagasaki survivors who were not shielded at the time of explosion are were 924.7 centigrays (cGy) at 1 km, 120.7 cGy at 1.5 km, 17.9 cGy at 2 km, and 2.9 cGy at 2.5 km from the hypocenter.28 The experimental protocol was approved by the Ethics Review Committee of Nagasaki University Graduate School of Biomedical Sciences (Protocol No. 0305150036-2).

Survivors Studied With Immunofluorescence for p53 Binding Protein 1 Expression

For this study, we used samples of the epidermis surrounding BCCs that had been surgically resected from A-bomb survivors. For controls, samples of the epidermis surrounding BCCs from calendar year-matched patients who were not exposed to the A-bomb were analyzed. All samples were formalin-fixed, paraffin-embedded tissues that were archived in the pathologic records of our department. The sun-exposed epidermis is exposed continuously to a low level of physical and chemical genotoxic agents, such as UV radiation, ionizing radiation, and oxidative stress. Thus, the level of GIN in the sun-exposed epidermis may be influenced by a genotoxic injury induced by external environmental factors. Therefore, to evaluate the level of GIN in the epidermis from A-bomb survivors and control populations, samples that were resected only from a nonexposed site, such as chest, vulva, axilla, thigh, buttock, and inguinal regions, were tested for 53BP1 expression with immunofluorescence.

Immunofluorescence for p53 Binding Protein 1 Expression

After antigen retrieval with microwave treatment in citrate buffer, deparaffinized sections were preincubated with 10% normal goat serum. Tissue sections were then reacted with anti-53BP1 rabbit polyclonal antibody (Bethyl Laboratories, Montgomery, Tex) at a 1:200 dilution. The slides subsequently were incubated with Alexa Fluor 488-conjugated goat antirabbit antibody (Invitrogen, Carlsbad, Calif). Specimens were counterstained with 4′6-diamidino-2-phenylindole dihydrochloride (DAPI-I; Vysis Inc., Downers Grove, Ill) and were studied and photographed using a high-standard, all-in-1 fluorescence microscope (Biorevo BZ-9000; KEYENCE, Japan, Osaka, Japan). Signals were analyzed in 10 viewing areas per specimen at ×1000 magnification.

Evaluation of Immunofluorescence Results

The pattern of 53BP1 immunoreactivity, as described in our previous report,21 was classified into 4 types: 1) the stable type (faint and diffuse nuclear staining), 2) the low DDR type (1 or 2 discrete nuclear foci), 3) the high DDR type (≥3 discrete nuclear foci), and 4) the abnormal type (intense, heterogeneous nuclear staining with occasional several small foci). The percentage of epidermal cells that expressed each type of 53BP1 immunoreactivity in each viewing area was calculated in each specimen.

Statistical Analyses

The effect of exposure distance on the IR of BCC in A-bomb survivors was measured as a hazard ratio (HR) with 95% confidence interval (CI) using a multivariate Cox proportional hazards model. The Cochran-Armitage trend test was used to evaluate associations between the type of 53BP1 expression in the epidermis and exposure distance groups. Furthermore, effects of sex and exposure distance on the incidence of BCC in nonexposed and sun-exposed sites among A-bomb survivors were evaluated as odds ratios (OR) with 95% CIs using a multivariate logistic regression model. The PHREG procedure in SAS software (version 8.2; SAS Institute, Cary, NC) was used for calculations. All tests were 1-tailed, and a P value <.05 was considered statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. Conflict of Interest Disclosures
  8. References

The Incidence Rate of Basal Cell Carcinoma and Its Association With Atom Bomb Radiation

Overall, 91,890 A-bomb survivors have been followed for 1,557,381 PY, and 146 patients have had a confirmed diagnosis of BCC, including 64 men and 82 women. The crude IR of BCC was 9.4 per 100,000 PY in the overall study population. The crude IRs of BCC in survivors by sex and by exposure distance are summarized in Table 1. The IR of BCC decreased significantly as distance increased from the hypocenter (HR per 1-km increment, 0.77; 95% CI, 0.68-0.88).

Table 1. Crude Incidence Rates of Basal Cell Carcinoma in Nagasaki Atomic Bomb Survivors by Sex and Exposure Distance Group
Distance, kmMenWomenTotal
PYCasesIRPYCasesIRPYCasesIR
  1. PY indicates person-years; IR, incidence rate.

≤1.541,0201639.055,2821119.996,3022728.0
1.6-2.9157,6161610.2264,060166.1421,676327.6
≥3.0384,561328.3654,842558.41,039,403878.4
Overall583,1976411.0974,184828.41,557,3811469.4

The proximal distance group (≤1.5 km; of 27 of 146 patients; 18.5%) included 16 BCCs from sun-exposed sites, 9 BCCs from nonexposed sites, and 2 BCCs from unknown sites. The intermediate distance group (1.6-2.9 km; 32 of 146 patients; 21.9%) included 26 BCCs from sun-exposed site s, 4 BCCs from nonexposed sites, and 2 BCCs from unknown sites. The distal distance group (≥3 km; 87 of 146 patients; 59.6%) included 74 BCCs from sun-exposed sites, 10 BCCs from nonexposed sites, and 3 BCCs from unknown sites. The clinical profiles of the patients with BCC by exposure distance group and site are summarized in Table 2.

Table 2. Summary of Each Clinical Factor by Exposure Distance Group and Site of Basal Cell Carcinoma in Atomic Bomb Survivors
VariableDistance Group
Proximal, ≤1.5 km (n=27)Intermediate, 1.6-2.9 km (n=32)Distal, ≥3 km (n=87)
NonexSun-exUkNonexSun-exUkNonexSun-exUk
  1. Nonex indicates nonexposed; Sun-ex, sun exposed; Uk, unknown; ATB, age at time of bombing; ATD, age at time of diagnosis.

No.9162426210743
No. of men/women4/510/62/01/312/141/14/625/493/0
Distance, km1.11.11.32.42.32.23.74.63.9
ATB, y20.52335.535.533.324.516.929.139.7
ATD, y65.668.677.182.976.353.164.272.979.9

p53 Binding Protein 1 Expression in Normal Epidermis Surrounding Basal Cell Carcinoma

For immunofluorescence analysis, samples from 7 of 9 patients (mean age, 67 years; men/women, 3/4) with nonexposed epidermis in the proximal distance group and samples from 5 of 10 patients (mean age, 60.6 years; men/women, 2/3) with nonexposed epidermis in the distal distance group were available. For control samples, samples from 7 individuals (mean age, 68.3 years; men/women, 5/2) with nonexposed epidermis also were analyzed. No family histories of skin cancer were evident in our patients. The clinical profiles of all patients with BCC in this study are summarized in Table 3. The results from immunofluorescence staining patterns for 53BP1 in the epidermis of each sample also are presented in Table 3. The mean numbers (±standard deviation) of epidermal cells that were analyzed for 53BP1 expression were 161.7 ± 39.1 cells (range, 111-224 cells), 174.6 ± 38.5 cells (range, 145-239 cells), and 191.6 ± 33.1 cells (range, 145-240 cells) per sample in the proximal distance, distal distance, and control groups, respectively. Statistical analysis with the Welch t test revealed no significant differences in the number of epidermal cells that were examined between the 3 groups. Of the 7 samples of nonexposed epidermis in the proximal distance group, 5 samples (71%) predominantly expressed DDR and abnormal type cells in keratinocytes around the basal layer (Fig. 1A,D). The other 2 samples (29%) predominantly had stable cell types but also included a small number (up to 5%) of high DDR types in the basal layer. In contrast, 4 of 5 samples in the distal distance group (Fig. 1B,E) and all samples in the control groups (Fig. 1C,F) predominantly expressed stable types in >70% of epidermal cells but also had up to 20% of low DDR type cells in the basal layer of the epidermis. The Cochran-Armitage trend test revealed that the mean percentage of cells expressing DDR and an abnormal type of 53BP1 in the epidermis of the proximal distance group had a significant tendency to be higher than the percentages in both the distal distance group and the control group (P < .001). However, there was no significant difference in the type of 53BP1 expression in the epidermis between the distal distance group and the control group.

Table 3. Clinical Profiles of Each Basal Cell Carcinoma Sample Used in Immunofluorescence Analysis and Results of Typing for p53 Binding Protein 1 Expression in Normal Epidermis
GroupAge, ySexDistance, kmDisease SitePH53BP1 Expression, %
StableLow DDRHigh DDRAbnormal
  • 53BP1 indicates p53 binding protein 1; PH, past history of other malignancy; DDR, DNA damage response.

  • *

    Squamous cell carcinoma.

Proximal distant group         
 160Woman0.5ChestThyroid, breast011.22.386.5
 270Woman0.7Vulva 67.527.84.60
 369Man1.0Inguinal 26.11854.11.8
 466Man1.1ButtockProstate77.917.54.60
 582Man1.2Buttock 5.80.9093.3
 669Woman1.3Back 47.13616.90
 753Woman1.4Heel 49.621.528.90
 Mean67 1.03  39.11915.925.9
Distal distant group         
 168Woman3ButtockSkin*74.516.88.70
 253Man3.6Back 86.6102.90.4
 365Man3.7Back 67.826.15.60.6
 466Woman3.8Abdomen 91.38.800
 551Woman5Buttock 91.78.300
 Mean60.6 3.82  82.4143.40.2
Control group         
 179WomanBack 918.40.60
 264ManBack 84.8141.10
 365ManBack 82.815.91.40
 458ManAxillaThyroid89.18.41.51
 566WomanBack 82.510.43.33.8
 665ManBack 77.916.35.80
 781ManPubic 77.417.33.12.2
 Mean68.3   83.6132.41
thumbnail image

Figure 1. Immunofluorescence of p53 binding protein 1 (53BP1) expression in the epidermis surrounding basal cell carcinoma at the nonexposed site. (A) This sample from the proximal distance group of atomic bomb survivors reveals many discrete nuclear 53BP1 foci in the epidermis around the basal layer. In contrast to A, samples from (B) the distal distance group of atomic bomb survivors and (C) the control group reveal only a few nuclear 53BP1 foci in the epidermal cells. Squares in D, E, and F with hematoxylin and eosin staining reveal corresponding areas of A, B, and C, respectively.

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Comparisons for Effects of Sex and Atom Bomb Radiation in the Incidence of Basal Cell Carcinoma Among Atom Bomb Survivors by Site

The effects of sex and exposure distance on the incidence of BCC at nonexposed and sun-exposed sites among A-bomb survivors were evaluated as ORs with 95% CIs using a multivariate logistic regression model. These results are presented in Table 4. When analyses were stratified by sex, the IR of BCC was significantly higher in men than in women for both sun-exposed sites (OR [vs women], 1.63; 95% CI, 1.09-2.43) and total sites (OR [vs women], 1.51; 95% CI, 1.04-2.19). However, there was no significant difference in the IR of BCC between men and women in for nonexposed sites (OR [vs women], 1.05; 95% CI, 0.40-2.75). Furthermore, when the analysis was stratified by distance group, the IR of BCC was significantly higher in the proximal distance group than in the distal distance group both for nonexposed sites (OR [vs the distal distance group], 5.86; 95% CI, 2.19-15.6) and for total sites (OR [vs the distal distance group], 2.17; 95% CI, 1.32-3.57). However, there was no significant difference in the IR of BCC between the proximal and distal distance groups at sun-exposed sites (OR [vs the distal distance group], 1.62, 95% CI, 0.89-2.94) or between the intermediate and distal distance groups for any sites.

Table 4. Comparisons of the Effect of Sex and Distance in the Incidence of Basal Cell Carcinoma Among Atomic Bomb Survivors
FactorNonexposed Site (n=23)Sun-exposed Site (n=116)Total (n=139)
OR95% CIOR95% CIOR95% CI
  1. OR indicates odds ratio; CI, confidence interval.

Sex      
 Men1.050.40-2.751.631.09-2.431.511.04-2.19
 Women1 1 1 
Distance, km      
 0-1.55.862.19-15.61.620.89-2.942.171.32-3.57
 1.6-2.90.260.03-2.000.890.56-1.420.810.51-1.27
 ≥31 1 1 

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. Conflict of Interest Disclosures
  8. References

The epidemiologic and molecular analyses of carcinogenesis in A-bomb survivors require clinical data from individuals and biologic materials with pathologic data on tumors. In this study, 2 databases were used to identify BCC resected from survivors: a clinical database providing exposure distance on Nagasaki survivors registered at our institute, which was established in 1972, and a pathologic database from the Nagasaki Tumor Tissue Registries, which were established in 1974. Our retrospective search of these independently established databases identified a total of 146 patients with BCC who were tracked from 1968 to 1999 and were exposed directly to Nagasaki A-bomb radiation. Among these survivors, an increased risk has been demonstrated for the development of BCC in individuals who were exposed at a closer distance. This concurs with previous reports26, 30 and provides further evidence that A-bomb radiation is associated significantly with skin carcinogenesis.

Several epidemiologic reports have suggested that an increased risk of cancer has continued for decades, and a higher risk of certain types of cancers still persists in survivors.1-4 Thus, a long-lasting health effect is considered to be a contributing factor in tumorigenesis in A-bomb survivors. In the current study, we demonstrated that there were several nuclear 53BP1 foci in the epidermis surrounding BCC of nonexposed skin in survivors who were exposed at a distance proximal to the hypocenter, suggesting a constitutive activation of DDR in the epidermis of A-bomb survivors. Human cancers develop through a multistep process that involves the accumulation of genetic mutations.31 It is well established that any DNA damage can induce DDR leading to GIN in injured cells. GIN results in the accumulation of genetic mutations that are implicated in both the initiation and the progression of cancers. Thus, we submitted that, compared with our control group of individuals who were not affected with A-bomb radiation, A-bomb radiation may induce a higher state of GIN in the epidermis of survivors that can be a long-lasting health effect contributing to tumorigenesis. Ionizing radiation effectively induces GIN, which is manifested in several DSBs in a dose-dependent manner. DSBs are repaired through error-prone nonhomologous end joining, single-strand annealing, and/or error-free homologous recombination.32 Although most DNA damage is repaired correctly or is eliminated through tumor suppressor function of p53, it is well known that the repair process disrupts the genomic structure, which may result in the induction of a mutation, gross rearrangement of chromatin, and consequent promotion of tumorigenesis.33-36 A-bomb radiation may induce minor disruption of the genomic structures, which may result in GIN for an extended time in the epidermis and, subsequently, may affect skin carcinogenesis in the survivors.

In our recent reports, we have proposed that immunofluorescence analysis of 53BP1 expression can be a useful tool for estimating the level of GIN in tissue sections and may serve as a valuable molecular marker of malignant potential even in formalin-fixed materials.21, 37 GIN seems to be induced at the precancerous stage during skin carcinogenesis, because actinic keratosis revealed a high DDR type of 53BP1 immunoreactivity.37 Furthermore, we noticed that, in the control group, a low DDR type of 53BP1 immunoreactivity frequently was observed in sun-exposed epidermis, whereas few 53BP1 nuclear foci were observed in nonexposed epidermis.37 Thus, the sun-exposed epidermis seems to have suffered frequently from a minor genotoxic injury induced by external environmental factors, whereas the endogenous DDR was observed only in the nonexposed epidermis of the control group. It is noteworthy that, in the current study, we demonstrated that a high level of the high DDR and abnormal type of 53BP1 expression in the epidermis surrounding BCC at the nonexposed site was observed only in the proximal distance group and not in the distal distance or control groups. UV exposure from sunlight is a major causative factor for skin cancer at sun-exposed sites. Although squamous cell carcinoma of the skin usually develops from UV-induced precancerous lesions, the pathogenesis of sporadic BCC is more controversial.38 Indeed, as noted in our patients, BCC did not always arise on sun-exposed areas. Thus, etiologies other than UV should be considered in BCC at nonexposed areas. It also is worth noting that the percentage of BCC observed on nonexposed areas was higher in the proximal distance group (9 of 27 patients; 33.3%) than in the intermediate distance group (4 of 32 patients; 12.5%) or the distal distance groups (10 of 87 patients; 11.5%). Furthermore, our multivariate analyses revealed that exposure to A-bomb radiation at a closer distance to the hypocenter was a strong risk factor for the incidence of BCC at nonexposed sites, but not at sun-exposed sites, in survivors. It appears that an elevated risk of BCC among the survivors is caused mainly by the higher IR of BCC on nonexposed skin. Furthermore, although the incidence of BCC at sun-exposed sites was significantly higher in men than in women, no sex effect was observed in the incidence of BCC at nonexposed sites among the survivors. The predominance risk among men for BCC at sun-exposed skin sites is plausible, because Japanese women generally dislike sun tanning from the cosmetic point of view and tend to shield their skin from UV exposure. In contrast, because we observed no effect for sex, contributing factors other than UV should be considered in the risk of BCC at nonexposed sites. Thus, it appears that radiation etiology is associated more strongly with tumorigenesis of BCC in the nonexposed skin of survivors.

The BCCs in survivors are unusual, in that they potentially are attributable to 2 types of radiation: UV and ionizing. This study demonstrated several nuclear 53BP1 foci in the epidermis surrounding BCC at nonexposed sites resected from A-bomb survivors who were exposed at a distance proximal to the hypocenter, similar to the foci reported in irradiated cells, suggesting a constitutive activation of DDR in the epidermis of survivors. It is suggested that ionizing radiation from the A-bomb may affect the development of BCC by inducing a higher level of GIN mainly in the basal layer of the epidermis among survivors. The survivors, particularly those who were exposed at a younger age, even now still have a high risk for cancers in various organs, including MPCs. The crucial mechanisms that can account for the continuously higher incidence of cancers in A-bomb survivors for decades remain to be determined. Further research on the molecular mechanisms to maintain a long-lasting GIN in the epidermis from survivors can contribute to an understanding of both radiation-associated carcinogenesis and the predisposition to cancers.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. Conflict of Interest Disclosures
  8. References

We thank Ms. Noguchi for her secretarial assistance in preparing this article.

Conflict of Interest Disclosures

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. Conflict of Interest Disclosures
  8. References

Supported in part through Nagasaki University Global Center of Excellence Program, by a Grant-in-Aid for Scientific Research from the Japanese Ministry of Education, Science, Sports, and Culture (20590367), and by a Grant for Research Project of Atomic Bomb Diseases from the Japanese Ministry of Health, Labor, and Welfare.

References

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. Conflict of Interest Disclosures
  8. References