REPORT

{gamma}-Radiation Sensitivity and Risk of Glioma

Melissa L. Bondy, Li-E. Wang, Randa El-Zein, Mariza de Andrade, Mano S. Selvan, Janet M. Bruner, Victor A. Levin, W. K. Alfred Yung, Phyllis Adatto, Qingyi Wei

Affiliations of authors: M. L. Bondy, L.-E. Wang, R. El-Zein, M. S. Selvan, P. Adatto, Q. Wei (Department of Epidemiology), J. M. Bruner (Department of Pathology), V. A. Levin, W. K. A. Yung (Department of Neuro-Oncology), The University of Texas M. D. Anderson Cancer Center, Houston; M. de Andrade, Department of Health Sciences Research, Mayo Clinic and Mayo Foundation, Rochester, MN.

Correspondence to: Melissa L. Bondy, Ph.D., Department of Epidemiology, Box 189, The University of Texas M. D. Anderson Cancer Center, Houston, TX (e-mail: mbondy{at}mdanderson.org).


    ABSTRACT
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Background: About 9% of human cancers are brain tumors, of which 90% are gliomas. {gamma}-Radiation has been identified as a risk factor for brain tumors. In a previous pilot study, we found that lymphocytes from patients with glioma were more sensitive to {gamma}-radiation than were lymphocytes from matched control subjects. In this larger case–control study, we compared the {gamma}-radiation sensitivity of lymphocytes from glioma patients with those from control subjects and investigated the association between mutagen sensitivity and the risk for developing glioma. Methods: We used a mutagen sensitivity assay (an indirect measure of DNA repair activity) to assess chromosomal damage. We {gamma}-irradiated (1.5 Gy) short-term lymphocyte cultures from 219 case patients with glioma and from 238 healthy control subjects frequency matched by age and sex. After irradiation, cells were cultured for 4 hours, and then Colcemid was added for 1 hour to arrest cells in mitosis. Fifty metaphases were randomly selected for each sample and scored for chromatid breaks. All statistical tests were two-sided. Results: We observed a statistically significantly higher frequency of chromatid breaks per cell from case patients with glioma (mean = 0.55; 95% confidence interval [CI] = 0.50 to 0.59) than from control subjects (mean = 0.44; 95% CI = 0.41 to 0.48) (P<.001). Using 0.40 (the median number of chromatid breaks per cell in control subjects) as the cut point for defining mutagen sensitivity and adjusting for age, sex, and smoking status, we found that mutagen sensitivity was statistically significantly associated with an increased risk for glioma (odds ratio = 2.09; 95% CI = 1.43 to 3.06). When the data were divided into tertiles, the relative risk for glioma increased from the lowest tertile to the highest tertile (trend test, P<.001). Conclusion: {gamma}-Radiation-induced mutagen sensitivity of lymphocytes may be associated with an increased risk for glioma, a result that supports our earlier preliminary findings.



    INTRODUCTION
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
About 9% of human cancers are brain tumors, of which 90% are gliomas (1). Although the etiology of brain tumors remains unclear, exposure to {gamma}-radiation has been identified as a risk factor (2). In a previous pilot study (3), we found that glioma patients were more sensitive to {gamma}-radiation than normal control subjects. The frequency of spontaneous chromosome aberrations, indicating genomic instability, has been shown to be associated with an increased risk for developing cancer (4,5). Chromosomal aberrations (or instability) are thought to be a measure of susceptibility to carcinogens that depends on inherited (genetic) and acquired (somatic) characteristics of cells. Susceptibility to genotoxic carcinogens may result from variations in the metabolism of carcinogens (6) and from variations in the ability of various individuals to repair carcinogen-induced DNA damage (7). Susceptibility to {gamma}-radiation may be genetically determined, because skin fibroblasts and peripheral blood cells from individuals genetically predisposed to developing cancer have a higher frequency of chromatid breaks than those from normal control subjects (8).

In the general population, the frequency of spontaneous chromosome aberrations is low, and many assays assessing these types of breaks may not be appropriate for epidemiologic studies that require a large number of samples to be screened. Hsu et al. (9), however, have developed an assay for mutagen sensitivity that measures genetic susceptibility by estimating the frequency of in vitro bleomycin-induced chromatid breaks in short-term lymphocyte cultures. The level of induced chromatid breaks is much higher than that of spontaneous breaks; thus, this assay is applicable to epidemiologic studies. The biologic rationale for the mutagen sensitivity assay is that the variation in the number of induced chromatid breaks arises from differences in the activity of DNA repair enzymes or factors that contribute to an individual's susceptibility to initial clastogenic effects (10). For instance, Dave et al. (11) have shown that chromatid break sites induced by bleomycin in vitro are not random but are predetermined by host susceptibility factors and specific mechanisms related to the interactions of free-radical oxygen with chromatids.

The mutagen sensitivity assay indirectly assesses the effectiveness of one or more DNA repair mechanisms (12) by measuring chromosomal damage after a fixed period of mutagen exposure. For example, cells from patients with ataxia-telangiectasia, who are sensitive to {gamma}-radiation, repair clastogen-induced chromosomal damage more slowly than cells from normal individuals, a finding that also supports the rationale for the mutagen sensitivity assay (13). Therefore, we have been conducting epidemiologic studies to validate the use of a mutagen sensitivity assay to detect an increased susceptibility to cancer.

Our pilot study (3) investigated genetic susceptibility to brain tumors in a small case–control study. In this study (3), we used {gamma}-radiation to induce chromosomal breaks in cultures of stimulated peripheral blood lymphocytes, because exposure to radiation is associated with an increased risk for brain tumors. We found that case patients had lower DNA repair activity than control subjects, as measured by increased chromosome sensitivity to {gamma}-irradiation, and that this chromosome sensitivity was an independent risk factor for gliomas (2).

To substantiate that preliminary finding, we expanded the pilot study to a larger, hospital-based, case–control study to confirm our previous findings that the mutagen sensitivity assay can be used to determine sensitivity to {gamma}-radiation. We also have investigated whether sensitivity to {gamma}-radiation is associated with an increased risk of developing glioma.


    SUBJECTS AND METHODS
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Study Subjects

The case subjects were patients with histopathologically confirmed, previously untreated, malignant gliomas. We sequentially recruited 364 participants, from whom we obtained blood samples. Twenty-two patients were later determined to have received radiotherapy and chemotherapy and thus were eliminated. Patients younger than 18 years (n = 17) and patients older than 60 years (n = 46) were also excluded. Non-Caucasian patients—11 Hispanic, 12 African-American, and three Asian—were excluded because the numbers were too small for meaningful results. In addition, viable cells for the assay were not produced in cultures from 34 samples. Thus, we studied 219 patients. Among these 219 case patients, the diagnosis for 106 (48.4%) was glioblastoma multiforme, for 39 (17.8%) was anaplastic astrocytoma, and for 74 (33.8%) was other gliomas, such as oligodendroglioma or mixed glioma. The case patients were registered at The University of Texas M. D. Anderson Cancer Center, Houston, from March 31, 1994, through July 31, 1999, and also participated in an ongoing family study of glioma, as described previously (3). All of the participants signed an informed consent before providing a blood sample and completing their interview. The study recruited participants sequentially but eliminated those having received chemotherapy or radiotherapy. For this study, we included only Caucasian case patients between the ages of 18 and 60 years because we were unable to recruit pediatric and adolescent control subjects. We excluded older (>=60 years) case subjects because we wanted to evaluate genetic susceptibility.

The control subjects were cancer-free donors at The University of Texas M. D. Anderson Cancer Center Blood Bank (n = 87) or visitors to, or relatives of, patients at The University of Texas M. D. Anderson Cancer Center, who were biologically unrelated to the case patients (n = 151). Control subjects were matched to case patients by age (±5 years), sex, and ethnicity.

Included in the 219 case patients are 45 case patients from our pilot study (3), and included in the 238 control subjects are 117 subjects from our pilot study (3). We included the study participants from the former pilot study to increase the statistical power of the study because they were recruited by using the same inclusion criteria.

A questionnaire administered to the case patients by trained interviewers yielded comprehensive data on their history of personal health, family history of illnesses including cancer, occupation, exposures, smoking, and alcohol consumption. The questionnaire used for many of the control subjects was brief and did not include the extensive details obtained from the case patients; in particular, their family history of cancer was not obtained. Thus, a limitation of this study is that we could not assess the relationship between family history of cancer and mutagen sensitivity in case patients and control subjects.

Mutagen Sensitivity Assay

{gamma}-Radiation was selected as the test mutagen because it induces single- and double-stranded DNA breaks and because radiation exposure is a documented risk factor for brain tumors (2). We used a previously established optimal 1.5-Gy dose of {gamma}-radiation to investigate mutagen sensitivity of the peripheral blood lymphocytes by counting chromatid breaks in metaphase preparations. This dose is in the range of the daily dose generally used in clinical practice (also similar to the amount of radiation therapy a patient receives as a single daily dose, generally), i.e., 1.2–2 Gy per fraction (3).

Two standard lymphocyte cultures were established from each subject, as described elsewhere (6). Briefly, for each culture, 1 mL of fresh blood was cultured in a T-25 plastic culture flask with 9 mL of RPMI-1640 medium containing phytohemagglutinin (112.5 µg/mL; Murex Diagnosis, Norcross, GA). After 67 hours of incubation, the cells of one culture were {gamma}-irradiated from a 137Cs source (Cesium Irradiator Mark 1, model 30; J. L. Shepherd and Associates, Glendale, CA), and the other culture was left untreated, to assess the baseline frequency of chromatid breaks for intrasubject comparison. The cells in one culture were exposed directly to incident {gamma}-irradiation at 15.58 Gy/minute for 5.8 seconds or approximately 0.26 Gy/second, and then irradiated and nonirradiated cultures were incubated for another 4 hours. Cells were then treated with Colcemid (0.04 µg/mL) for 1 hour to arrest them in mitosis and harvested. Air-dried slides were prepared, coded, and stained with 4% Giemsa without banding, and 50 metaphases were scored for each individual. Only frank chromatid breaks were recorded; chromatid gaps or attenuated regions were discarded. We then calculated the average number of chromatid breaks per cell. Any individual with a more than 0.40 chromatid break per cell, the median number in control subjects, was considered to be mutagen sensitive.

Statistical Analysis

For the mutagen sensitivity analysis, we calculated the mean number of induced chromatid breaks per cell and used Student's t test to determine differences between case patients and control subjects. We used the means, their 95% confidence intervals (CIs), and the P value for unequal variances, which is a more conservative value. We calculated odds ratios (ORs) and 95% CIs as estimates of relative risk to determine the associations between the number of chromatid breaks per cell and the risk of developing glioma. The {chi}2 test was used to determine distribution differences in the frequency of the number of chromatid breaks between case patients and control subjects; a probability level of .05 was used as the criterion for statistical significance. Nonparametric bootstrap samplings were generated to assess the sensitivity of the cutoff point and the validity of the results. Because case patients and control subjects were frequency matched only, the OR adjusted for age and sex was also calculated. All data analysis was performed with SAS (Version 6.12; Statistical Analysis System, Inc., Cary, NC) and S-plus (Version 4; Mathsoft, Inc., Seattle, WA) statistical software. All statistical tests were two-sided.


    RESULTS
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The study included 219 case patients with glioma and 238 control subjects (Table 1Go). We excluded the few non-Caucasian subjects from our analysis. The mean age at diagnosis was 43.2 years (standard deviation [SD] = ±11.5 years; median = 45 years) for case patients and 44.3 years (SD = ±10.8 years; median = 47 years) for control subjects (P = .268). Case patients included 132 males and 87 females (male/female ratio = 1.5 : 1); control subjects included 131 males and 107 females (male/female ratio = 1.2 : 1). Ever smokers were 54.7% of case patients and 50% of control subjects. No statistical difference was observed for any of the variables assessed between case patients and control subjects, indicating that case patients and control subjects were closely matched (Table 1Go).


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Table 1. Distribution of selected variables in glioma patients and control subjects
 
Case patients showed a statistically significantly higher frequency of chromatid breaks per cell (mean = 0.55; 95% CI = 0.50 to 0.59) than control subjects (mean = 0.44; 95% CI = 0.41 to 0.48) (P<.001). After stratifying for potential confounding variables, such as age, sex, and smoking status, we observed a statistically significantly higher number of chromatid breaks per cell in case patients than in control subjects for all variables, indicating that sensitivity to {gamma}-radiation was an independent risk factor (Table 2Go). In addition, we found no statistically significant difference in the mean number of the chromatid breaks per cell between smokers and nonsmokers when we stratified case patients (P = .23) or control subjects (P = .08) by smoking status (Table 2Go). Impaired repair function, not smoking, may have caused the increased number of induced breaks in patients with glioma.


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Table 2. {gamma}-Radiation-induced mutagen sensitivity in glioma patients and control subjects*
 
In this dataset, we did not find differences in family history of cancer and mutagen sensitivity, as measured by the mean number of chromatid breaks per cell among case patients with (n = 78; mean = 0.54 [95% CI = 0.45 to 0.62]) and without (n = 139; mean = 0.56 [95% CI = 0.50 to 0.61]) a family history of cancer (P = .694) (data not shown). The family history of cancer was unknown for two case patients. We are unable to present the case–control data for family history of cancer and mutagen sensitivity because of incomplete information from control subjects, which is a limitation of this study.

After dividing mutagen sensitivity into two groups by the median value for control subjects (0.40 chromatid break per cell), we found that the crude OR for glioma associated with high mutagen sensitivity was 2.13 (95% CI = 1.46 to 3.11) compared with low sensitivity. After adjustments in logistic regression analysis for age, sex, and smoking status, mutagen sensitivity remained a statistically significantly independent risk factor for gliomas (adjusted OR = 2.09; 95% CI = 1.43 to 3.06). We divided the data into tertiles and used the lowest tertile as the referent group to determine a dose–response relationship. Relative risk for glioma increased from the lowest tertile to the highest tertile of the number of chromatid breaks per cell (crude ORs = 1.00, 1.51, and 2.41, respectively; adjusted ORs = 1.00, 1.46, and 2.36, respectively; trend test, P<.001; Table 3Go).


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Table 3. Logistic regression analysis for {gamma}-radiation-induced mutagen sensitivity in case patients with glioma and in control subjects*
 
Finally, we found no statistically significant differences in mutagen sensitivity by histologic type of tumor. The mean number of chromatid breaks per cell was 0.54 (95% CI = 0.48 to 0.60) for the 106 glioblastoma multiformes, 0.61 (95% CI = 0.48 to 0.73) for the 39 anaplastic astrocytomas, and 0.53 (95% CI = 0.46 to 0.60) for the 74 other gliomas (oligodendrogliomas or mixed glioma) (Table 4Go)


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Table 4. Mutagen sensitivity by histologic type of glioma
 

    DISCUSSION
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The mutagen sensitivity assay measures interindividual differences in DNA repair activity by determining the rate at which chromatid breaks are repaired. Therefore, both the mechanism of the mutagen action and the individual's intrinsic DNA repair activity affect the outcome. For example, individuals with xeroderma pigmentosum show extreme sensitivity to UV radiation but not to ionizing radiation. In contrast, patients with ataxia-telangiectasia resist UV DNA damage but are sensitive to ionizing radiation (14). Therefore, a postulated underlying mechanism for mutagen sensitivity associated with an increased risk for cancer, in part, may reflect the presence of an altered DNA repair pathway.

Pandita and Hittelman (10) suggested that the mutagen sensitivity phenotype may also involve inherent alterations in chromatin structure that, after mutagen exposure, increase the probability that DNA damage will be translated into chromosome damage. Wei et al. (14) tested DNA repair activity in 16 established lymphoblastoid cell lines by using an assay for host cell reactivation in parallel with the assay for mutagen sensitivity. They reported that decreased DNA repair activity was associated with a statistically significantly higher rate of mutagen-induced chromatid breaks, suggesting that repair fidelity may be hampered in individuals who are hypersensitive to mutagens.

To our knowledge, the present study is the largest case–control study to investigate whether sensitivity to {gamma}-radiation is associated with the risk of brain tumors. Our results confirm our previously published pilot study (3), suggesting that sensitivity to {gamma}-irradiation is statistically significantly associated with an increased risk of glioma. Our results also corroborate other studies in which mutagen sensitivity was found to be an independent risk factor for other cancers, including cancers of the lung (15), upper aerodigestive tract (16–18), head and neck (19), and colon (9), and for multiple primary cancers (20). These studies also detected interindividual variation in mutagen sensitivity among normal control subjects, suggesting that the sensitivity phenotype is constitutional (16,17). Cloos et al. (21) reported that mutagen sensitivity, determined by counting bleomycin-induced chromatid breaks, may be associated with an increased risk of developing second primary tumors. The apparently broad effect of mutagen sensitivity on diverse cancers also suggests that multiple genes in various DNA repair pathways may contribute to the integrated phenotype. As Berwick and Vineis (7) suggested, the mutagen sensitivity assay measures a general nonspecific impairment of the DNA repair machinery. Efforts to sort out the polymorphic variants associated with different DNA repair pathways in the general population are under way (22).

Sigurdson et al. (23) reported that mutagen-sensitive patients with glioma had poorer survival than nonsensitive patients with glioma, possibly because acquired genetic abnormalities further diminish the reduced DNA repair activity in these patients. Theoretically, the most susceptible patients are those with a low exposure to known carcinogens who develop tumors at young ages. In the current study, we observed no association between age and the number of chromatid breaks per cell. The young patients (<40 years) had an intermediate number of chromatid breaks that fell between that for patients aged 40–49 years and that for patients aged 50–60 years. Although we would have liked to have investigated the relationship between a family history of cancer and mutagen sensitivity in case patients and control subjects, our data for control subjects were limited. Consequently, this lack of information must be viewed as a limitation of our study. However, we did not observe any statistically significant differences in the mean number of chromatid breaks per cell among the case patients with and without a family history of cancer, suggesting that a family history of cancer may not be a confounding factor.

In conclusion, our findings confirm that the sensitivity to {gamma}-radiation and the subsequent inability to repair radiation-induced DNA damage may increase the risk for brain tumorigenesis. Identification of genes that account for the mutagen sensitivity phenotype (e.g., genes in the various DNA repair pathways) will help to clarify the molecular mechanisms underlying mutagen sensitivity. There are some limitations in the study population because of the possibility that the control subjects and case patients may not have come from the same population. In the future, such results should also benefit cancer prevention by enabling risk assessment to identify individuals with an increased risk for brain or other cancers by using a more rigorously selected study population.


    NOTES
 
Supported in part by Public Health Service (PHS) grants CA70917 (to M. L. Bondy), CA55261 (to V. A. Levin), and CA70334 (to Q. Wei) from the National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services (DHHS); and by PHS grant ES07784 from the National Institute of Environmental Health Sciences, NIH, DHHS.


    REFERENCES
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 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Manuscript received February 9, 2001; revised August 6, 2001; accepted August 13, 2001.


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