Affiliations of authors: Departments of Epidemiology (L-EW, PX, SSS, CIA, MRS, QW), Surgical Oncology (JEL, MIR, PFM, JEG, JNC), Pathology (VGP), Dermatology (MD), Head and Neck Surgery (GLC, RSW), and Clinical Cancer Prevention (SML), The University of Texas M. D. Anderson Cancer Center, Houston, and DermSurgery Associates, Houston, TX (LHG)
Correspondence to: Qingyi Wei, MD, PhD, Department of Epidemiology, Unit 1365, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030 (e-mail: qwei{at}mdanderson.org).
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ABSTRACT |
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INTRODUCTION |
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To investigate this question, it is important to have an assay to determine cellular capacity to repair damage caused by ultraviolet (UV) light. Such biomarkers for genetic susceptibility to cancer are vital for identifying at-risk individuals. The mutagen sensitivity assay, which measures the number of mutagen-induced chromatid breaks per cell in cultured primary peripheral blood lymphocytes exposed to a test mutagen, was developed by T. C. Hsu (19) and has been shown to provide a useful biomarker for susceptibility to different types of cancer, such as thyroid, upper aerodigestive, head and neck, lung, and colon (1924). It has been reported that bleomycin-induced chromatid breaks reflect an inherited component of disease rather than an environmental one (25,26). Because patients with these types of cancers tended to have more bleomycin-induced chromatid breaks than did cancer-free control subjects, it was postulated that the higher sensitivity to bleomycin-induced chromatid breaks originating from DNA strand breaks may reflect the DNA repair capacity of the host cells (27,28).
The mutagen sensitivity assay has since been modified using etiologically related agents as the test mutagens to assess genetic susceptibility to cancers. Benzo[a]-pyrene diol epoxide, an ultimate tobacco carcinogen, was used in studies of lung cancer (29), head and neck cancer (30), and breast cancer (31), and gamma radiation was used in studies of glioma (32,33). These studies showed that the mutagen sensitivity assay is an effective tool for measuring genetic susceptibility to cancer.
Prolonged exposure to sunlight is a well-known risk factor for skin cancer, and UV-B of wavelength 290320 nm is the major component of the solar spectrum that induces DNA lesions (34,35). We previously showed that XP cells are highly sensitive to UV-B irradiation, as indicated by high frequencies of UV-Binduced chromatid breaks per cell (36), a finding consistent with the existence of a defect in DNA repair in XP cells. However, to the best of our knowledge, no published studies have established an association between UV-induced mutagen sensitivity and risk of skin cancer in the general population. Here, we report our results from a hospital-based casecontrol study of skin cancer in which we tested the hypothesis that UV-induced chromatid breaks, as detected in the mutagen sensitivity assay, are associated with the development of skin cancer, both NMSC (BCC and SCC) and CMM.
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SUBJECTS AND METHODS |
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The study included patients with BCC, SCC, or CMM who registered at the Melanoma and Skin Center at The University of Texas M. D. Anderson Cancer Center and DermSurgery Associates between July 1996 and March 2001. There was no limitation on age, sex, or ethnicity. Control subjects were reportedly cancer-free healthy people selected from unrelated visitors who were accompanying other cancer patients to the clinics at M. D. Anderson Cancer Center. The exclusion criteria were previous chemotherapy or radiotherapy and metastasis for patients with NMSC or CMM and previous cancer (except for NMSC for the study cases) and any blood transfusion in the last 6 months for all participants. Written informed consent was obtained from all participants, and a standardized, self-administered questionnaire was used to collect demographic data and data on risk factors, including natural hair color, eye color, skin color, history of sunlight exposure (including freckling in the sun as a child, tanning ability, and number of sunburns), medical history, and family history of first-degree relatives with any cancer. Each participant donated 20 mL of blood after diagnosis for case patients and after recruitment for control subjects. Because we recruited only few minorities (NMSC: one Asian, two African Americans, 21 Mexican Americans; CMM: six Mexican Americans), this analysis focused on non-Hispanic whites only. The study protocol was approved by the institutional review board of the University of Texas M. D. Anderson Cancer Center.
Mutagen Sensitivity Assay
Chromosome sensitivity to UV-B was measured using a modified mutagen sensitivity assay as described previously by Cherry and Hsu (19). In this assay, mutagen sensitivity is expressed as the number of UVB-induced chromatid breaks per cell measured 24 hours after a one-time exposure to incident UV-B irradiation (150 J/m2). In brief, short-term cultures of isolated fresh lymphocytes were established in RPMI 1640 medium supplemented with 20% fetal bovine serum with phytohemagglutinin at a final concentration of 56.25 µg/mL (Murex Biotech Limited, Dartford, England) to stimulate T-lymphocyte growth. After 48 hours of culture, 4 x 106 cells in 1.5 mL of culture medium were transferred to a 60-mm tissue culture dish and placed in a biologic hood without a cover for direct exposure to UV light (15 W unfiltered UV-B lamps; Sankyo Denki Co. Ltd., Tokyo, Japan) of wavelength 302 nm at an incident dose of 150 J/m2. After irradiation, 2 mL of fresh medium was added to the dish, and the cells were allowed to grow for another 23 hours. They were then treated with colcemid (Gibco BRL, Carlsbad, CA) at a final concentration of 0.06 µg/mL to induce mitotic arrest, and the cells in suspension were collected 1 hour later by centrifugation at 250g for 7 minutes. We used conventional chromosome preparation procedures: the cells were treated for 14 minutes with 60 mM hypotonic KCl solution and were incubated for 15 minutes in freshly prepared methanol : acetic acid (3 : 1 vol/vol), after which air-dried slides were prepared as previously described (19). The slides were then stained with 4% Giemsa (Biomedical Specialties, Santa Monica, CA) for 7 minutes. Each slide was evaluated for chromosomal aberrations with a Nikon Labphoto-2 photomicroscope (Nikon, Inc., Instrument Group, Melville, NY). The number of simple chromatid breaks was scored from 50 well-spread metaphase cells for both UV-exposed and unexposed cultures from each subject and expressed as chromatid breaks per cell, because Lee et al. (37) showed that the statistical efficiency of reading 50 and 100 metaphase spreads is similar. The criteria of Cherry and Hsu (19) were used to record the aberrations: a chromatid break was scored as one break, and each isochromatid break set and exchange figure (or interstitial deletion) was scored as two breaks. Gaps were not included in the analyses.
Statistical Analysis
Because more than 95% of the aberrations were simple chromatid breaks, and because these were rare in unexposed cells, the statistical analyses focused exclusively on the frequency of UV-induced chromatid breaks per cell, and the number of chromatid breaks per cell was analyzed as a continuous variable. The Student's t test was used to compare the mean number of chromatid breaks per cell between groups. Because the chromatid breaks per cell data were not normally distributed, we also performed the Student's t test on log-transformed data. We used the medians (i.e., 0.24) and quartiles (i.e., 25th of 0.16, 50th of 0.24, and 75th of 0.36) of chromatid breaks per cell in the control group as the cutoff values to calculate crude odds ratios (ORs) and 95% confidence intervals (CIs). Correlation analysis was used to explore the relationships among sun exposure variables that were each categorized into two groups. Univariate and multivariable logistic regression analyses with adjustment for age and sex were performed to calculate the adjusted odds ratio and 95% confidence interval for each selected variable of interest. Some subjects did not provide information on some sun exposure variables, dysplastic nevi, or family history of skin cancer, and these variables without further information were treated as missing data in the analysis. We included all the selected variables in the multivariable logistic regression analyses for those subjects who provided complete information. Then we performed a further analysis of the interactions between UV-B-induced mutagen sensitivity and selected variables. Odds ratios, 95% confidence intervals, and P values for interactions and trend tests were first obtained from multivariable logistic regression models. A more-than-multiplicative interaction was suggested when OR11 > OR10 x OR01, in which OR11 = the OR when both factors were present, OR01 = the OR when only factor 1 was present, OR10 = the OR when only factor 2 was present (38). To assess evidence for departure from a multiplicative model, we modeled interaction terms between variables using standard unconditional logistic regression. We were specifically interested in searching for interactions indicating a more-than-multiplicative relationship (i.e., interaction terms from the logistic regression with positive coefficients), because these interactions identify subgroups of individuals who may be at particularly high risk for developing skin cancers. We were also interested in identifying departures from additive models. Empirically, a more-than-additive interaction was indicated if OR11 > OR10 + OR01 1. When the test for multiplicative interaction was not rejected, further tests for additive interaction were performed by a bootstrapping test of goodness of fit of the null hypothesis of an additive model with no interaction against an alternative hypothesis that allows an additive interaction. To perform the hypothesis test for additive models, we implemented bootstrapping using Stata 8.2 (StataCorp LP, College Station, TX). All statistical tests were two-sided, and P<.05 was considered statistically significant. We analyzed all data, except for additive models, using SAS software (version 8e; SAS Institute, Cary, NC).
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RESULTS |
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The mean spontaneous chromatid breaks per cell value derived from 50 metaphase of nonirradiated cells was 0.02 (29,39), which was less than 1/10 the frequency in UV-irradiated cells (0.28 on average in the control subjects). Therefore, we used only UV-induced chromatid breaks per cell for statistical comparisons, as recommended (40). Because there were no statistically significant differences in UV-B sensitivity, as measured by UV-induced chromatid breaks, between case patients with and without previous NMSC (60 and 83 BCC case patients, P = .738; 41 and 47 SCC case patients, P = .748; 21 and 217 CMM case patients, P = .165) (data not shown), we did not perform a separate analysis of patients with a history of NMSC.
Univariate analysis of UV-induced mutagen sensitivity revealed that the median values of chromatid breaks per cell were 0.32 (range = 0.04 to 0.92) for patients with BCC, 0.32 (range = 0.08 to 0.86) for patients with SCC, 0.28 (range = 0.06 to 1.44) for patients with CMM, and 0.24 (range = 0.02 to 1.00) for the control subjects. The mean values of chromatid breaks per cell were 0.36 (95% CI = 0.33 to 0.39) for patients with BCC, 0.35 (95% CI = 0.32 to 0.38) for patients with SCC, 0.30 (95% CI = 0.28 to 0.33) for patients with CMM, and 0.28 (95% CI = 0.27 to 0.30) for the control subjects (Table 2). Because the medians and means were similar, the results of both log-transformed and untransformed data were also similar (data not shown). Therefore, we present the results of the untransformed data only. Compared with the frequency of UV-B-induced chromatid breaks in the control subjects, those in both BCC and SCC case patients were statistically significantly higher (P =.001 and P<.001, respectively), but those in CMM case patients were not higher (P = .22) (Table 2). Among these groups, there was no difference in the means of UV-induced chromatid breaks between BCC and SCC (mean ± standard deviation = 0.36 ± 0.17 versus 0.35 ± 0.14 breaks per cell; P = .64), but both were statistically significantly higher than that of CMM (0.30 ± 0.19 breaks per cell) (P = .002 and .025, respectively).
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We then performed multivariable logistic regression analyses to calculate odds ratios and 95% confidence intervals with adjustment only for age and sex to avoid attrition due to missing data for selected risk factors. Mutagen sensitivity values were fitted in the logistic regression model as either continuous or categorical variables. We found that risk associated with an increment of 0.1 chromatid breaks per cell value was 1.28 (95% CI = 1.14 to 1.44) for BCC, 1.30 (95% CI = 1.11 to 1.53) for SCC, and 1.06 (95% CI = 0.97 to 1.17) for CMM, after adjustment for age and sex (Table 3). Using the median frequency value of chromatid breaks per cell of the control subjects as the cutoff point, high chromatid breaks per cell values were associated with a nearly threefold increased risk for both BCC (OR = 2.78, 95% CI = 1.79 to 4.30) and SCC (OR = 2.62, 95% CI = 1.50 to 4.60) but were not associated with an increase in CMM (OR = 1.24, 95% CI = 0.88 to 1.73) (Table 3).
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Next, we included all the risk factors in the multivariable logistic regression model for those subjects who had provided complete information (i.e., 117 BCC patients, 65 SCC patients, 215 CMM patients, and 277 control subjects). With simultaneous adjustment for all variables listed in Table 1, we found that statistically significantly increased risk for BCC was associated with fair skin (OR = 1.79, 95% CI = 1.05 to 3.06), freckling in the sun (OR = 1.89, 95% CI = 1.09 to 3.26), and family history of skin cancer (OR = 2.80, 95% CI = 1.57 to 4.99); for SCC was associated with lifetime sunburns with blistering (OR = 2.14, 95% CI = 0.96 to 4.77) and family history of skin cancer (OR = 4.66, 95% CI = 2.09 to 10.4); and for CMM was associated with blond or red hair (OR = 1.71, 95% CI = 1.09 to 2.67), poor tanning ability (OR = 1.74, 95% CI = 1.13 to 2.70), and dysplastic nevi (OR = 6.57, 95% CI = 2.86 to 15.1) (Table 4). More importantly, independent of these variables, risks associated with increased UVB-induced chromatid breaks per cell values were not substantially changed (OR = 3.28, 95% CI = 1.94 to 5.54 for BCC; OR = 3.14, 95% CI = 1.55 to 6.37 for SCC; OR = 1.24, 95% CI = 0.84 to 1.82 for CMM) (Table 4).
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DISCUSSION |
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Although mutagen sensitivity was measured in peripheral lymphocytes rather than in tumor and skin tissue, it has been demonstrated that high susceptibility to induced chromatid breaks has a genetic basis (26). Furthermore, spontaneous DNA breaks and those induced by mutagens or carcinogens in lymphocytes that lead to chromosome aberrations are relevant to cutaneous carcinogenesis (36,41). In XP patients, for example, with a genetically determined defect in DNA repair and a high sensitivity to UV-induced chromosomal aberrations, risk of NMSC and CMM is extraordinarily high. However, XP patients have a much higher incidence of NMSC than CMM in their lifetime (913), suggesting that factors other than impaired DNA repair contribute to CMM in XP patients (10).
There is ample evidence that UV-radiation is associated with risk of developing NMSC and CMM in the general population (38), but the relationships between sun exposure and incidence of BCC, SCC, and CMM appear to be different. That is, risk of BCC is associated with intermittent sun exposure, but beyond a certain level, the risk does not increase as sun exposure increases (5,42), suggesting that genetic predisposition is responsible for the early onset of BCC in the low-dose exposure range (14,15). In contrast, risk of SCC is associated with total accumulated sun exposure without any threshold (5,43,44). Finally, risk of CMM is strongly associated with intermittent sun exposure, particularly that occurring in early age (45), but not with ambient solar erythemal UV radiation (mainly UV-B) (5).
It has also been shown that, in keratinocytes, low doses of UV-B can enhance DNA repair but higher doses can reduce it (46), possibly due to elimination of cells with an excess of DNA damage by apoptosis. The higher levels of chromatid breaks induced by nonlethal UV-B doses in lymphocytes from patients with BCC and SCC than in control subjects that we observed in this study provide further evidence that UV-induced chromosomal aberrations may also be involved in sunlight-related BCC and SCC. Melanocytes, the cells that give rise to CMM, are more resistant to the lethal effects of UV than keratinocytes, possibly due to resistance to apoptosis, and therefore they are more likely to survive with mutations resulting from unrepaired DNA damage (47), which may increase the probability of carcinogenesis in later life as a result of intermittent sunlight exposure at a young age (45). However, the lymphocytes from CMM patients were more resistant to the nonlethal UV-B dose used in this study than those from NMSC patients, suggesting that the UV-induced chromosomal aberrations play a lesser role in sunlight-related CMM.
Although the frequency of UV-induced chromosomal aberrations may be determined by cellular DNA repair capacity, as suggested in the XP patients (10), there are no reported data to suggest that this is the case in the general population. Several studies have investigated the association between DNA repair capacity and risk of skin cancer in the general population with a host cell reactivation assay (1418,48,49), but there are few studies that have investigated the role of UV-induced chromosomal aberrations in the etiology of skin cancer in the general population. Au et al. (50,51) reported that three patients with epidermodysplasia verruciformis, who are prone to developing skin cancer, were sensitive to UV light, as characterized by a high frequency of induced chromosome aberrations. An early study of cell lines that were derived from patients with melanoma and a family history of multiple primary melanomas in several generations showed an increased sensitivity to UV light and inhibition of DNA replication (52). Another study tested for chromosomal instability in patients with CMM (53) and found that the numbers of UV-induced micronuclei and sister chromatid exchanges were high, particularly in familial case patients, and were in a range similar to that found in XP heterozygotes. Sanford et al. (54) found that high sensitivity of lymphocytes to x-ray radiation was associated with hereditary dysplastic nevi with or without melanoma and with sporadic dysplastic nevi or sporadic melanoma. In a smaller study, patients with both CMM and dysplastic nevus syndrome had a statistically significantly lower mean chromatid breaks per cell value than patients with CMM only, suggesting that different genetic factors are involved in the etiology of CMM with and without dysplastic nevus syndrome (55). Although these studies were small, the results appeared to support the role of UV sensitivity in the etiology of CMM.
However, in this large study of 238 CMM case patients and 329 control subjects, we found no evidence that an increased risk of CMM is associated with higher UVB-induced chromatid breaks per cell values (adjusted OR = 1.24; 95% CI = 0.88 to 1.73). Our finding suggests that UVB-induced chromosomal aberrations do not play a major role in the etiology of sporadic CMM and indirectly supports the finding of Setlow et al. (56) that UV light at wavelengths higher than 320 nm are more important than UV light at lower wavelengths in the development of sun exposurerelated CMM. Our finding is also consistent with the fact that UV-induced signature mutations are often found in NMSC (57,58) but not in CMM (59).
Furthermore, we found some evidence for geneenvironment interaction between known risk factors and mutagen sensitivity in NMSC but not in CMM. We were interested in interactions exceeding a multiplicative relationship because these indicate potential combinations of risk factors that may be of value for identifying individuals at particularly high risk of developing skin cancer. Departure from an additive model may suggest that the factors affect different pathways, whereas factors in the same pathway may act jointly, increasing risk in a multiplicative fashion. Interestingly, most of the positive multiplicative interactions were observed for SCC. For example, high sensitivity to UV, as measured by the induction of chromatid breaks, interacted with hair color, tanning ability, and family history of skin cancer in SCC but interacted only with lifetime sunburns in BCC. Based on the reported incidence rates (5) and the mutagen sensitivity data of this study, it appears that sunlight exposure may weight less and that genetically impaired DNA repair may weight more on the occurrence of BCC (14,15). This supposition suggests that mutagen sensitivity is an independent risk factor for NMSC, because more-than-additive interactive effects were more commonly observed between mutagen sensitivity and other risk factors, such as hair color, skin color, freckling, and family history. In contrast, sunlight exposure may weight more on the occurrence of SCC (5) (also as indicated by higher risks associated with both tanning ability and lifetime sunburns and sensitivity to UV-induced chromatid breaks), but mutagen sensitivity may weight less. It remains unclear whether sunlight exposure or mutagen sensitivity may have played a role in the development of CMM, although it is clear that suboptimal DNA repair is associated with an increased risk of CMM in this study population (17).
The study has several potential limitations. Whether mutagen sensitivity measured in lymphocytes is a valid marker of UV-induced DNA damage of normal cells in the target tissue remains to be determined. Cloos et al. (60) compared the number of bleomycin-induced chromatid breaks in peripheral blood lymphocytes, oral fibroblasts, and oral keratinocytes from 30 people and found that keratinocytes were more sensitive than fibroblasts to environmental factors related to cancer risk. For skin cancer, the target tissue may also be influenced by exposure to environmental factors other than sunlight, making it difficult to determine the genetic factors involved in its etiology. Another limitation results from the study design. In our hospital casecontrol design, the control subjects were visitors to the hospital rather than patients, and they may not come from the same residential areas as the case patients (61). Also, some uncontrolled confounders could link to genetic factors that may be the underlying determinants of mutagen sensitivity. However, we had excluded any control subjects who were related to the case patients, and thus the possible link of mutagen sensitivity to family history should have been eliminated.
The study also has several strengths. Because all blood samples were collected before any chemotherapy or radiotherapy, the measurement of mutagen sensitivity could not have been affected by these factors. Furthermore, lymphocytes are not directly exposed to UV from the sun, so they should be useful surrogates for measuring inherent sensitivity to UV-induced chromatid breaks for the skin or the target tissue. All slides were read by only one cytogeneticist. Thus, possible personal variation in the measurements was reduced to the minimum. As a phenotype marker, the mutagen sensitivity represents the outcome of many different pathways that may have been involved in DNA damage and repair in response to UV irradiation. Because CMM is a rare disease and is clinically apparent soon after development, it is likely that there were no or nearly no prevalent undetected case patients among the control subjects.
In summary, in this hospital-based casecontrol study, we found that the frequency of UV-Binduced chromatid breaks was statistically significantly higher in NMSC (i.e., BCC and SCC) patients than in control subjects but was the same in CMM patients and control subjects. A higher frequency of chromatid breaks was associated with a more than twofold increased risk for both BCC and SCC, and a doseresponse relationship was found between mutagen sensitivity and risk for both BCC and SCC. There was evidence of multiplicative interactions between mutagen sensitivity and selected variables on risk for NMSC but not for CMM, particularly for mutagen sensitivity with sunburn in BCC and mutagen sensitivity with hair color, tanning ability, and family history of skin cancer in SCC. These findings suggest that in vitro UVB-induced mutagen sensitivity reflects susceptibility to NMSC but not CMM. However, because of the inherent selection bias of subjects in this hospital-based casecontrol study, the findings need further validation by prospective studies. Also, properties of the mutagen sensitivity assay after optimal long-term storage should be investigated to make it feasible for prospective studies.
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NOTES |
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We thank Zhaozheng Guo, Yawei Qiao, Jianzhong He, and Kejing Xu for laboratory assistance; Xiangjun Gu for his assistance in statistical analysis; Betty Jean Larson and Joanne Sider for assistance in preparing the manuscript; and Ann Sutton for scientific editing.
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Manuscript received June 6, 2005; revised September 7, 2005; accepted November 7, 2005.
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