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Clinical Cancer Research 13, 6532, November 1, 2007. doi: 10.1158/1078-0432.CCR-07-0969
© 2007 American Association for Cancer Research
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Cancer Susceptibility and Prevention

Repair Capacity for UV Light–Induced DNA Damage Associated with Risk of Nonmelanoma Skin Cancer and Tumor Progression

Li-E Wang1, Chunying Li1, Sara S. Strom1, Leonard H. Goldberg9, Abenaa Brewster2, Zhaozheng Guo1, Yawei Qiao1, Gary L. Clayman3, J. Jack Lee4, Adel K. El-Naggar5, Victor G. Prieto5, Madeleine Duvic6, Scott M. Lippman7, Randal S. Weber3, Margaret L. Kripke8 and Qingyi Wei1

Authors' Affiliations: Departments of 1 Epidemiology, 2 Clinical Cancer Prevention, 3 Head and Neck Surgery, 4 Biostatistics, 5 Pathology, 6 Dermatology, 7 Thoracic/Head and Neck Medical Oncology, and 8 Immunology, The University of Texas M. D. Anderson Cancer Center; and 9 DermSurgery Associates, Houston, Texas

Requests for reprints: Qingyi Wei, Department of Epidemiology, Unit 1365, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-3020; Fax: 713-792-0807; E-mail: qwei{at}mdanderson.org.


   Abstract
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Materials and Methods
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Purpose: To examine the role of suboptimal DNA repair capacity (DRC) for UV light–induced DNA damage in the development of nonmelanoma skin cancer (NMSC) and tumor progression.

Experimental Design: We conducted a hospital-based case-control study of 255 patients with newly diagnosed NMSC [146 with basal cell carcinoma (BCC) and 109 with squamous cell carcinoma (SCC)] and 333 cancer-free controls. We collected information on demographic variables and risk factors from questionnaires, tumor characteristics from medical records, and lymphocytic DRC phenotype by the host-cell reactivation assay. Multivariable logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (95% CI).

Results: Overall, there was a relative 16% reduction in DRC in NMSC patients compared with controls (P < 0.001 for BCC and for SCC, respectively). DRC below the controls' median value was associated with increased risk significantly for BCC (OR, 1.62; 95% CI, 1.07-2.45) but borderline for SCC (OR, 1.63; 95% CI, 0.95-2.79) after adjustment for age, sex, and other assay-related covariates. When the highest tertile of controls' DRC was used as the reference, the intermediate and low DRC were associated with a statistically significant trend for increasing risk for both BCC (Ptrend = 0.007) and SCC (Ptrend = 0.020). However, patients with aggressive or multiple SCC tended to have a higher DRC than those with nonaggressive or single SCC.

Conclusions: Reduced DRC is an independent risk factor for BCC and single or nonaggressive SCC but not for multiple primaries, local aggressiveness, or recurrence of NMSC.

Nonmelanoma skin cancer (NMSC), consisting mainly of basal and squamous cell carcinomas (BCC and SCC, respectively), is the most common form of human malignancies, with estimated more than 1 million new cases (accounting for more than 40% of all cancers) annually in the United States (1). Although the role of UV light in the etiology of NMSC is well known, only a fraction of individuals who have been exposed to increasing levels of solar UV radiation (2–4) will develop NMSC, suggesting a genetic susceptibility to UV light–induced carcinogenesis in the general population.

Epidemiologic studies have consistently found that sunlight exposure is directly associated with risk of NMSC in humans (3, 5–7). An early study of watermen from the eastern shore of Maryland found that average annual exposure to ambient UVB radiation was strongly correlated with the prevalence of SCC, whereas BCC did not have such a correlation (8), especially in watermen younger than 60 years of age (9). Because of the association between defects in DNA repair genes (10) and the poor DNA repair phenotype (11) that causes a high incidence of BCC and SCC in xeroderma pigmentosum (XP) patients (12), this watermen study provided much enthusiasm for further studying the DNA repair capacity (DRC) as a marker for genetic susceptibility to NMSC in the general population.

In an early Maryland study, it was shown that those who had a suboptimal DRC had an increased risk of BCC compared with those who had a normal DRC and that there was an age-related decline in DRC in the controls between ages of 20 and 60 years (13). These findings were replicated in an Italian population (14) and a more recent Puerto Rican study (15) but not in an Australian population (16), although these studies had included relatively small sample sizes.

To further test the hypothesis that reduced DRC phenotype is a risk factor for NMSC in the U.S. general population, we conducted a larger case-control study on DRC phenotype in both BCC and SCC in a Texan population using the same host-cell reactivation assay, as used in the studies described above (13–16), which measures host-cell nucleotide excision repair capacity or DRC phenotype. Because it is unclear whether the aggressive tumor behavior of some NMSC is due to delayed diagnosis/treatment or to genomic instability affected by host factors such as DRC phenotype, we also tested the hypothesis that DRC phenotype is associated with tumor behavior.


   Materials and Methods
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Study subjects. The NMSC patients gave informed consent and were enrolled at The University of Texas M. D. Anderson Cancer Center. The exclusion criteria were prior chemotherapy or radiotherapy for the new tumors, history of cancer (except for NMSC for the patients), and blood transfusion in the last 6 months for all subjects. After signing the informed consent, the subjects completed a structured self-administered questionnaire to provide information on demographics and known risk factors such as 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. The study protocol was approved by the M. D. Anderson institutional review board.

Between July 1996 and June 2001, 373 eligible patients with newly diagnosed or surgically removed, histopathologically confirmed NMSC evaluated at M. D. Anderson were recruited, of which 24 non-Whites (1 Asian, 2 Blacks, 21 Hispanics) and 94 subjects whose cryopreserved samples did not provide enough viable cells to be used for the DRC assay were excluded. Therefore, we included 255 eligible NMSC (146 BCC and 109 SCC) cases in the final analysis. During a similar time period, 367 cancer-free subjects who had no previous history of malignancies were selected from among hospital visitors, who were genetically unrelated to cases or to each other. Of these controls, 34 subjects whose cryopreserved samples did not have enough viable cells to be used for the DRC assay were also excluded. Therefore, 333 controls were included in the final analysis. All study participants were non-Hispanic Whites between 19 to 89 years of age. The tumors were classified as clinically aggressive if the lesions were ≥4 cm in one surface dimension; invaded muscle, bone, or cartilage; or had metastasized to lymph nodes or distant sites as previously described (17).

The host-cell reactivation assay. The blood processing and host-cell reactivation assay procedures have been published elsewhere (18). Briefly, each subject donated a one-time 30-mL blood sample. Within 8 h, the lymphocytes were isolated from the whole blood by the Ficoll-gradient centrifugation method and frozen for storage in a –80°C freezer as previously described (18). Four EBV-immortalized human lymphoblastoid cell lines from the Human Genetic Mutant Cell Repositories (Camden, NJ) were used as experimental controls: two apparently normal cell lines (GM00892B and GM00131A) and two XP cell lines (GM02345B and GM02246B) that are deficient in nucleotide excision repair (18).

The host-cell reactivation assay was used to measure cellular DRC in phytohemagglutinin-stimulated T-lymphocytes using a reporter gene (pCMVcat) as a DNA repair readout (19). The measured DRC of the lymphocytes reflects that of the donor, because, in the DNA repair deficiency syndrome XP, deficient DRC is detected in all tissues including lymphocytes (20). The transfections with T-lymphocytes were done by the DEAE-dextran method (21) with ~0.25 µg of either untreated plasmids or plasmids that were treated with UV light [an incident UVC dose of 800 J/m2 at a wavelength of 254 nm from a 15-W unfiltered germicidal UVC lamp (Sankyo Denki Co. Ltd.)] before transfection. The expression of chloramphenicol acetyltransferase was measured 40 h after transfection. For calculating DRC (%), the expression level of the undamaged plasmids was used as the baseline DRC (defined as 100%; ref. 19).

Single-nucleotide polymorphism selection and genotyping. To determine the underlying genetic factors for the suboptimal DRC, we genotyped the reported five common (i.e., the minor allele frequency ≥0.05) nonsynonymous single-nucleotide polymorphisms [SNP; i.e., Ala499Val (C>T, rs2228000) and Lys939Gln (A>C, rs2228001) in XPC; Asp312Asn (G>A, rs1799793) and Lys751Gln (A>C, rs13181) in XPD; and His1104Asp (G>C, rs17655) in XPG] in the eight core nucleotide excision repair genes (i.e., ERCC1, XPA, XPB, XPC, XPD, XPE, XPF, and XPG) identified in European descendents in the National Institute of Environmental Health Science database.10 We used previously described primers, PCR annealing time, and restriction enzyme (New England Biolabs) conditions for XPCAla499Val and XPCLys939Gln (22), XPDAsp312Asn (23) and XPDLys751Gln (24), and XPGHis1104Asp (25). The genotyping assays for 10% of the samples were repeated, and the results were 100% concordant.

Statistical analysis. The differences in distributions of demographic variables and known risk factors between cases and controls were examined using the {chi}2 test. DRC was first analyzed as a continuous variable before and after natural logarithmic transformation. Student's t test was used to compare the differences in DRC between groups. Correlation analyses were done for DRC and selected variables. The median and tertile of controls' DRC were used as the cutoff values to calculate odds ratios (OR) and 95% confidence intervals (95% CI) in multivariate unconditional logistic regression models with and without adjustment for age, sex, and covariates such as known risk factors and assay-related variables (i.e., blastogenic rate, cell storage time, and baseline chloramphenicol acetyltransferase expression level).

Clinical data on aggressiveness of the tumors were used to examine whether DRC was associated with this tumor phenotype. We defined age and assay-related variables as the continuous ones and the other covariates as the dichotomized variables as shown in Table 1 . All the statistical analyses were done with Statistical Analysis System software (version 9.1, SAS Institute, Inc.).


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  		Table 1. Distribution of selected known risk factors between patients with NMSC and control subjects and logistic regression analysis

 

   Results
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Discussion
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Characteristics of the study population. The distributions of age, sex, and selected risk factors (hair color, eye color, skin color, tanning ability after prolonged sun exposure, number of lifetime blistering sunburns, freckling in the sun as a child, dysplastic nevi, and family history of skin cancer) and the ORs of sunlight exposure-related variables and family history of skin cancer in this study population were shown in Table 1. Due to the hospital setting, we recruited younger and more female control subjects (≤55 years, 52.4%; females, 52.5%) than case patients (40.4% and 39.0%, respectively, for BCC; 19.3% and 11.9%, respectively, for SCC; Table 1). Therefore, these two variables were adjusted for in later multivariable logistical regression analysis as potential confounding factors. Because BCC patients tended to be younger and SCC patients tended to be older among case patients, we used all 333 control subjects for comparisons with either BCC or SCC case patients to reduce the number of attrition of the controls. Because this was a hospital-based study, the risk estimates for the known risk factors were not meant to measure the true risk but rather to control their confounding in the main effect of DRC as a risk factor of NMSC in this study population.

Stratification analysis of DRC by selected variables. As shown in Table 2 , overall, the controls had significantly higher DRC (mean ± SD, 10.3 ± 5.4) than did patients with BCC (8.6 ± 3.4), representing a 16.5% relative reduction in DRC (P < 0.001), and patients with SCC (8.7 ± 3.6), representing a 15.5% relative reduction (P < 0.001). The differences in DRC between the controls and BCC or SCC cases remained unchanged after log transformation to normalize the DRC data (data not shown) or were not affected by the assay variables such as the blastogenic rate, the baseline chloramphenicol acetyltransferase expression level of the undamaged plasmids, and the cell storage (cryopreservation) time, consistent with what we showed before (18).


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  		Table 2. Comparison of differences in DRC between NMSC cases and cancer-free controls

 
There was no evidence of an age-related decline in DRC in controls in this study population compared with previously reported data (13); however, there was a trend of an age-related decline in DRC in SCC patients, although not statistically significant (Ptrend = 0.153), but a significant age-related increase in DRC in BCC patients (Ptrend = 0.033). Compared with the controls, DRC was significantly lower in young (≤65 years) BCC cases but in older (>55 years) SCC cases (Table 2). When stratified by other selected risk factors, in the controls, those who had freckling in the sun as a child had statistically significantly lower DRC (9.5%; compared with those without freckling, 10.7%; P = 0.049) and those who did not have family history of skin cancer had statistically significantly lower DRC (9.9%; compared with those with family history of skin cancer, 12.0%; P = 0.007); in the cases, a statistically significantly lower DRC was observed in BCC patients who also had freckling in the sun as a child (8.0%; compared with those without freckling, 9.3%; P = 0.012) and blond or red hair (7.5%; compared with those with black or brown hair, 9.0%; P = 0.013) and SCC patients who were female (6.6%; compared with males, 9.0%; P = 0.023) and who had freckling in the sun as a child (7.8%; compared with those without freckling, 9.3%; P = 0.036). However, the significant difference in DRC between the BCC cases and controls remained (P < 0.05) for most of the subgroups except for the subgroups of ages >65 years, blue eye color, poor tanning ability, and having dysplastic nevi. These stratified data may reflect a reduced statistical power likely due to the reduced sample sizes in the subgroups. For SCC cases, the significant difference in DRC between the cases and controls (P < 0.05) remained for over half of the subgroups except for those of ages ≤55 years, blond or red hair color, blue eye color, dark brown skin color, poor tanning ability, lifetime sunburns, and having dysplastic nevi (Table 2).

DRC and tumor behavior. We evaluated whether the DRC phenotype was associated with tumor behavior and histology as well as the number of tumors. Compared with the controls, the DRC was statistically significantly lower for BCC patients regardless of the tumor behaviors (n = 22, mean = 8·8%, and P = 0.028 for aggressive BCC; n = 124, mean = 8·6%, and P < 0.001 for nonaggressive BCC), except for those BCC cases who had more than one BCC (n = 8, mean = 9.2%, P = 0.584 for aggressive BCC; n = 21, mean = 9.2%, P = 0.386 for nonaggressive BCC; Table 3 ). In contrast, a lower DRC was only observed in cases with nonaggressive SCC (n = 70, mean = 8.2%, and P < 0.001), particularly those cases with single SCC (n = 37, mean = 7.0%, and P < 0.001), but not in cases with aggressive SCC (n = 39, mean = 9.6%, and P = 0.333), either with single (n = 21, mean DRC = 8.8%, and P = 0.099) or multiple (n = 18, mean DRC = 10.5%, and P = 0.844) SCC, or in multiple nonaggressive SCC (n = 33, mean DRC = 9.6%, and P = 0.322). Among cases, whereas there was no difference in DRC between aggressive and nonaggressive BCC (P = 0.786), DRC was significantly lower in nonaggressive SCC than in aggressive SCC (P = 0.046). Furthermore, among nonaggressive SCC, DRC was significantly lower in patients with single SCC than in those with multiple SCC (P = 0.002; Table 3). Because some patients had both BCC and SCC, we combined the BCC and SCC patients together by the number of tumors. Compared with controls, the DRC was significantly lower in all cases with single NMSC (n = 175, mean = 8.2%, and P < 0.001), either BCC (n = 117, mean = 8.5%, and P < 0.001) or SCC (n = 58, mean = 7.7%, and P < 0.001), but not in cases with multiple NMSC (≥2 tumors; n = 80, mean = 9.7%, and P = 0.228), either BCC (n = 29, mean = 9.2%, and P = 0.168) or SCC (n = 51, mean = 9.9%, and P = 0.535; Table 3). However, DRC was significantly higher in cases with multiple NMSC than in patients with single NMSC (P = 0.002), particularly in patients with multiple SCC than in patients with single SCC (P = 0.001; Table 3).


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  		Table 3. Differences in DRC between NMSC cases and controls by tumor characteristics

 
Association between DRC and risk of NMSC. We then evaluated the main effect of DRC on NMSC risk in multivariable logistic regression models with adjustment for the factors listed in Table 1 and assay-related variables [i.e., blastogenic rate (%), baseline chloramphenicol acetyltransferase expression (cpm), and cell storage time (months)] by using the maximum likelihood method (Table 4 ). DRC values were first fitted in the models as both a continuous variable and a log-transformed variable. Significantly increased risk for BCC was associated with a unit decrease in either DRC (%; OR, 1.10; 95% CI, 1.04-1.16) or its log-transformed values (OR, 2.35; 95% CI, 1.43-3.85) after adjustment for age, sex, and assay-related variables. Likewise, when the DRC values were dichotomized by the median DRC of the controls, low DRC was associated with a 1.62-fold increased risk for BCC (95% CI, 1.07-2.45; Table 4). Furthermore, when the DRC values were divided into tertiles according to the controls' DRC values, a dose-response relationship between increased risk and decreased DRC was evident: efficient (upper tertile), intermediate (mid-tertile), and suboptimal (lower tertile) DRC were associated with the adjusted ORs of 1.00, 1.61 (95% CI, 0.95-2.73), and 2.04 (95% CI, 1.23-3.38; Ptrend = 0.007; Table 4). The risks of BCC associated with suboptimal DRC were even more pronounced when we included all selected variables in the same logistic model, including 113 BCC cases and 279 controls (because some subjects had missing data; Table 4).


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  		Table 4. Logistic regression analysis of DRC in NMSC patients and cancer-free controls

 
Similarly, significantly increased risk for SCC was also associated with a unit increase in either DRC (OR, 1.10; 95% CI, 1.02-1.18) or its log-transformed values (OR, 2.64; 95% CI, 1.37-5.10) after adjustment for age, sex, and assay-related variables. When the DRC values were dichotomized by the median DRC of the controls, the low DRC was associated with a 1.63-fold increased risk for SCC, which is only borderline significant (95% CI, 0.95-2.79; Table 4). Furthermore, when the DRC values were divided into tertiles according to the controls' DRC values, a dose-response relationship between increased risk and decreased DRC was also evident (Table 4). Nevertheless, when we included all selected variables in one logistic regression model with 83 SCC cases and 279 controls without any missing data, neither these estimates nor the dose-response relationship was significant for SCC except for the intermediate DRC (Table 4).

Association between DNA repair genotypes and phenotype. Finally, we evaluated the associations between genotypes of the five functional SNPs or nonsynonymous SNPs in nucleotide excision repair/XP genes (i.e., XPCAla499Val and XPCLys939Gln, XPDAsp312Asn and XPDLys751Gln, and XPGHis1104Asp) and DRC in both cases and controls. Because, in XP patients, only those who inherited two copies of the mutant alleles will develop the disease phenotype (12), we expected that those who had the homozygous minor allele genotypes of any of the nucleotide excision repair genes would have the suboptimal DRC. As shown in Table 5 , all homozygotes of XP minor alleles, except for XPG, in both the controls and BCC patients, and all homozygotes of XP minor alleles in SCC patients had the lowest DRC, compared with those who had the genotypes of common alleles in the same group (Table 5). To combine all homozygous genotypes of minor alleles, we created a new variable with none, any one, or two or more homozygous minor allele genotypes. It was apparent that the increased number of homozygous minor allele genotypes was also associated with decreased DRC in a dose-responsive manner for groups of controls and SCC patients (Ptrend = 0.026 and Ptrend = 0.044, respectively), but this trend was not significant in BCC patients (Ptrend = 0.347; Table 5). Therefore, it is likely that the genotypes of XP minor alleles may have been the contributing genetic factors of the observed suboptimal DRC, although many rare nonsynonymous SNPs of the nucleotide excision repair/XP genes were not genotyped in this study population.


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  		Table 5. Comparison of differences in DRC between NMSC case patients and cancer-free control subjects by common nonsynonymous SNPs in the nucleotide excision repair genes

 

   Discussion
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NMSC is a paradigm for studying the association between UV-induced DNA damage and the DRC phenotype in the etiology of skin cancer in the general population because XP provides an excellent disease model that links defective DRC and risk of skin cancers in families affected by this genetic syndrome. Kraemer et al. (12) published the first comprehensive estimation of risk of developing neoplasms that occurred between 1874 and 1982 in 726 XP patients from 41 countries. Compared with the general population, XP patients younger than 20 years had an estimated 2,000-fold increased risk of having BCC and SCC of the skin (20). Such a role for DRC in sunlight-induced skin cancers in the general population was also recently recognized. Because the incidence of BCC, compared with SCC, is less dependent on exposure to sunlight (6), genetic factors are more likely to play a role in the etiology of BCC than of SCC. Therefore, BCC also serves as an excellent disease model for studying gene-environment interactions in skin cancer, whereas the incidence of SCC is more exposure dependent (6) and thus may be less DRC-dependent because even an optimal DRC could have been overwhelmed by exposure to excessive UV light, as seen in SCC in this study population.

In the present study of 255 NMSC cases and 333 controls, the largest study among the published studies of its kind to date, we found that, overall, there was a relative 16.0% reduction in DRC in all NMSC case patients (16.5% reduction in BCC and 15.5% reduction in SCC), compared with control subjects. Further, lower DRC was observed in case patients with BCC regardless of tumor behavior but not in case patients with more than one BCC. In contrast, lower DRC was only observed in case patients with a single nonaggressive SCC but not in those with multiple nonaggressive SCC or aggressive SCC. Consistently, low DRC was significantly associated with risk for BCC but only marginal for SCC; risk of BCC increased as the DRC decreased, but such a dose-effect relationship was not obvious for SCC after adjustment for known risk factors for NMSC. These findings provide additional evidence that reduced DRC is an independent risk factor for BCC and maybe for single and nonaggressive SCC in the general population. The uncertainty for overall risk of SCC may also be due to our inclusion of a smaller sample size of SCC case patients compared with that for BCC case patients, but it is likely that BCC and SCC may have a different etiology in terms of the involvement of DRC.

In this study, however, we did not find evidence of an age-related decline in DRC, as reported by other studies (13–15), in the controls of a Texas population. This may be attributed either to the older age of this study population (mean; 53.7 years; range, 19-89 years) or to the high level of ambient sunlight exposure in Texas, which is likely closer to that in Australia (16), where no age-related decline in DRC in the control population was observed. Skin color may have provided more protection in Puerto Ricans (15), although the biological basis for these differences is unclear. The current study, although using UV as the damaging agent for the plasmids that was used for the host-cell reactivation assay, revealed that women, regardless of either cases or controls, tended to have a lower DRC compared with men, a finding consistent with that of a larger control subjects reported in another large independent study using tobacco carcinogen benzo[a]pyrene diol epoxide as the damaging agent (26). Moreover, the current study provided further evidence that young BCC patients had the lowest DRC compared with all other age subgroups, a consistent finding that has been found in all published studies (13–15), except for the Australian study (16).

Our study also provides some new findings that cases who had a single nonaggressive SCC also tended to have a lower DRC than those who had aggressive SCC, but those who had more than one NMSC had a significantly higher DRC than those who had only one NMSC, a finding not consistent with that reported in the Puerto Rican study (15). Furthermore, we showed that such suboptimal DRC has a genetic basis (i.e., those individuals who carried homozygotes of XP minor alleles had a suboptimal DRC and thus were at increased risk of UV-induced skin cancers) as shown in this study population. Therefore, the present study on DRC and NMSC provided additional support for a role of suboptimal DRC in the etiology of NMSC and new evidence for the underlying genetic factors for the observed suboptimal DRC.

The new findings in the present study are intriguing but provide some clues to the etiology and progression of NMSC. Because the association between risk and UV exposure is less dose responsive in BCC than in SCC (6), suboptimal DRC may play a more important role in the etiology of BCC when the level of UV-induced DNA damage is low. We observed in this study population that patients who had a BCC or single and nonaggressive NMSC tended to have the lowest DRC; likewise, we observed the highest frequencies of UV-induced chromosomal aberrations in BCC patients (27), suggesting a major role of suboptimal DRC in the etiology of single NMSC. When the level of UV-induced DNA damage is high or accumulated due to chronic exposure to sunlight as seen in SCC, the DRC may be up-regulated, as what we have observed in SCC in this study as well as in previously reported smoking-induced up-regulation of DRC (26), but such an adaptive increase in DRC in response to damage to DNA seemed to have been overwhelmed by the levels of UV-induced damage, leading to a high risk of SCC. However, it is also possible that when the level of DNA damage is high, genetic and other factors become important in the initiation of carcinogenesis in aggressive or multiple SCC in the presence of an adaptive increase in DRC; furthermore, once the tumor occurs, it is conceivable that an adaptive high level of DNA repair could be error prone, leading to genomic instability and thus more rapid tumor progression, thereby accounting for more aggressive tumor behaviors. However, these hypotheses need further mechanistic investigations.

In conclusion, the findings of this study provide further evidence that reduced DRC is a risk factor for BCC and maybe for single or nonaggressive SCC in the general population. This study also provided new evidence of the underlying genetic factors for the observed suboptimal DRC. However, reduced DRC may not be associated with multiple primaries, local aggressiveness, or recurrence of NMSC. Although the main findings in this study are rather robust, most of the significant findings from the subgroup analyses were no longer significant after adjustment for multiple testing, or the results were not significant at all due to diminished sample sizes or statistical power in the subgroup analyses. Further, lymphocytes used as the surrogate tissue in this study may not represent the target tissues (i.e., keratinocytes in the skin) where the tumors had arisen. Therefore, larger, better-matched, and preferably population-based studies, as well as mechanistic studies, using the target tissues are needed to validate our findings.


   Acknowledgments
 
We thank Dr. Larry Grossman (Johns Hopkins University) for providing pCMVcat and scientific advice, Dr. Margaret R. Spitz for critical review, Margaret Lung for subject recruitment, Monica Domingue for assistance in the preparation of the manuscript, and Ann Sutton from the Department of Scientific Publications for the scientific editing.


   Footnotes
 
Grant support: NIH grants CA 100264 (Q. Wei), CA 68233 (G.L. Clayman), ES 11740 (Q. Wei), and CA 16672 (The University of Texas M. D. Anderson Cancer Center).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

10 http://egp.gs.washington.edu. Back

Received 4/24/07; revised 7/15/07; accepted 7/27/07.


   References
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