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[Cancer Research 64, 3009-3013, May 1, 2004]
© 2004 American Association for Cancer Research

Advances in Brief

Polymorphisms in DNA Double-Strand Break Repair Genes and Skin Cancer Risk

Jiali Han1,3, Graham A. Colditz1,2, Leona D. Samson4 and David J. Hunter1,2,3

1 Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts; 2 Department of Epidemiology, Harvard Center for Cancer Prevention and 3 Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts; and 4 Biological Engineering Division and the Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 
UV can cause a wide range of DNA lesions. UVA-induced oxidative DNA damage and blocked DNA replication by UVB-induced photoproducts can lead to double-strand breaks (DSBs). We selected 11 haplotype-tagging single nucleotide polymorphisms in three DSB repair genes XRCC2, XRCC3, and LigaseIV and evaluated their associations with skin cancer risk in a nested case-control study within the Nurses’ Health Study [219 melanoma, 286 squamous cell carcinoma (SCC), 300 basal cell carcinoma (BCC), and 873 controls]. We observed that the XRCC3 18085T (241Met) allele and its associated haplotype were significantly inversely associated with the risks of SCC and BCC, whereas the XRCC3 4552C allele along with its associated haplotype and the XRCC2 30833A allele were significantly associated with increased BCC risk. The LigaseIV 4044T and 4062T alleles were associated with decreased BCC risk; two of four haplotypes were significantly associated with altered BCC risk. A trend toward decreased risk of nonmelanoma skin cancer was found in those harboring a greater number of putative low risk alleles (P for trend, 0.05 for SCC, <0.0001 for BCC). The main effects of these genotypes were essentially null for melanoma risk. This study provides evidence to suggest the role of the DSB repair pathway in skin cancer development, especially for BCC.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results and Discussion
 REFERENCES
 
UV is capable of causing a wide range of DNA lesions. Although UVB exposure does not directly produce DNA double-strand breaks (DSBs), it has been suggested that UV-induced photoproducts cause blockage of DNA replication, which can lead to the formation of DSBs, chromosomal aberrations, and recombination during the course of replication arrest (1) . Reactive oxygen species generated after the absorption of UVA by cellular chromophores can cause oxidative DNA damage that can lead to single and DSBs (2) . Homologous recombination and nonhomologous end-joining are two distinct mechanisms in the repair of DSBs in mammalian cells. In the homologous recombination pathway, as RAD51 paralogues, XRCC2 and XRCC3 facilitate the formation of RAD51 foci. Hamster cells deficient in XRCC2 or XRCC3 exhibited defects in Rad51 focus formation (3 , 4) and a decrease in homologous recombination induced by DSB (5 , 6) , implying the critical roles of XRCC2 and XRCC3 in homologous recombination. In the nonhomologous end-joining pathway, after bound by the complex of the Ku 70 and 80 heterodimer and DNA-dependent protein kinase, the break is repaired by the complex of LigaseIV and XRCC4 (7) . Inactivation of the LigaseIV gene in mice led to embryonic lethality; these mouse cells showed increased sensitivity to infrared and defects in V(D)J joining (8) . Genetic polymorphisms in DSB repair genes may influence DNA repair capacity and confer predisposition to UV-induced skin cancer. We selected 11 haplotype-tagging single nucleotide polymorphisms (SNPs) in three DSB repair genes XRCC2, XRCC3, and LigaseIV, which have been resequenced by the National Institute of Environmental Health Sciences Environmental Genome Project5 and evaluated their associations with skin cancer risk in a nested case-control study within the Nurses’ Health Study. We additionally investigated whether these variations in the DSB repair genes modify the association of sunlight exposure with skin cancer risk.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results and Discussion
 REFERENCES
 
Study Population.
The Nurses’ Health Study was established in 1976, when 121,700 female registered nurses between the ages of 30 and 55 years completed a self-administered questionnaire on their medical histories and baseline health-related exposures. Updated information has been obtained by questionnaires every 2 years. Between 1989 and 1990, blood samples were collected from 32,826 of the cohort members. Eligible cases in this study consisted of women with incident skin cancer from the subcohort who gave a blood specimen, including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) cases with a diagnosis anytime after blood collection up to June 1, 1998, and melanoma cases (including in situ cases) up to June 1, 2000, with no previously diagnosed skin cancer. All available pathologically confirmed melanoma and SCC cases, and 300 self-reported BCC cases randomly selected from ~2600 available self-reported BCC cases were included. The validity of self-report of BCC is high in this medically sophisticated population (90%; Ref. 9 ). All of the SCC and BCC cases had no history of melanoma diagnosis. A common control series (case: control = 1:1) was randomly selected from participants who gave a blood sample and were free of diagnosed skin cancer up to and including the questionnaire cycle in which the case was diagnosed. One control was matched to each case by year of birth (±1 year) and race (Caucasian, Asian, Hispanic, others). At the time we selected cases and controls, 47 cases and 69 controls were deceased. As we wished to obtain additional information by supplementary questionnaire, we randomly selected a second matched living control when the first control was deceased. The nested case-control study consisted of 219 melanoma cases (including 77 in situ cases), 286 SCC cases, 300 BCC cases, and 874 matched controls. Because of the absence of African-American cases, 1 African-American control was excluded to avoid potential population stratification. We mailed to 758 living cases and 804 living controls a supplementary questionnaire on lifetime sun exposure and other skin cancer risk factors. Six hundred ninety-five cases responded, 15 cases refused to participate, and 48 cases did not respond after three mailings (participation rate = 92%). Among controls, 713 responded, 9 refused, and 82 did not respond (participation rate = 89%). The study protocol was approved by the Committee on Use of Human Subjects of the Brigham and Women’s Hospital (Boston, MA).

Exposure Data.
Information regarding skin cancer risk factors was obtained from the prospective biennial questionnaires and the retrospective supplementary questionnaire. Information on natural hair color and childhood and adolescent tendency to sunburn or tan was asked in the 1982 prospective questionnaire and ethnic group in the 1992 questionnaire. The retrospective supplementary questionnaire consisted of questions in three major areas: (a) pigmentation, constitutional, and susceptibility factors; (b) history of residence (states and towns), sun exposure habits, and severe sunburns at different ages; and (c) family history of skin cancer (father, mother, and siblings). In addition, the 11 states of residence of cohort members at baseline (1976) were grouped into three regions: Northeast (Connecticut, Massachusetts, Maryland, New Jersey, New York, and Pennsylvania); Northcentral (Michigan and Ohio); and West and South (California, Texas, and Florida). The comparison of the responses to the questions asked on both retrospective supplementary questionnaires and prospective questionnaires indicated that the retrospective assessment was not likely to substantially bias the estimates of risk in this study (data not shown).

To estimate sunlight exposure for each subject, an UV database of winter and summer radiation indices for all 50 states of the United States was developed based on the reports from the climatic atlas of the United States. A cumulative lifetime sun exposure was developed by combining the UV database and the information obtained from the supplementary questionnaires. Questions about sun exposure while wearing a bathing suit were used to define a cumulative lifetime sun exposure variable for this behavior.

SNP Identification.
The XRCC2, XRCC3, and LigaseIV genes were resequenced by the National Institute of Environmental Health Sciences Environmental Genome Project at the University of Washington.5 The multiple ethnicity group of 90 samples used for screening was from the NIH DNA Polymorphism Discovery Resource available from the Coriell Institute for Medical Research. The ethnicity of individual samples is unknown. We performed haplotype estimation based on these 90 Coriell samples using the Partition-Ligation Expectation Maximization Algorithm of Qin et al. (10) . Haplotypes were inferred based on the SNPs with >1% allele frequency found in the exons and 5'-untranslated region and 3'-untranslated region regions of the XRCC2, XRCC3, and LigaseIV genes (Table 1)Citation . We selected haplotype-tagging SNPs for the estimated haplotypes with frequency > 2%, which was set to ascertain alleles that occurred at 5% prevalence among the 23 Caucasians in the 90 individuals in the sample set used for resequencing (11) . We genotyped these haplotype-tagging SNPs in the present case-control study of mostly Caucasian women. Because the XRCC2 C29560T did not pass the Taqman assay, XRCC2 A31342G, which was in 100% genotype concordance in the 90 samples, was genotyped instead.


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  		Table 1 Inferred haplotypes for XRCC2, XRCC3, and Ligase IVa

 
Laboratory Assays.
Genotyping was performed by the 5'-nuclease assay (TaqMan), using the ABI PRISM 7900HT Sequence Detection System (Applied Biosystems, Foster City, CA), in 384-well format. TaqMan primers and probes were designed using the Primer Express Oligo Design software v2.0 (ABI PRISM). Laboratory personnel were blinded to case-control status, and blinded quality control samples were inserted to validate genotyping procedures; concordance for the blinded samples was 100%. Primers, probes, and conditions for genotyping assays are available upon request. To confirm the absence of the XRCC3 G10371A (Arg94His) polymorphism in our population, we genotyped 177 Caucasian women participants by Pyrosequencing (Pyrosequencing, Inc., Uppsala, Sweden).

Statistical Analysis.
We used a {chi}2 test to assess whether the genotypes were in Hardy-Weinberg equilibrium and to determine Ps for differences in haplotype frequencies between cases and controls. Unconditional logistic regression was used to calculate odds ratio and 95% confidence interval to assess the risk of skin cancer for genotypes. A test for trend was calculated by treating the three genotypes as ordinal variables for each polymorphism. We used a likelihood ratio test to evaluate heterogeneity in the effects of the genotypes on different types of skin cancer in polytomous logistic regression models (12) . To summarize multiple variables, we constructed a multivariate confounder score to create a constitutional susceptibility score for each type of skin cancer (13) . Briefly, we applied the logistic regression coefficients from a multivariate model, including age, race, natural skin color, natural hair color, child or adolescent tendency to burn, and the number of palpably raised moles on arms, to each individual’s values for the latter four of these variables and summed the values to compute a constitutional susceptibility score in the logit scale. We used this score to define women with low, intermediate, and high constitutional susceptibility based on tertiles among controls. In the gene-environment interaction analyses, the number of severe lifetime sunburns that blistered and cumulative sun exposure with a bathing suit was categorized into tertiles with cut points based on the distribution of controls. To test statistical significance of interactions between environmental exposures and the XRCC3 Thr241Met polymorphism, we modeled the genotype as a dichotomous variable (carrier versus noncarrier) and environmental exposures as ordinal variables to test significance of a single multiplicative interaction term. All Ps were two-sided.


   Results and Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
REFERENCES
 
The mean age at diagnosis of cases was 64.1 years and that of controls was 64.5 years. Self-reported major ethnicity was similar between cases and controls in this study population (cases versus controls: Caucasian, 85.3 versus 85.7%; others, 11.7 versus 11.6%; 1 Asian melanoma case and 1 control; and 1 Hispanic SCC case and 2 controls). Significantly positive associations were observed for lighter natural skin color, lighter natural hair color, child or adolescent tendency to burn, and the number of palpably raised moles on arms with the risk of all three types of skin cancer. The risk for the highest tertile of the susceptibility score was ~3-fold higher for SCC and BCC and 4-fold higher for melanoma, compared with the lowest tertile. A family history of skin cancer was a risk factor for the three types of skin cancer. Cases of each skin cancer type were more likely to have used sunlamps or attended tanning salons. The number of lifetime severe sunburns that blistered was significantly associated with all three types of skin cancer. Women in the West and South regions were more likely to be diagnosed with SCC or BCC compared with those in Northeast.

We genotyped 11 haplotype-tagging SNPs in these three genes to infer common haplotypes in Caucasians. The genotype distributions of these SNPs were in Hardy-Weinberg equilibrium among controls. Imputed common haplotypes with frequency > 5% are shown in Table 2Citation . Compared with the haplotypes listed in Table 1Citation , no additional common haplotype in the three genes was observed in the present study. Three common haplotypes in XRCC2 were inferred, which accounted for 92% of the chromosomes in the study population. There was no significant difference in frequency distribution in cases and controls for any inferred haplotype. The XRCC3 G10371A (Arg94His) polymorphism, with reported 3% allele frequency in the panel of 90 multiple ethnic samples, was observed neither in two 384-well format plates in the current study by TaqMan assay, nor in a different set of 177 Caucasian women participants by Pyrosequencing. This is consistent with the previous report of no observation of this variant among 36 Caucasians (14) , suggesting that this polymorphism may be a population-specific SNP in other ethnic groups. On the basis of the other two polymorphisms in XRCC3, only three haplotypes were imputed in this population. As shown in Table 2Citation , the haplotype with the 241Met variant was significantly less common in BCC and SCC cases than controls. The haplotype with the 4552C variant was significantly more common in BCC cases than controls. For the LigaseIV gene, the haplotype with no variant allele at three polymorphic sites was significantly more common in BCC cases than controls, whereas the haplotype with the two variant alleles in the 5'-untranslated region was significantly less common in BCC cases than controls.


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  		Table 2 Frequencies of inferred common haplotypes in cases and controlsa

 
These haplotype-tagging SNPs are mutually exclusive to each other on these common haplotypes, except for the Ligase IV C4044T and C4062T. Therefore, the carriage of these SNPs can be viewed as the carriage of the corresponding haplotypes. Associations of these individual polymorphisms with skin cancer risk are shown in Table 3Citation . The XRCC2 C29244T, which had a prevalence of 6% in the 90 multiple ethnic samples, only existed at 0.2% among controls in the present population. We observed that the XRCC2 G30833A was associated with a significantly increased risk of BCC. Consistent with the XRCC3 haplotype analysis (Table 2)Citation , we observed a significantly positive association of the XRCC3 A4552C polymorphism with BCC risk and a significantly inverse association of the XRCC3 C18085T (Thr241Met) with the risks of BCC and SCC in this study. A significantly positive association of XRCC3 Thr241Met with melanoma was previously reported in a United Kingdom case-control study (n, cases = 125; n, controls = 211; Ref. 15 ). However, the result was not subsequently confirmed in a larger study (n, cases = 305; n, controls = 319; Ref. 16 ). We also did not observe the relation of XRCC3 Thr241Met with melanoma risk in this study. The LigaseIV C4044T and C4062T polymorphisms were inversely associated with BCC risk. There was no statistically significant heterogeneity in the main effect of each genotype on the three types of skin cancer, although our power to detect heterogeneity was modest (Table 3)Citation .


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  		Table 3 Genotypes and skin cancer riska

 
The functional effects of the two nonsynonymous polymorphisms of XRCC2 G31479A (R188H) and XRCC3 C18067T (T241M) on cell survival after mitomycin C-induced DNA interstrand cross-linking have been studied in in vitro experiments (17 , 18) . Neither of the two variants displayed a substantial effect on damage sensitivity. The XRCC3 241Met allele was not associated with radiation-induced G2-phase delay (19) . The association of the XRCC3 241Met allele with higher bulky DNA adduct levels (20) suggests a possible role of XRCC3 in repairing these adducts. These functional data suggest that the XRCC3 Thr241Met may only be associated with slightly decreased DNA repair capacity. In the present study, this polymorphism showed significantly inverse associations with BCC and SCC risks. A possible explanation is that keratinocytes with slightly impaired DNA repair capacity may accumulate excess DNA damage, inducing apoptosis, and, in turn, decreasing the risk of nonmelanoma skin cancer.

Given the potential functional relevance of the XRCC3 Thr241Met polymorphism, we evaluated potential gene-environment interactions between this polymorphism and sun exposure on skin cancer risk. The positive trends of lifetime severe sunburns with melanoma risk and of cumulative sun exposure with a bathing suit with SCC risk were stronger among XRCC3 241Met carriers (P for trend, 0.002 and <0.0001, respectively) than among noncarriers (P for interaction for both, 0.03). Both positive trends were because of the decreased risk among the Met carriers with the lower level of exposure, which was attenuated among those with higher exposure level. It was noteworthy that the 241Met allele was significantly associated with lifetime sunburns among controls (P, {chi}2 for trend, 0.005). No significant interactions were observed between the XRCC3 Thr241Met and other risk factors on the risk of any other skin cancer types.

Evidence has emerged for the involvement of multiple DNA repair genes in cancer development (21) . We defined low-risk allele to summarize our findings and explore the potentially synergistic effects of the five polymorphisms in DSB repair genes that showed significant or marginally significant main effect individually. The putative low-risk alleles are the variant alleles for XRCC3 C18085T (Thr241Met), LigaseIV C4044T and LigaseIV C4062T, and wild-type alleles for XRCC2 G30833A and XRCC3 A4552C. The associations of the number of these putative low-risk alleles carried and skin cancer risk are presented in Fig. 1Citation . A trend toward decreased risk of nonmelanoma skin cancer was found in those harboring a greater number of putative low risk alleles (P for trend, 0.33 for melanoma, 0.05 for SCC, <0.0001 for BCC). The test for heterogeneity of effect of the number of low-risk alleles across the three types of skin cancer is of borderline significance (P, 0.05). This exploratory analysis suggests a combined effect of DSB repair gene variants in nonmelanoma skin cancer development, particularly for BCC.



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  		Fig. 1. The associations of the number of putative low-risk alleles and skin cancer risk. The multivariate odds ratios (ORs) were adjusted for variables in the multivariate model C in Table 3Citation . Error bar represents 95% confidence interval. The "low-risk" alleles were defined on the basis of the findings of the present study. The low-risk alleles are the variant alleles for XRCC3 C18085T (Thr241Met), LigaseIV C4044T and LigaseIV C4062T, and wild-type alleles for XRCC2 G30833A and XRCC3 A4552C. A trend toward decreased risk of nonmelanoma skin cancer was found in those harboring a greater number of putative low-risk alleles [P for trend, 0.33 for melanoma, 0.05 for squamous cell carcinoma (SCC), <0.0001 for basal cell carcinoma (BCC)]. The test for heterogeneity of effect of the number of low-risk alleles across the three types of skin cancer is borderline significant (P, 0.05). The number of controls in each category was 122 for one to three alleles, 206 for four alleles, 201 for five alleles, and 222 for six to nine alleles.

 
This study is an initial attempt to infer haplotype structures and select haplotype-tagging SNPs based on resequencing data from the National Institute of Environmental Health Sciences Environmental Genome Project, and evaluate their association with skin cancer risk in our study of mainly Caucasians. We observed that some haplotypes and variants in the XRCC2, XRCC3, and LigaseIV genes in DSB repair pathway were associated with altered skin cancer risk, especially for BCC. The nested case-control design, high follow-up rate, and high response rate for the retrospective supplementary questionnaire strengthen the validity of this study. This study provides preliminary evidence to suggest the role of the DSB repair pathway in skin cancer development, especially for BCC. Given the number of comparisons, the findings should be interpreted with caution and confirmed by other studies.


   ACKNOWLEDGMENTS
 
We thank Dr. Hardeep Ranu, Craig Labadie, Robert O’Brien, Pati Soule, and Alicia Whittington for their laboratory assistance, Rong Chen, David Coppola, and Karen Corsano for their programming support. We also thank the participants in the Nurses’ Health Study for their dedication and commitment.


   FOOTNOTES
 
Grant support: NIH Grants CA97746 and CA87969.

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.

Note: L. Samson is an Ellison American Cancer Society Research Professor.

Requests for reprints: Jiali Han, Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115. E-mail: jiali.han{at}channing.harvard.edu

5 Internet address: http://egp.gs.washington.edu/. Back

Received 1/25/04. Revised 2/27/04. Accepted 3/ 5/04.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 

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