The Hogg1 Ser326cys Polymorphism and Lung Cancer Risk: a Meta-Analysis

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The hOGG1 Ser326Cys Polymorphism and Lung Cancer Risk: A Meta-analysis

Haixin Li,1 Xishan Hao,1 Wei Zhang,2 Qingyi Wei,3 and Kexin Chen1 Department of 1Epidemiology and Biostatistics, Tianjin Medical University Cancer Institute and Hospital, Tianjin, P.R. China, and Departments of 2Pathology and 3Epidemiology, the University of Texas M.D.Anderson Cancer Center, Texas

Abstract

The potentially functional polymorphism Ser326Cys in dominant model of the Ser326 allele (OR, 1.06; 95% CI, the human 8-oxoguanine DNA glycosylase (hOGG1) 0.93-1.21 for Cys/Cys+Ser/Cys versus Ser/Ser). How- gene has been implicated in lung cancerrisk,but ever, significantly increased risks were found among published studies have mixed findings. To summarize Asian subjects (OR, 1.18; 95% CI, 1.01-1.38 forCys/ published data, we did a comprehensive meta-analysis. Cys+Ser/Cys versus Ser/Ser) in a dominant model. In Two investigators extracted data independently from stratified analyses by control source, compared with the 17 case control studies published in the PubMed Ser/Ser genotype, lung cancer risk associated with the using the search phrases ‘‘hOGG1/OGG1/OGG and hOGG1 Cys/Cys genotype was significantly increased polymorphism/genetic variation and lung cancer.’’ The in population-based studies (OR, 1.32; 95% CI, 1.04- meta-analysis included 6,375 cancercases and 6,406 1.67) but not in hospital-based studies (OR, 1.18; 95% control subjects. The results showed that individuals CI, 0.98-1.42); in stratified analyses by the smoking carrying the hOGG1 Cys/Cys genotype did not have status, however, the increased risk was observed only significantly increased risk of lung cancer [odds ratios among nonsmokers in a dominant model (OR, 1.32; (OR), 1.15; 95% (confidence interval) CI, 0.94-1.41] 95% CI, 1.04-1.67). The meta-analysis suggested that compared with those with the Ser/Ser genotype; a careful matching should be considered in future similarly, no significant association with lung cancer larger genetic association studies including multiple risk was found either in the recessive (OR, 1.09; 95% ethnic groups. (Cancer Epidemiol Biomarkers Prev CI, 0.90-1.32 for Cys/Cys versus Ser/Cys+Ser/Ser) or 2008;17(7):1739–45)

Introduction

DNA is continuously exposed to the assaults by various DNA; the resulting apurinic/apyrimidinic site is then endogenous and exogenous mutagens or carcinogens. incised, and the repair is completed by successive actions Among them, the oxidants, as one of the most common of a phosphodiesterase, a DNA polymerase, and a DNA threats to genomic stability, are thought to cause ligase (5, 6). oxidative damage to DNA and mutations, leading to Previous studies have revealed the presence of several activation of oncogenes, inactivation of tumor suppressor polymorphisms at the hOGG1 locus.A study on small genes, or carcinogenesis (1, 2).However, multiple DNA cell lung cancer found 2 homozygous mutations at repair enzymes protect DNA against such oxidative codons 85 and 131 (7).Later, two single nucleotide damage.For instance, one of the most common forms of polymorphisms, codon 46 Arg/Gln and codon 154 Arg/ oxidative damage is DNA 8-hydroxydeoxyguanine His, were described in another study, in which the caused by oxidative stress.8-hydroxydeoxyguanine is hOGG1-Gln46 allele was shown to have a reduced mutagenic or carcinogenic, resulting in G: C to T: A activity for excision of 8-OH-G, whereas the hOGG1- transversions.The 8-hydroxydeoxyguanine lesions His154 allele was less effective in the repair than the are subject to the base-excision repair, especially by the hOGG1-Ser326 allele (8).Furthermore, the codon 229 8-oxoguanine DNA glycosylase (OGG1), a key enzyme in Arg/Gln in exon 4 has been reported in a recent study the repair of 8-oxoguanine and other types of oxidative (9), in which it was shown that human KG-1 leukemia DNA damage (3), and base-excision repair facilitates the cells had a homozygous Arg229Gln amino acid substi- release of 8-hydroxydeoxyguanine and the cleavage of tution in hOGG1 that was thought to alter the function DNA at the apurinic/apyrimidinic site (4).The human of hOGG1, resulting in elevated levels of genomic 8-oxoG OGG1 hOGG1 hOGG1 ( ), encoded by the gene on and hypersensitivity to 8-hydroxydeoxyguanosine chromosome 3p26, catalyzes the cleavage of the glyco- nucleoside and ionizing radiation observed in these cells. sylic bond between the modified base and the sugar In addition, two other hOGG1 single nucleotide poly- moiety, leaving an abasic apurinic/apyrimidinic site in morphisms, 7143A/G and 11657A/G, located further downstream in a noncoding region, were found to be associated with prostate cancer risk (10, 11).However, Received 1/1/08; revised 3/25/08; accepted 4/22/08. among these polymorphisms of hOGG1, more studies Requests for reprints: Kexin Chen, Department of Epidemiology and Biostatistics, focused on the common single nucleotide polymorphism Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R.China. Ser326Cys.The C/G polymorphism at bp 1245 (C1245G) Phone: 86-22-23340123-5226; Fax: 86-22-23537796.E-mail: [email protected] a hOGG1 Copyright D 2008 American Association for Cancer Research. in the 1 -specific exon 7 of the gene results in an doi:10.1158/1055-9965.EPI-08-0001 amino acid substitution of serine (Ser) with cysteine

Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008

Table 1. Study characteristics and genotype prevalence from published studies on the relation of the Human hOGG1 Ser326Cys polymorphism to lung cancer risk

Ref no.First Year Location Ethnicity No. author of cases (31) Kohno 1998 Japan Asian 45 (28) Sugimura 1999 Japan Mixed 241 (29) Wikman 2000 Germany Caucasian 105 (18) Ito 2002 Japan Asian 138 (16) Le 2002 America Mixed 298 (30) Sunaga 2002 Japan Asian 198 (32) Lan 2004 China Asian 118 (17) Park 2004 America Caucasian 179 (20) Vogel 2004 Denmark Caucasian 256 (27) Hung 2005 Eastern European countries Caucasian 2,155 (24) Liang 2005 China Asian 227 (15) Kohno 2006 Japan Asian 1,097 (22) Lee 2006 Korea Asian 200 (33) Loft 2006 Denmark Caucasian 251 (19) Sorensen 2006 Denmark Caucasian 431 (21) Zienolddiny 2006 Norway Caucasian 326 (34) De Ruyck 2007 Belgium Caucasian 110

*P < 0.05.

(Cys) at codon 326 (Ser326Cys; rs1052133; ref.12). dominant model) in English.So it was still included in The hOGG1 protein encoded by the wild-type Ser326 the meta-analysis.The 17 studies included in the final allele exhibited substantially higher DNA repair activity analysis had a total of 6,375 cancer cases and 6,406 than the Cys326 allele because the Cys allele more likely controls that had the genotyping data for the hOGG1 caused a low activity of the enzyme, and the change of Ser326Cys polymorphism. hOGG1 Ser to Cys was speculated to alter human cancer Data Extraction. Two authors (Haixin Li and Kexin susceptibility (13, 14).Subsequently, many studies have Chen) extracted data and reached a consensus on all of investigated the association of genetic variation in the eligibility items, including author, journal and year of hOGG1 and cancer susceptibility as well as gene publication, location of study, selection and character- environment interactions, most of which focused on the istics of cancer cases and controls, control source, single nucleotide polymorphism Ser326Cys (13–17). demographics, ethnicity, smoking status, and genotyping Several studies have suggested that Cys326 allele is information.For those studies that included subjects of associated with increased lung cancer risk (13, 15–17), different ethnic groups, data were extracted separately particularly among individuals homozygous for the for each of ethnic groups categorized as Caucasians, Cys326 allele, although the findings of these association Asians, or Mixed that included more than one ethnic studies have been inconsistent (18–21).To comprehen- group, such as both Caucasians and Asians, but no sively evaluate the role of the hOGG1 Ser326Cys Africans were identified in these studies. polymorphism in the risk of lung cancer, we did a Meta-analysis. The risks (odds ratios, OR) of lung meta-analysis based on searchable published association cancer associated with the hOGG1 Ser326Cys polymor- studies. phism were estimated for each study independently. We estimated the risk first for the variant homozygous Materials and Methods Cys/Cys genotype, compared with the wild-type homozygous Ser/Ser genotype and then for the Cys/Cys Identification and Eligibility of Relevant Studies. versus (Ser/Cys+Ser/Ser) or (Cys/Cys+Ser/Cys) versus Relevant studies were identified in the PubMed Ser/Ser, assuming recessive and dominant effect models, database4 using combinations of the search phrases respectively.Besides comparisons using all subjects, ‘‘hOGG1/OGG1/OGG and polymorphism/genetic varia- subgroup analyses were done according to the ethnicity tion and lung cancer’’ (the last search update on (Caucasian, Asian, and mixed), control sources (hospital- November 15, 2007).In a total of 38 retrieved relevant and population-based), and smoking status (never references, 17 publications were identified to be eligible smoker and ever smoker). for the inclusion in the meta-analysis because these Statistical Analysis. We calculated OR and 95% 17 studies had a case control study design that assessed hOGG1 confidence intervals (CI) to estimate lung cancer risk the association between the Ser326Cys polymor- associated with the hOGG1 Ser326Cys polymorphism phism and risk of lung cancer using human genomic for each study.Inevitably, studies included in the DNA samples.Of all screened studies, one (22) was meta-analysis differed in the variables of interest, and written in Korean, which nevertheless provided relevant hOGG1 thus, any kind of variability among studies may be data about Ser326Cys polymorphism (only for a termed heterogeneity.In the meta-analysis, the heterogeneity can be assessed by ORs for different stratum of each variable included in the analysis.We also did the Q test to assess the heterogeneity between indivi- 4 http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed dual studies, and the heterogeneity was considered

Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008

Table 1. Study characteristics and genotype prevalence from published studies on the relation of the Human hOGG1 Ser326Cys polymorphism to lung cancer risk (Cont’d)

No. Matching Source of Genotype 1/2 Genotype 2/2 Hardy-Weinberg of controls controls (heterozygotes) (rare-allele homozygotes) test P 42 No clear NA 47.6 16.7 0.94 197 No clear Hospital 54.3 13.7 0.08 105 Age, sex, smoking intensity Hospital 40.1 1.9 0.07 240 No clear Hospital 49.2 22.5 0.84 405 Age, sex, ethnicity Population 43.2 13.1 0.35 152 No clear Hospital 43.4 23.7 0.13 109 Age, sex, region, type of fuel Population 39.4 13.8 0.23 350 Age, sex, ethnicity Screening 24.9 2.3 0.86 269 Age, sex, duration of smoking Population 33.8 7.1 0.24 2,163 Age, sex, center, region Hospital 33.1 3.7 0.22 227 Age, sex, ethnicity Hospital 54.2 33.5 0.04* 394 No clear Hospital 48.2 20.6 0.63 200 No clear NA 261 Age, sex, smoking Population 33.7 7.3 0.2 796 Sex, duration of smoking Population 35.7 4.1 0.25 386 Age, sex, smoking Population 30.3 19.4 0.00015* 110 Sex Hospital 41.8 3.6 0.18 significant, if the P value is <0.05, which was used to consistent with that expected from the Hardy-Weinberg estimate summary ORs and 95% CIs by weighing the equilibrium, except for two studies (21, 24). results of each study by a factor of within- and between- Quantitative Synthesis. We included 6,375 cancer study variance according to a random effect model, and P patients and 6,406 control subjects in the final analysis. if the value is >0.05 in heterogeneity evaluation, a fixed hOGG1 effect model was then used to estimate summary ORs Individuals carrying the Cys/Cys genotype and 95% CIs.Publication bias was assessed by a funnel did not have significantly increased lung cancer risk compared with those carrying the Ser/Ser genotype plot and Egger’s test (23).All analyses were done using P Statistical Analysis System software (v.8.1; SAS Institute) (OR, 1.15; 95% CI, 0.94-1.41; = 0.02 for heterogeneity; and Review Manage (v.5.0). All the P values were data not shown).Similarly, no significant association two-sided. with lung cancer risk was found in either a recessive model (OR, 1.09; 95% CI, 0.90-1.32 for Cys/Cys versus Ser/Cys+Ser/Ser; P = 0.02 for heterogeneity; data not Results shown) or a dominant model (OR, 1.06; 95% CI, 0.93-1.21 for Cys/Cys+Ser/Cys versus Ser/Ser; P = 0.003 for Meta-analysis Database. The basic information heterogeneity; Fig.1). including cancer type, ethnicity of the study populations, In the stratified analysis by ethnicity, significantly and the numbers of cases and controls of each study are increasedriskswerefoundamongAsiansubjects listed in Table 1.There were a total of 17 case control (OR, 1.18; 95% CI, 1.01-1.38 for Cys/Cys+Ser/Cys studies, and the distribution of genotypes for the hOGG1 versus Ser/Ser; P = 0.32 for heterogeneity; Fig. 2) in a polymorphism in the controls of all studies was dominant model.However, among Caucasian subjects,

Figure 1. ORs of lung cancer associated with the hOGGI Cys/Cys+Ser/Cy genotypes compared with the Ser/Ser genotype. For each study, the estimates of OR and its 95% CIare plotted with a box and a horizontal line. x, pooled OR and its 95% CI.

Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008

Figure 2. ORs of lung cancer associated with the hOGGI Cys/Cys+Ser/Cy genotypes compared with the Ser/Ser genotype among Asian subjects. For each study, the estimates of OR and its 95% CIare plotted with a box and a horizontal line. x, pooled OR and its 95% CI.

no significant association with lung cancer risk was heterogeneity) among smokers in dominant model found in either a dominant model (OR, 0.99; 95% CI, (data not shown). 0.83-1.19 for Cys/Cys+Ser/Cys versus Ser/Ser; P = 0.003 Bias Diagnostics. In the bias diagnosis, we found that for heterogeneity; data not shown) or a recessive model the summary ORs were changing around 1 in early (OR, 1.08; 95% CI, 0.78-1.49 Cys/Cys versus Ser/ studies.In a random effect model, the summary OR for Cys+Ser/Ser; P = 0.04 for heterogeneity; data not Cys/Cys versus Ser/Ser was 1.01 for studies published shown).After excluding two studies whose controls before 2002, 1.29 during 2004 to 2005, and 0.98 during had inconsistent genotype distribution with that of 2006 to 2007.In the funnel plot analysis of publication the Hardy-Weinberg equilibrium, there were signifi- bias (in the contrast of homozygous genotype plotted cant differences in terms of the variant Cys326 allele against the precision), the shape of the funnel plot frequency in control subjects among three ethnic groups seemed symmetrical, suggesting that the main estimate (Caucasian, 21.7%; Asian, 42.2%; Mixed, 37.8%; of the association belonged to the larger study (Fig.6). P < 0.0001; Fig. 3). In further sensitivity analysis, we Furthermore, the Egger’s test provided statistical evi- found that the ORs in the Park’s study, whose controls dence of the funnel plot symmetry (23).In the linear were selected from cancer screening center, were regression analysis, the intercept value provided admea- significantly apart away from those of other studies sure of asymmetry—the larger its deviation from zero, with either hospital- or population-based controls.When the more pronounced the asymmetry.We observed the Park’s study was excluded, there was no evidence an intercept value of 0.44, which did not deviate from of heterogeneity in the quantitative analysis among zero (t = 0.57; P = 0.575). Caucasians (P = 0.23 for heterogeneity). Further stratified analysis by control source was done for the remaining studies after the two studies Discussion were excluded because the distributions of the genotyping data of their controls deviated from that of the We conducted a meta-analysis of published studies to Hardy-Weinberg equilibrium.Compared with the Ser/ evaluate the association between the hOGG1 Ser326Cys Ser genotype, the OR for the hOGG1 Cys/Cys genotype polymorphism and lung cancer risk because no such was 1.32 (95% CI, 1.01-1.71; Fig. 4) for population-based meta-analysis has been published to date.We found no studies and 1.18 (95% CI, 0.98-1.42; Fig. 5) for hospital- statistical evidence of an overall effect of the Ser326Cys based studies.By comparing the genotype distribution in polymorphism on lung cancer risk in either recessive or controls between population- and hospital-based studies, we found that the proportion of the Cys/Cys genotype among controls in hospital-based studies was a nonsig- nificantly higher than those in population-based studies (13.6% versus 12%; P > 0.05; Table 2). These data imply that in those studies whose controls were selected from hospitals, the estimate for lung cancer risk may be underestimated. In the stratified analysis by smoking status, because of different smoking status grouped into one reference group in each study, we had to use smoking information from those studies with data on ever smokers versus never smokers.As a result, only four studies were included in the stratified analysis.The hOGG1 polymorphism was found to be associated with a significantly increased risk among nonsmokers (OR, 1.32; 95% CI, 1.04-1.67 for Cys/Cys+Ser/Cys versus Ser/Ser; P =0.82 for heterogeneity; data not shown) but with a nonsignif- icantly decreased risk (OR, 0.94; 95% CI, 0.83-1.06 Figure 3. Variant Cys326 allele frequency among control for Cys/Cys+Ser/Cys versus Ser/Ser; P =0.44for subjects between the three major ethnicities.

Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008

Figure 4. ORs of lung cancer associated with the hOGGI Cys/Cys genotype compared with the Ser/Ser genotype in population-based studies excluding one study that deviated from the Hardy-Weinberg equilibrium. For each study, the estimates of OR and its 95% CI are plotted with a box and a horizontal line. x. pooled OR and its 95% CI. dominant effect models.Compared with the homozy- that this allele may be differently distributed among gous Ser/Ser genotype, the variant Cys/Cys homozy- ethnic groups (16–18, 27–29).This ethnic difference gous genotype was not significantly associated with might reflect the fact that different ethnic and environ- overall lung cancer risk in all subjects from 17 eligible mental exposures may have modified the associations.It studies included in the analysis. seems that Asians may have a much higher susceptibility Generally, oxidative damage to DNA is continuously to lung cancer due to having a higher frequency of the produced as a result of endogenous oxidative stress and variant Cys326 allele. exposure to chemical carcinogens.If hOGG1 is dysfunc- In the case-control studies included in the analysis, tional, the damage could be left unrepaired, leading some controls were selected from populations living in to mutations or carcinogenesis.Some studies have the same community and others from hospitalized suggested that the amino acid change in hOGG1 may patients admitted for diseases other than lung cancer. affect the catalytic properties of the enzyme (25, 26).One Compared among different control populations, hospital explanation for the functional relevance of the polymor- inpatients were relatively easier, more convenient, and phism is that the variant allele may be tightly linked to economical to be recruited as the needed controls. other possibly functional polymorphisms in hOGG1 or However, they may just represent a sample of ill-defined other genes involved in repair of oxidative damage to reference population, and selection bias sometimes DNA.Another possible explanation is that the cannot be avoided, particularly if genotyping data were Cys326Cys genotype may be deficient in repair of associated with the disease conditions the controls had. oxidative damage to DNA only under conditions of Indeed, we found that the proportion of the Cys/Cys excessive cellular oxidative stress (25).However, these genotype among controls in hospital-based studies was a hypotheses need to be tested in future studies. slightly higher than that in population-based controls In the stratified analysis by ethnicity, a fixed 18% (13.6% versus 12%), which may explain why the OR increased lung cancer risk associated with the Ser326Cys (for the hOGG1 Cys/Cys versus Ser/Ser) in population- polymorphism in a dominant effect model (i.e., Ser/ based studies were higher than that in hospital-based Cys+Cys/Cys versus Ser/Ser) was found in Asian, but studies (1.32 versus 1.18); in particular, one study used not in Caucasian, subjects.The frequency of variant controls selected from cancer screening center (17), who Cys326 allele among Asian subjects was much higher had an ever lower proportion of the Cys/Cys genotype, than that of Caucasians (42.2% versus 21.7%), suggesting and generated a much greater OR (4.1 for Cys/Cys

Figure 5. ORs of lung cancer associated with the hOGGl Cys/Cys genotype compared with the Ser/Ser genotype in hospital-based studies excluding one study that deviated from the Hardy-Weinberg equilibrium. For each study, the estimates of OR and its 95% CI are plotted with a box and a horizontal line. x, pooled OR and its 95% CI.

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Table 2. The distribution of Cys/Cys and Ser/Ser smoking.These hypotheses also need to be tested in genotype among control groups from hospital-, future studies. population-, and cancer screening–based studies There are some limitations inherent in this meta- analysis.First, selection bias could have played a role Control source Genotype distribution of control group Total because the genotype distribution of this polymorphism Cys/Cys Ser/Ser among control subjects deviated from the Hardy-Wein- berg equilibrium at least in two studies (21, 24).Second, Hospital based 283 (13.6%) 1,792 (86.4%) 2,075 lack of the original data limited our further evaluation of Population based 139 (12%) 1,020 (88%) 1,159 Cancer Screening 8 (3%) 255 (97%) 263 potential gene-gene and gene-environment interactions. Total 589 (14.3%) 3,544 (85.7%) 4,133 Third, lack of information on disease status, genotypes, and well-documented smoking status may also influence NOTE: m2 = 24.452, P < 0.0001 for overall comparison between , ,and . the results.Fourth, most of the studies except for two m2 = 1.775, P > 0.05 for comparison between and . (15, 27) had a relatively small sample sizes (<500 cases and 500 controls) and included only one ethnic group. Finally, the studies included in the analysis may have versus Ser/Ser) than that observed in other studies used different genotyping methods that had different included in this meta-analysis.Therefore, the use of a quality control issues. proper, representative control population is important in In summary, large studies including different ethnic reducing biases in reported case-control studies. groups with a careful matching between cases and It is believed that tobacco carcinogens that induce controls should be considered in future association 8-hydroxydeoxyguanine are a major cause for develop- studies to confirm results from this meta-analysis ment of lung cancers, and that the risk for developing and to further evaluate the effect of gene-gene and lung cancer could be modulated by the hOGG1 poly- gene-environment interactions on the hOGG1 polymor- morphism.In this meta-analysis, we found it difficult to phism–associated lung cancer risk.Another area of assemble the data that had different grouping methods interest is functional studies of the two hOGG1 poly- for reporting tobacco use.As a result, from 4 of the morphic protein forms in DNA repair ability and their 17 studies (15, 24, 27, 30), we could extract the hOGG1 potential use as biomarkers for lung cancer risk in Asian polymorphism data for smokers and nonsmokers only. populations. Although the hOGG1 polymorphism was not associated with lung cancer risk in smokers, significant associations were found in nonsmokers.The nonsmokers with Disclosure of Potential Conflicts of Interest hOGG1 Cys/Cys+Cys/Ser genotypes had an increase No potential conflicts of interest were disclosed. lung cancer risk by 32% compared with those with the hOGG1 Ser/Ser genotype.It is possible that individuals Acknowledgments hOGG1 with the variant 326Cys allele were more The costs of publication of this article were defrayed in part by susceptible to smoking-related cancer even being ex- the payment of page charges.This article must therefore be posed to low levels of tobacco smoke, and it is also likely hereby marked advertisement in accordance with 18 U.S.C. that these nonsmokers may have been exposed to passive Section 1734 solely to indicate this fact.

Figure 6. Funnel plot analysis to detect publication bias. Each point rep- resents an individual study for the indicated association. For each study, the OR is plotted on a loga- rithmic scale against the precision (the reciprocal of the SE). If bias is absent, small studies will have ORs that are widely scattered but still centered around the OR estimates provided by large, more precise studies.

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