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Breast Cancer Res Treat (2010) 123:203–212 DOI 10.1007/s10549-010-0751-0

EPIDEMIOLOGY

Associations between XPD polymorphisms and risk of breast cancer: a meta-analysis Zheng Jiang • Chunxiang Li • Ye Xu Sanjun Cai • Xishan Wang

•

Received: 19 November 2009 / Accepted: 18 January 2010 / Published online: 29 January 2010 Ó Springer Science+Business Media, LLC. 2010

Abstract Studies on polymorphisms of Xeroderma Pigmentosum Group D Protein (XPD) and breast cancer risk are inconclusive. To elucidate the role of XPD genotypes, all available studies were considered in this meta-analysis. The study provided 11,362/10,622 cases/controls for XPD K751Q and 9010/9873 cases/controls for XPD D312N, respectively. Overall, no apparent effects of 751Q allele compared to 751K on breast cancer risk was found in all subjects [RE OR = 1.04, 95% confidence interval (CI) (0.97–1.10), P = 0.28]. Insignificant effects were also found under other genetic contrasts (homologous contrast, dominant model, and recessive model). However, the 751Q allele showed significantly increased risk in Caucasians [FE OR = 1.05, 95% CI (1.00–1.11), P = 0.035]. In addition, insignificant risk effects of D312N polymorphism on breast cancer susceptibility were observed in all subjects under any genetic contrast, but protective effects of 312NN genotype were observed under recessive model [P = 0.02,

Zheng Jiang and Chunxiang Li equally contributed to this work.

Electronic supplementary material The online version of this article (doi:10.1007/s10549-010-0751-0) contains supplementary material, which is available to authorized users. Z. Jiang Y. Xu S. Cai (&) Department of Colorectal Surgery, Cancer Hospital, Fudan University, Shanghai 200032, China e-mail: [email protected] C. Li Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China X. Wang (&) Department of Abdominal Surgery, The Affiliated Tumor Hospital, Harbin Medical University, Harbin 150086, China e-mail: [email protected]

OR = 0.53, 95% CI (0.32, 0.90)] and homozygote contrast [P = 0.03, OR = 0.55; 95% CI (0.32, 0.96)] in Asians. In summary, our meta-analysis suggested 312N allele might act as a recessive allele in its association with breast cancer and the 751Q allele may play a plausible role in breast cancer development whereas the ethnic background should be carefully concerned in further studies. Keywords Breast cancer Genetic polymorphism Meta-analysis XPD

Introduction Breast cancer is the second most frequent cause of cancer death among women [1]. The well-established risk factors for breast cancer were attributed to endogenous and exogenous DNA damage in etiological studies. Unrepaired DNA may lead to unregulated cell growth and cancer. DNA repair molecules have been proposed as candidate cancer-susceptibility genes for the importance of maintaining genomic integrity in the prevention of carcinogenesis [2–4]. The role of the nucleotide-excision repair (NER) pathway is to repair bulky lesions of DNA such as pyrimidine dimers [5]. Defects in this pathway may predispose an individual to malignancies. Xeroderma Pigmentosum Group D Protein (XPD) served as the key protein unwinding damaged DNA is the major gene involved with repairing of NER [6]. Common polymorphisms of XPD may alter protein function and an individual’s capacity to repair damaged DNA. Both K751Q (Lys-to-Gln substitution at codon 751 in exon 23) and D312N (Asp-to-Asn substitution at codon 312 in exon 10) are common polymorphisms of XPD. Tang et al. [7] first reported no relationship of XPD polymorphisms at codon 751 and 312 and breast cancer risk.

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However, subsequent studies revealed the conclusion remain inconsistent [8, 9]. Studies on the polymorphisms of XPD had shown different trends of the risk in breast cancer might owe to the relatively small size and different patient population. Therefore, it is highly necessary to perform a quantitative and systemic study with rigorous methods. Meta-analysis is a powerful means of resolving disparate results. To address the association between XPD polymorphisms and breast cancer risk, a meta-analysis was performed from all eligible studies in this study.

Materials and methods Identification and eligibility of relevant studies To identify all articles that examined the association of XPD K751Q and D312N polymorphisms with breast cancer, we conducted a literature search of the PubMed database up to October 2009 using the following MeSH terms and Keywords: ‘‘ERCC2 protein, human,’’ ‘‘ERCC2,’’ ‘‘breast neoplasm,’’ ‘‘XPD,’’ and ‘‘breast cancer.’’ Additional studies were identified by a hand search of references of original studies or review articles on this topic and by personal contact with the authors if necessary. Eligible studies included in the meta-analysis had to meet the following criteria: (a) a case–control breast cancer study of any of the two polymorphisms with complete genotype distribution data, (b) the diagnosis of breast cancer patients was confirmed pathologically and controls were confirmed to be free of breast cancer; and (c) written in English. Data extraction Two investigators independently extracted data and reached a consensus on all of the items. The following information was extracted from each study: first author, years of publication, ethnicity (country) of study population, genotyping methods, and characteristics of the patients and the controls. For two studies [12, 20] including subjects of different ethnicities, data were extracted separately and categorized as Caucasian and Mixed. However, if the authors did not clearly state the ethnic information or we could not separate them according to genotypes, the term ‘‘mixed ethnicity’’ was used (Table 1). Statistical analysis The meta-analysis evaluated overall association between XPD K751Q allele Q and breast cancer risk compared to allele K, as well as other genetic contrasts including homozygote contrast (QQ vs. KK), the recessive genetic

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Breast Cancer Res Treat (2010) 123:203–212

model [QQ vs. (KQ ? KK)], and the dominant genetic model [(QQ ? KQ) vs. KK]. The same contrasts were performed for D312N polymorphism. The effect of association was indicated as odds ratios (OR) with the corresponding 95% confidence interval (CI), and the OR was calculated according to the method of Woolf [28]. The pooled OR was estimated using fixed effects (FE) (Mantel–Haenszel) models and random effects (RE) (DerSimonian and Laird) models [29]. The significance of the pooled OR was determined by the Z-test; a Pvalue of \0.05 was considered significant. A Chi-squarebased Q-statistic test [29] and an I2 test [30] were performed to assess the heterogeneity between studies (I2 \ 25% no heterogeneity; I2 = 25–50% moderate heterogeneity; I2 [ 50% large or extreme heterogeneity). The heterogeneity was considered statistically significant with P \ 0.10. Publication bias was investigated by funnel plot, and an asymmetric plot suggested possible publication bias. The funnel plot asymmetry was assessed by Egger’s linear regression test [31]. The t test was performed to determine the significance of the asymmetry, and a P value of \0.05 was considered a significant publication bias. Hardy–Weinberg Equilibrium (HWE) was tested by the Chi-square test. Meta-analysis was carried out using Stata version 8.0 (Stata Corporation, College Station, TX, USA).

Results Eligibility To include all of the published articles, MeSH terms and keywords were used as the retrieve strategy. We found 43 published articles evaluated XPD and breast cancer, nine were irrelevant, two articles [15, 32] were excluded because they were conducted on overlapping populations with other eligible studies [13, 15], two articles [33, 34] were review/meta-analyses, and nine studies [35–43] were excluded due to other reason (seven of them [35–41] were excluded due to reporting reasons, i.e., no reporting of the relevant genotype frequencies, whereas others [42, 43] were excluded for examining the association between adverse events of radiotherapy or smoking and breast cancer). As a result, data from only 21 articles met the inclusion criteria (Table 1). The studies were published between 2002 and 2008. In all studies, the cases and controls were matched for age. The controls were free of breast cancer. For determination of the genetic polymorphisms of XPD K751Q and D312N, validated genotyping methods were used in all studies. All studies were conducted in various populations of different ethnicities: eight were conducted in populations of Caucasian ethnicity [8, 10, 15, 16, 18, 19, 21, 24], three involved Asians [9, 14, 17], and


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Table 1 Characteristics of eligible studies considered in the meta-analysis First author (year)

Ethnicity (country)

Genotyping method

SNP studies

PCR–RFLP

K751Q; Hospital-based D312N

103 121 controls were matched by age cases

Justenhoven et al. Caucasian MALDI-TOF MS (2004) [10] (Germany)

K751Q; PopulationD312N based


Shi et al. (2004) [11]

Mixed (USA)

PCR–RFLP

K751Q; Hospital-based D312N

69 79 controls were matched to the cases by cases age

Terry et al. (2004) [12]

Mixed (USA)

Fluorescence polarization

K751Q

Populationbased

1,053 1,102 controls were matched by age cases

Dufloth et al. (2005) [13]

Mixed (Brasil)

PCR–RFLP

D312N

Hospital-based


Lee et al. (2005) [14]

East Asian (Korea)

Single-base extension assay

K751Q

Hospital-based

577 507 controls cases

Kuschel et al. (2005) [15]

Caucasian (UK)a

ABI sequence detection system


1,676 1,718 controls were matched by age and cases geographical area

Metsola et al. (2005) [16]

Caucasian (Finland)

PCR–RFLP

K751Q

Populationbased

483 482 controls were matched by age and cases geographical area

Zhang et al. (2005) [17]

East Asian (China)

PCR–RFLP


220 310 controls were matched by age and cases ethnicity

Brewster et al. (2006) [18]

Caucasian (USA)

Taqman or 50 nuclease assay K751Q

Debniak et al. (2006) [19]

Caucasian (Poland)

PCR–RFLP


1,830 511 controls were matched by age, cases gender and geographical area

Mechanic et al. (2006) [20]

Mixed (USA)

ABI sequence detection system or Taqman assay


2,045 1,818 controls were matched by cases geographical area

Onay et al. (2006) [21]

Caucasian (Canada)

TaqMan assay

K751Q

Populationbased


Shen et al. (2006) Mixed [22] (USA)

Fluorescence polarization or K751Q; PopulationTaqman assay D312N based


Crew et al. (2007) [23]

Mixed (USA)

Taqman assay

D312N

Populationbased

1,053 1,102 controls were matched by age cases

Costa et al. (2007) [24]

Caucasian (Portugal)

PCR–RFLP

K751Q

Populationbased

285 442 controls were matched by age, cases gender, and geographical area

Jorgensen et al. (2007) [25]

Mixed (USA)

The patented fluorogenic method

D312N

Nested

321 321 controls were matched by gender, cases age, and menopausal status

Li et al. (2008) [9]

East Asian (China)

DHPLC

K751Q

Hospital-based

486 479 controls were matched by age, cases gender, and geographical area

Rajarama et al. (2008) [26]

Mixed (USA)

TaqMan or MGB Eclipse assays

K751Q

Populationbased

858 1,083 controls were matched by age cases

Shore et al. (2008) [27]

Mixed (USA)

PCR–RFLP

K751Q

Populationbased

612 612 controls were matched by age, date cases and menopausal status

Synowiec et al. (2008) [8]

Caucasian (Poland)

PCR–RFLP

K751Q

Unknown


Tang et al. (2002) Mixed [7] (USA)

a

Study-design (case–control)

Populationbased

Cases

Controls

321 321 controls were matched by age and cases gender and menopausal status

Over 98% of cases and controls are white

ten mixed [7, 11–13, 20, 22, 23, 25–27]. For ten ‘‘mixed’’ studies, nine were conducted in USA and one in Brazil. Furthermore, we also examined the articles in the ‘‘mixed’’ groups in detail, except for two studies [12, 20] the others cannot be categorized into other groups due to insufficient detail, which limited us to evaluate the association between two polymorphisms and breast cancer risk in additional categories, i.e., African American, or Hispanic (Fig. 1).

Meta-analysis database A total of 11,362 cases and 10,622 controls for K751Q and 9010 cases and 9873 controls for D312N were included. Details of the cases and controls were listed in Table 1. Genotypic and allelic frequencies of cases and controls for K751Q and D312N are shown in Table 2. The allele frequency of 751Q is 35.5% and 34.4% in the case and the

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Fig. 1 Allele frequencies and their 95% CIs of the XPD codon a 751 and b 312 polymorphisms among control subjects by different ethnicities. Each data point represents a separate study for the indicated association.

control, respectively. There was no significant difference in terms of the variant 751Q allele frequency between the three major ethnicities (Caucasian, 33.3%; 95% confidence interval (95% CI), 27.6–39.1; East Asian, 22.2%; Mixed, 33.9%; 95% CI, 31.1–36.7; P [ 0.05; Fig. 1a). Meanwhile, for 312N allele, the frequency is 31.1% and 32.5% in the case and the control, respectively. Nor significant difference existed between the various ethnicities (Caucasian, 35.4%; East Asian, 19.1%; Mixed, 29.7%; P [ 0.05; Fig. 1b). In two D312N studies [20, 23], the distributions of genotypes in the control group were not in HWE (P \ 0.05).

OR = 0.99, 95% CI (0.85–1.16)] in all subjects (Table 3). The 312NN genotype showed an association with decreasing breast cancer susceptibility in East Asian individuals under homozygote contrast [P = 0.03, OR = 0.55, 95% CI (0.32–0.96)] and recessive model contrast [P = 0.02, OR = 0.53, 95% CI (0.32–0.90)] (Fig. 3b), but showed insignificant effects on breast cancer risk in mixed and Caucasian population under any contrast. In addition, to eliminate the bias caused by two studies [20, 23] that were not in HWE, we carried out separately a meta-analysis excluding them, and the results were in agreement with the findings from foregoing analysis (Figure s1).

Main results and subgroup analysis Test of heterogeneity The heterogeneity results and the effect of the association between polymorphisms of XPD and the risk of breast cancer for the genetic contrasts under investigation are shown in Figs. 2, 3, and Table 3. For K751Q, moderate heterogeneity existed among the 18 eligible studies (P = 0.02, I2 = 46%). The RE model showed that the 751Q allele was not associated with the risk of breast cancer compared with the K allele (OR = 1.04, 95% CI in parenthesis (0.97–1.10), P = 0.28). The contrasts of homozygote, recessive model, and dominant model were also insignificant. In subgroups analyses, the 751Q allele showed nonsignificant risk effects on Asians [RE OR = 0.76 (0.45–1.28), P = 0.30] and ethnic mixed [FE OR = 1.02 (0.96–1.08), P = 0.52]. However, significantly increased risk was shown in Caucasians [FE OR = 1.05 (1.00–1.11), P = 0.035] (Fig. 3a). For D312N polymorphism, there was extreme heterogeneity among 11 studies (P \ 0.00001, I2 = 78%). Insignificantly effects of D312N polymorphism on breast cancer susceptibility were observed under allele contrast [P = 0.53, OR = 0.96, 95% CI (0.86, 1.08)] (Fig. 2b), homologous contrast [P = 0.25, OR = 0.88, 95% CI (0.71–1.09)], recessive model [P = 0.15, OR = 0.88, 95% CI (0.73–1.05)] and dominant model [P = 0.95,

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There was moderate heterogeneity among the 18 studies including the K751Q polymorphism (I2 = 46.3, df = 17, P = 0.02) and extreme heterogeneity among the 11 studies including the D312N polymorphism (I2 = 78.0, df = 10, P \ 0.00001). Therefore, we evaluated the source of heterogeneity for the N allele (N vs. D) and Q allele (Q vs. K) by ethnicity and publication year. When we categorized the 18 studies included the K751Q polymorphism by ethnicity, the difference of ethnicity did significantly contribute to the observed heterogeneity (P = 0.007), so did publication year (P = 0.003). For D312N polymorphism, ethnicity (P = 0.004) and publication year (P = 0.027) produced the same results. Sensitivity analysis Sensitivity analysis was performed both by sequential remove of individual studies and cumulative statistics for all comparisons of all subjects and subgroups. The pooled ORs of K751Q and D312N were not influenced by any individual study. It should be noted that the results did not change as articles, genotype frequency shown deviated from others, were excluded.


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Table 2 Distribution of XPD K751Q and D312N genotypes and alleles among cases and controls included in the meta-analysis First author (year)

Ethnicity (country)

Genotype (K751Q K [ Q)

Genotype (D312N D [ N)

Cases

Controls

Controls

Cases

Controls

Controls

KK/KQ/QQ

KK/KQ/QQ

Q% HWE (P)

DD/DN/NN

DD/DN/NN

N% HWE (P)

Tang et al. (2002) [7]

Mixed (USA)

45/42/16

54/46/21

36.4 0.05

52/31/7

55/25/2

17.7 0.67

Justenhoven et al. (2004) [10]

Causcasian (Germany)

224/265/97

264/292/87

36.2 0.66

347/173/47

276/255/79

33.9 0.1

29/32/8

46/27/6

24.7 0.47

1529/1530/ 497 475/50/3

1401/1473/ 430 401/41/3

35.3 0.17 5

0.1

89/111/20

119/140/51

39

0.37

38.3 0.12

Terry et al. (2004) [12]

Mixed (USA)

387/513/153

453/498/151

36.3 0.45

Shi et al. (2004) [11]

Mixed (USA)

30/31/8

38/35/6

29.7 0.59

Dufloth et al. (2005) [13]

Mixed (Brasil)

93/63/21

58/48/11

29.9 0.82

664/772/240

683/791/244

37.2 0.54

Metsola et al. (2005) [16] Causcasian (Finland)

147/238/96

155/237/88

43

Zhang et al. (2005) [17]

Kuschel et al. (2005) [15] Causcasian (UK) Lee et al. (2005) [14]

East Asian (China)

East Asian (China)

0.88

74/112/34

99/165/46

41.5 0.09

Brewster et al. (2006) [18] Causcasian (USA)

107/182/31

126/165/35

36

Debniak et al. (2006) [19] Causcasian (Poland)

703/850/277

187/245/79

39.4 0.93

180/252/79

672/785/269

Mechanic et al. (2006) [20]

Mixed (USA)

940/885/209

838/784/190

32.1 0.74

1107/770/ 145

1006/661/141 26.1 0.03

Onay et al. (2006) [21]

Causcasian (Canada)

146/194/58

165/167/40

33.2 0.82 60/80/16

59/64/30

0.08

Shen et al. (2006) [22]

Mixed (USA)

63/66/25

74/57/22

33

Costa et al. (2007) [24]

Causcasian (Portugal)

127/125/30

331/260/69

30.2 0.1

0.05

Crew et al. (2007) [23] Jorgensen et al. (2007) [25]

Mixed (USA) Mixed (USA)

Synowiec et al. (2008) [8] Causcasian (Poland)

15/24/4

30/17/1

19.8 0.42

Rajarama et al. (2008) [26] Mixed (USA)

342/377/120

428/494/158

39.3 0.43

Shore et al. (2008) [27]

Mixed (USA)

251/292/68

259/282/70

34.5 0.61

Li et al. (2008) [9]

East Asian (China)

432/51/3

392/80/7

4790/5082/ 1490

4634/4663/ 1325

Total

Publication bias Funnel plots and Egger’s test were performed to assess publication bias. The data suggested that there was no evidence of publication bias in XPD K751Q (t = 0.44, P = 0.663) (Fig. 4a) and D312N (t = 0.33, P = 0.751) (Fig. 4b).

Discussion In the present study, to clarity controversial results from previous reports, we collected all available studies and carried out a meta-analysis to examine the association of

40.5 0.1

415/478/138 490/454/139 110/128/22 102/142/29

33.8 0.04 36.6 0.05

4393/3635/ 982

32.5

9.8 0.22 34.6

4627/4067/ 1179

XPD K751Q and D312N polymorphisms with susceptibility to breast cancer. Eighteen studies on K751Q genotype (21,984 subjects) and eleven studies on D312N genotype (18,883 subjects) were critically reviewed. We subgrouped the articles into three groups (Asian, Caucasian, and Mixed). Meta-analysis showed Asian individuals of the 312NN genotype have a protective role in breast cancer. Meanwhile, our data also showed the 751Q allele might be a risk factor in the susceptibility of breast cancer in Caucasian individuals, but it showed nonsignificant role in all subjects, Asian and ethnic-mixed population. These observations are not surprising, because XPD is known to play a key role in NER, which in turn is crucial in, for example, the elimination of bulky DNA adducts.

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Fig. 2 Meta-analysis of XPD polymorphisms in breast cancer in worldwide population. The study is shown by a point estimate of the OR and accompanying 95% CI: a Overall analysis for allele contrast under FE (M–H) and RE (D?L) model for K751Q; b overall analysis for allele contrast under FE and RE model for D312N. The weight is displayed in a percentage form, not the real weight in the calculation of the pooled OR. The calculation of the weight for every study was different in the fixed-effects model and in the random effects model. WeightMH = Wi = bici/Ni,

WeightDL = Wi* = (a-1 ? b-1 ? c-1 ? d-1 ? D2)-1, where MH, i i i i Mantel–Haenszel method, DL, DerSimonian and Laird method, i was the number of the study, a was the population of the case with intervention, b was the population of the case without intervention, c was the population of the control with intervention, and d was the population of the control without intervention. N was the total number of cases and controls and D2 was the between-study variance of all the eligible studies. The pooled OR was influenced by the weights

XPD is the major gene involved with the unwinding damaged DNA of the NER pathway. NER pathway repairs bulkly lesions such as pyrimidine dimers, other photoproducts, larger chemical adducts, and cross-links [5]. During NER, XPD participates in the opening of the DNA helix to allow the excision of the DNA fragment containing the damaged base [44]. The amino acid substitutions within the conserved region may alter XPD function, which might in turn influence the capacity to repair damaged DNA and increase the susceptibility to cancers. The 312 variant has

the acidic moiety of the aspartic acid removed and the 751 variant (lysine to glutamine) completely changes the electronic configuration of the amino acid, which is a major change located in the important domain of interaction between XPD protein and its helicase activator [45]. The K751Q variant has been linked to deficiencies in NER repair in some functional studies [46–48]. In the present study, it was shown that 751Q allele increased the risk of breast cancer in Caucasians. However, our data indicated no significant association between the 751Q

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Fig. 3 Meta-analysis of XPD polymorphisms in breast cancer in subgroups. Point estimates of the odds ratio (OR) for each study and the accompanying 95% CI: a allele contrast under FE and RE model for K751Q in Caucasians; b genotype contrasts under FE and RE model for D312N in Asians (NN vs. DD, homozygote contrast; NN vs. (DD ? DN), recessive genetic model)

allele and breast cancer susceptibility in all subjects. We found that the pattern of allele and genotype frequencies was very different in the study by Synowiec et al. [8] (the allele frequency is 19.8%) and Li et al. [9] (the allele frequency is 9.8%) as compared with the other populations of the same ethnicity (www.hapmap.org) (the prevalence of Q allele was 37.5% in Caucasians and 32.2–36.7% in Asians). For D312N polymorphism, the data indicated that the amino acids substitution did not increase the risk significantly in all subjects. Stratified analysis showed that the variant has no effect on breast cancer risk in Caucasians and Mixed individuals whereas it has significant susceptibility in East Asian subjects. Our results implied that the effects of K751Q and D312N polymorphisms on breast cancer are related with ethnic background, however, due to limited size sample we suggest a careful matching on ethnicity for future larger genetic association studies. Heterogeneity for K751Q and D312N among the studies was observed. To eliminate heterogeneity, we tried to

subgroup the studies as far as possible (based on publication year, ethnicity, control group and so on), but it also existed. To our knowledge, the reasons of the heterogeneity may be elucidated partly by the following: (a) wide variation in the allele frequency across different populations existed; (b) inaccurate genotyping actually enlarged the variation in the polymorphic allele frequencies reported among different ethnicities; (c) selection bias that could have had an effect because the genotype distribution among control subjects of two D312N studies [20, 23] deviated from the HWE. Because publication bias may cause heterogeneity in the results [49], both Begg’s funnel plots and Egger’s test were conducted to assess it, and no significant publication bias was detected. To explore the source of heterogeneity, the effects of ethnicity and publication year on heterogeneity have been evaluated and we found both significantly contribute to the overall heterogeneity in relation to the K751Q and D312N polymorphism, suggesting it is possible that some characteristics in

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Table 3 Summary of ORs for various genetic contrasts performed when investigating the association of XPD K751Q and D312N polymorphisms with breast cancer Contrast

Comparisons

FE OR (95% CI)

RE OR (95% CI)

I2 for heterogeneity (%)

P value for heterogeneity

P value for Z test

K751Q in breast cancer Q vs. K

QQ vs. KK

QQ vs. (KQ ? KK)

(QQ ? KQ) vs. KK

All

1.03 (0.99–1.07)

1.04 (0.97–1.10)

46.3

0.02

Causcasian

1.05 (1.00–1.11)

1.07 (1.00–1.14)

32.7

0.15

0.28 0.035

Asian

0.81 (0.66–0.99)

0.76 (0.45–1.28)

83.8

0.01

0.30

Mixed (USA)

1.02 (0.96–1.08)

1.02 (0.96–1.08)

12.3

0.33

0.52

All

1.07 (0.98–1.17)

1.07 (0.98–1.16)

0

0.63

0.14

Causcasian

1.11 (0.98–1.26)

1.12 (0.97–1.31)

20.1

0.27

0.11

Asian

0.86 (0.53–1.41)

0.77 (0.34–1.73)

36.3

0.21

0.55

Mixed (USA)

1.04 (0.92–1.18)

1.04 (0.92–1.18)

0

0.88

0.55

All

1.04 (0.96–1.13)

1.04 (0.96–1.13)

0

0.91

0.34

Causcasian

1.07 (0.96–1.21)

1.07 (0.95–1.20)

0

0.55

0.24

Asian

0.94 (0.60–1.47)

0.83 (0.38–1.82)

36

0.21

0.78

Mixed (USA)

1.00 (0.89–1.12)

1.00 (0.89–1.12)

0

0.98

1.00

All Causcasian

1.05 (0.99–1.11) 1.09 (1.00–1.18)

1.06 (0.97–1.15) 1.13 (1.00–1.28)

46 48.4

0.02 0.06

0.19 0.06

Asian

0.72 (0.56–0.93)

0.72 (0.44–1.17)

71.6

0.06

0.19

Mixed (USA)

0.94 (0.87–1.02)

0.94 (0.87–1.02)

0

0.71

0.13

D312N in breast cancer N vs. D

NN vs. DD

NN vs. (DD ? DN)

(NN ? DN) vs. DD

All

0.99 (0.94–1.03)

0.96 (0.86–1.08)

78

\0.00001

0.53

Causcasian

0.96 (0.91–1.02)

0.88 (0.66–1.16)

93

\0.00001

0.36

Asian

0.87 (0.70–1.07)

0.87 (0.70–1.07)

0

0.39

0.19

Mixed (USA)

1.04 (0.97–1.12)

1.04 (0.91–1.20)

57

0.04

0.55

All

0.97 (0.88–1.07)

0.88 (0.71–1.09)

66

0.001

0.25

Causcasian

0.97 (0.86–1.08)

0.87 (0.65–1.17)

80

0.002

0.36

Asian

0.55 (0.32–0.96)

0.55 (0.32–0.96)

0

0.58

0.03

Mixed (USA)

1.00 (0.85–1.18)

0.98 (0.72–1.33)

51

0.07

0.89

All

0.96 (0.88–1.06)

0.88 (0.73–1.05)

56

0.01

0.15

Causcasian

0.99 (0.89–1.10)

0.92 (0.75–1.13)

65

0.04

0.42

Asian Mixed (USA)

0.53 (0.32–0.90) 0.94 (0.80–1.10)

0.54 (0.32–0.90) 0.92 (0.70–1.20)

0 44

0.56 0.11

0.02 0.45

All

0.99 (0.94–1.06)

0.99 (0.85–1.16)

78

\0.00001

0.95

Causcasian

0.94 (0.88–1.02)

0.89 (0.69–1.15)

90

\0.00001

0.38

Asian

0.96 (0.73–1.25)

0.96 (0.73–1.25)

0

0.71

0.75

Mixed (USA)

1.09 (0.99–1.20)

1.11 (0.94–1.30)

45

0.11

0.07

different study populations and/or inherited limitations of the recruited studies may partially contribute to the observed overall heterogeneity. There are several limitations should be kept in mind in this meta-analysis. First, selection bias could have played a role because the genotype distribution of the polymorphism among control subjects deviated from the HWE at least in two studies [20, 23]. Second, the overall outcomes were based on individual unadjusted OR, while a more precise evaluation should be adjusted by other potentially suspected factors.

123

Third, relatively small sample sizes included in Asians may also influence the results, and further studies are necessary to detect the potential role of two polymorphisms. Finally, different genotyping methods used in the studies included in the analysis may have different quality control issues. In conclusion, our meta-analysis had suggested 312N allele might act as a recessive allele in its association with breast cancer and 751Q allele may play a plausible role in breast cancer development, whereas the ethnic background should be carefully concerned in further studies.


Fig. 4 Begg’s funnel plot of the egger’s test of allele comparison for publication bias, each point represents a separate study for the indicated association: a funnel plot for Q vs. K allele comparison in K751Q polymorphism; b funnel plot for N vs. D allele comparison in D312N polymorphism. The vertical axis represents log [OR] and the horizontal axis means the standard error of log [OR]. Horizontal line and sloping lines in funnel plot represent fixed-effects summary OR and expected 95% CI for a given standard error, respectively

References 1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ (2007) Cancer statistics, 2007. CA Cancer J Clin 57:43–66. doi: 10.3322/canjclin.57.1.43 2. Cairns J (1982) Aging and cancer as genetic phenomena. Natl Cancer Inst Monogr 60:237–239 3. Knudson AG Jr (1989) The genetic predisposition to cancer. Birth Defects Orig Artic Ser 25:15–27 4. Shields PG, Harris CC (1991) Molecular epidemiology and the genetics of environmental cancer. JAMA 266:681–687. doi: 10.1001/jama.266.5.681 5. Squire JA, Whitmore GF, Phillips RA (1998) The basic science of oncology. McGraw-Hill, New York 6. Friedberg EC (2001) How nucleotide excision repair protects against cancer. Nat Rev Cancer 1:22–33. doi:10.1038/35094000 7. Tang D, Cho S, Rundle A, Chen S, Phillips D, Zhou J, Hsu Y, Schnabel F, Estabrook A, Perera FP (2002) Polymorphisms in the DNA repair enzyme XPD are associated with increased levels of PAH–DNA adducts in a case–control study of breast cancer. Breast Cancer Res Treat 75:159–166. doi:10.1023/A:10196 93504183

211 8. Synowiec E, Stefanska J, Morawiec Z, Blasiak J, Wozniak K (2008) Association between DNA damage, DNA repair genes variability and clinical characteristics in breast cancer patients. Mutat Res 648:65–72. doi:10.1016/j.mrfmmm.2008.09.014 9. Li J, Jin W, Chen Y, Di G, Wu J, Shao ZM (2008) Genetic polymorphisms in the DNA repair enzyme ERCC2 and breast tumour risk in a Chinese population. J Int Med Res 36:479–488 10. Justenhoven C, Hamann U, Pesch B, Harth V, Rabstein S, Baisch C, Vollmert C, Illig T, Ko YD, Bru¨ning T, Brauch H (2004) ERCC2 genotypes and a corresponding haplotype are linked with breast cancer risk in a German population. Cancer Epidemiol Biomarkers Prev 13:2059–2064 11. Shi Q, Wang LE, Bondy ML, Brewster A, Singletary SE, Wei Q (2004) Reduced DNA repair of benzo[a]pyrene diol epoxideinduced adducts and common XPD polymorphisms in breast cancer patients. Carcinogenesis 25:1695–1700. doi:10.1093/ carcin/bgh167 12. Terry MB, Gammon MD, Zhang FF, Eng SM, Sagiv SK, Paykin AB, Wang Q, Hayes S, Teitelbaum SL, Neugut AI, Santella RM (2004) Polymorphism in the DNA repair gene XPD, polycyclic aromatic hydrocarbon-DNA adducts, cigarette smoking, and breast cancer risk. Cancer Epidemiol Biomarkers Prev 13: 2053–2058 13. Dufloth RM, Costa S, Schmitt F, Zeferino LC (2005) DNA repair gene polymorphisms and susceptibility to familial breast cancer in a group of patients from Campinas, Brazil. Genet Mol Res 4:771–782 14. Lee SA, Lee KM, Park WY, Kim B, Nam J, Yoo KY, Noh DY, Ahn SH, Hirvonen A, Kang D (2005) Obesity and genetic polymorphism of ERCC2 and ERCC4 as modifiers of risk of breast cancer. Exp Mol Med 37:86–90 15. Kuschel B, Chenevix-Trench G, Spurdle AB, Chen X, Hopper JL, Giles GG, McCredie M, Chang-Claude J, Gregory CS, Day NE, Easton DF, Ponder BA, Dunning AM, Pharoah PD (2005) Common polymorphisms in ERCC2 (Xeroderma pigmentosum D) are not associated with breast cancer risk. Cancer Epidemiol Biomarkers Prev 14:1828–1831. doi:10.1158/1055-9965.EPI04-0807 16. Metsola K, Kataja V, Sillanpa¨a¨ P, Siivola P, Heikinheimo L, Eskelinen M, Kosma VM, Uusitupa M, Hirvonen A (2005) XRCC1 and XPD genetic polymorphisms, smoking and breast cancer risk in a Finnish case–control study. Breast Cancer Res 7:987–997. doi:10.1186/bcr1333 17. Zhang L, Zhang Z, Yan W (2005) Single nucleotide polymorphisms for DNA repair genes in breast cancer patients. Clin Chim Acta 359:150–155. doi:10.1016/j.cccn.2005.03.047 18. Brewster AM, Jorgensen TJ, Ruczinski I, Huang HY, Hoffman S, Thuita L, Newschaffer C, Lunn RM, Bell D, Helzlsouer KJ (2006) Polymorphisms of the DNA repair genes XPD (Lys751Gln) and XRCC1 (Arg399Gln and Arg194Trp): relationship to breast cancer risk and familial predisposition to breast cancer. Breast Cancer Res Treat 95:73–80. doi:10.1007/ s10549-005-9045-3 19. Debniak T, Scott RJ, Huzarski T, Byrski T, Masojc´ B, van de Wetering T, Serrano-Fernandez P, Go´rski B, Cybulski C, Gronwald J, Debniak B, Maleszka R, Kładny J, Bieniek A, Nagay L, Haus O, Grzybowska E, Wandzel P, Niepsuj S, Narod SA, Lubinski J (2006) XPD common variants and their association with melanoma and breast cancer risk. Breast Cancer Res Treat 98:209–215. doi:10.1007/s10549-005-9151-2 20. Mechanic LE, Millikan RC, Player J, de Cotret AR, Winkel S, Worley K, Heard K, Heard K, Tse CK, Keku T (2006) Polymorphisms in nucleotide excision repair genes, smoking and breast cancer in African Americans and whites: a populationbased case–control study. Carcinogenesis 27:1377–1385. doi: 10.1093/carcin/bgi330

123

212 21. Onay VU, Briollais L, Knight JA, Shi E, Wang Y, Wells S, Li H, Rajendram I, Andrulis IL, Ozcelik H (2006) SNP-SNP interactions in breast cancer susceptibility. BMC Cancer 6:114. doi: 10.1186/1471-2407-6-114 22. Shen J, Desai M, Agrawal M, Kennedy DO, Senie RT, Santella RM, Terry MB (2006) Polymorphisms in nucleotide excision repair genes and DNA repair capacity phenotype in sisters discordant for breast cancer. Cancer Epidemiol Biomarkers Prev 15:1614–1619. doi:10.1158/1055-9965.EPI-06-0218 23. Crew KD, Gammon MD, Terry MB, Zhang FF, Zablotska LB, Agrawal M, Shen J, Long CM, Eng SM, Sagiv SK, Teitelbaum SL, Neugut AI, Santella RM (2007) Polymorphisms in nucleotide excision repair genes, polycyclic aromatic hydrocarbon-DNA adducts, and breast cancer risk. Cancer Epidemiol Biomarkers Prev 16:2033–2041. doi:10.1158/1055-9965.EPI-07-0096 24. Costa S, Pinto D, Pereira D, Rodrigues H, Cameselle-Teijeiro J, Medeiros R, Schmitt F (2007) DNA repair polymorphisms might contribute differentially on familial and sporadic breast cancer susceptibility: a study on a Portuguese population. Breast Cancer Res Treat 103:209–217. doi:10.1007/s10549-006-9364-z 25. Jorgensen TJ, Visvanathan K, Ruczinski I, Thuita L, Hoffman S, Helzlsouer KJ (2007) Breast cancer risk is not associated with polymorphic forms of xeroderma pigmentosum genes in a cohort of women from Washington County, Maryland. Breast Cancer Res Treat 101:65–71. doi:10.1007/s10549-006-9263-3 26. Rajaraman P, Bhatti P, Doody MM, Simon SL, Weinstock RM, Linet MS, Rosenstein M, Stovall M, Alexander BH, Preston DL, Sigurdson AJ (2008) Nucleotide excision repair polymorphisms may modify ionizing radiation-related breast cancer risk in US radiologic technologists. Int J Cancer 123:2713–2716. doi: 10.1002/ijc.23779 27. Shore RE, Zeleniuch-Jacquotte A, Currie D, Mohrenweiser H, Afanasyeva Y, Koenig KL, Arslan AA, Toniolo P, Wirgin I (2008) Polymorphisms in XPC and ERCC2 genes, smoking and breast cancer risk. Int J Cancer 122:2101–2105. doi:10.1002/ijc.23361 28. Woolf B (1955) On estimating the relation between blood group and disease. Ann Hum Genet 19:251–253. doi:10.1111/j.14691809.1955.tb01348.x 29. Lau J, Ioannidis JP, Schmid CH (1997) Quantitative synthesis in systematicreviews. Ann Intern Med 127:820–826 30. Higgins JPT, Thompson SG, Deek JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560. doi: 10.1136/bmj.327.7414.557 31. Egger M, Davey SG, Schneider M, Minder C (1997) Bias in metaanalysis detected by a simple, graphical test. BMJ 315:629–634 32. Dufloth RM, Arruda A, Heinrich JK, Schmitt F, Zeferino LC (2008) The investigation of DNA repair polymorphisms with histopathological characteristics and hormone receptors in a group of Brazilian women with breast cancer. Genet Mol Res 7:574–582. doi:10.4238/vol7-3gmr376 33. Manuguerra M, Saletta F, Karagas MR, Berwick M, Veglia F, Vineis P, Matullo G (2006) XRCC3 and XPD/ERCC2 single nucleotide polymorphisms and the risk of cancer: a HuGE review. Am J Epidemiol 164:297–302. doi:10.1093/aje/kwj189 34. Goode EL, Ulrich CM, Potter JD (2002) Polymorphisms in DNA repair genes and associations with cancer risk. Cancer Epidemiol Biomarkers Prev 11:1513–1530 35. Nexø BA, Vogel U, Olsen A, Nyegaard M, Bukowy Z, Rockenbauer E, Zhang X, Koca C, Mains M, Hansen B, Hedemand A, Kjeldgaard A, Laska MJ, Raaschou-Nielsen O, Cold S, Overvad K, Tjønneland A, Bolund L, Børglum AD (2008) Linkage disequilibrium mapping of a breast cancer susceptibility locus near RAI/PPP1R13L/iASPP. BMC Med Genet 9:56. doi: 10.1186/1471-2350-9-56 36. Lubin´ski J, Korzen´ M, Go´rski B, Cybulski C, Debniak T, Jakubowska A, Jaworska K, Wokołorczyk D, Medrek K, Matyjasik

123


37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

J, Huzarski T, Byrski T, Gronwald J, Masojc´ B, Lener M, Szyman´ska A, Szyman´ska-Pasternak J, Serrano-Ferna`ndez P, Piegat A, Ucin´ski R, Domagała P, Domagała W, Chosia M, Kładny J, Go´recka B, Narod S, Scott R (2009) Genetic contribution to all cancers: the first demonstration using the model of breast cancers from Poland stratified by age at diagnosis and tumour pathology. Breast Cancer Res Treat 114:121–126. doi:10.1007/s10549008-9974-8 Briollais L, Wang Y, Rajendram I, Onay V, Shi E, Knight J, Ozcelik H (2007) Methodological issues in detecting gene–gene interactions in breast cancer susceptibility: a population-based study in Ontario. BMC Med 5:22. doi:10.1186/1741-7015-5-22 Stone J, Gurrin LC, Byrnes GB, Schroen CJ, Treloar SA, Padilla EJ, Dite GS, Southey MC, Hayes VM, Hopper JL (2007) Mammographic density and candidate gene variants: a twins and sisters study. Cancer Epidemiol Biomarkers Prev 16:1479–1484. doi:10.1158/1055-9965.EPI-07-0107 Lunn RM, Helzlsouer KJ, Parshad R, Umbach DM, Harris EL, Sanford KK, Bell DA (2000) XPD polymorphisms: effects on DNA repair proficiency. Carcinogenesis 21:551–555. doi:10.1093/ carcin/21.4.551 Yin J, Li J, Vogel U, Wang H (2005) Polymorphisms of DNA repair genes: ERCC1 G19007A and ERCC2/XPD C22541A in a northeastern Chinese population. Biochem Genet 43:543–548. doi:10.1007/s10528-005-8170-3 Silva SN, Bezerra de Castro G, Faber A, Pires M, Oliveira VC, Azevedo AP, Cabral MN, Manita I, Pina JE, Rueff J, Gaspar J (2006) The role of ERCC2 polymorphisms in breast cancer risk. Cancer Genet Cytogenet 170:86–88. doi:10.1016/j.cancergency to.2006.04.017 Chang-Claude J, Popanda O, Tan XL, Kropp S, Helmbold I, von Fournier D, Haase W, Sautter-Bihl ML, Wenz F, Schmezer P, Ambrosone CB (2005) Association between polymorphisms in the DNA repair genes, XRCC1, APE1, and XPD and acute side effects of radiotherapy in breast cancer patients. Clin Cancer Res 11:4802–4809. doi:10.1158/1078-0432.CCR-04-2657 Faraglia B, Chen SY, Gammon MD, Zhang Y, Teitelbaum SL, Neugut AI, Ahsan H, Garbowski GC, Hibshoosh H, Lin D, Kadlubar FF, Santella RM (2003) Evaluation of 4-aminobiphenylDNA adducts in human breast cancer: the influence of tobacco smoke. Carcinogenesis 24:719–725. doi:10.1093/carcin/bgg013 Lehmann AR (2001) The xeroderma pigmentosum group D (XPD) gene: one gene, two functions, three diseases. Genes Dev 15:15–23. doi:10.1101/gad.859501 Coin F, Marinoni JC, Rodolfo C, Fribourg S, Pedrini AM, Egly JM (1998) Mutations in the XPD helicase gene result in XP and TTD phenotypes, preventing interaction between XPD and the p44 subunit of TFIIH. Nat Genet 20:184–188. doi:10.1038/2491 Au WW, Navasumrit P, Ruchirawat M (2004) Use of biomarkers to characterize functions of polymorphic DNA repair genotypes. Int J Hyg Environ Health 207:301–313. doi:10.1078/1438-463900294 Vodicka P, Kumar R, Stetina R, Sanyal S, Soucek P, Haufroid V, Dusinska M, Kuricova M, Zamecnikova M, Musak L, Buchancova J, Norppa H, Hirvonen A, Vodickova L, Naccarati A, Matousu Z, Hemminki K (2004) Genetic polymorphisms in DNA repair genes and possible links with DNA repair rates, chromosomal aberrations and single-strand breaks in DNA. Carcinogenesis 25:757–763. doi:10.1093/carcin/bgh064 Pavanello S, Pulliero A, Siwinska E, Mielzynska D, Clonfero E (2005) Reduced nucleotide excision repair and GSTM1-null genotypes influence anti-B[a]PDE-DNA adduct levels in mononuclear white blood cells of highly PAH-exposed coke oven workers. Carcinogenesis 26:169–175. doi:10.1093/carcin/bgh303 Ioannidis JP (2008) Interpretation of tests of heterogeneity and bias in meta-analysis. J Eval Clin Pract 14:951–957