Meta-analysis on the association of nucleotide excision repair geneXPD A751C variant and cancer susceptibility among Indianpopulation

Raju Kumar Mandal • Suraj Singh Yadav •

Aditya K. Panda

Received: 19 June 2013 / Accepted: 13 December 2013 / Published online: 22 December 2013

� Springer Science+Business Media Dordrecht 2013

Abstract Polymorphism A751C (A[C) in XPD gene has

shown susceptibility to many cancers in Indian population;

however the results of these studies are inconclusive. Thus,

we performed this meta-analysis to estimate the association

between XPD A751C polymorphism and overall cancer

susceptibility. We quantitavely synthesized all published

studies of the association between XPD A751C polymor-

phism and cancer risk. Pooled odds ratios (ORs) and 95 %

CI were estimated for allele contrast, homozygous, het-

erozygous, dominant and recessive genetic model. A total

of thirteen studies including 3,599 controls and 3,087

cancer cases were identified and analyzed. Overall signif-

icant results were observed for C allele carrier (C vs. A:

p = 0.001; OR 1.372, 95 % CI 1.172–1.605) variant

homozygous (CC vs. AA: p = 0.001; OR 1.691, 95 % CI

1.280–2.233) and heterozygous (AC vs. AA: p = 0.001;

OR 1.453, 95 % CI 1.215–1.737) genotypes. Similarly

dominant (CC?AC vs. AA: p = 0.001; OR 1.512, 95 %

CI 1.244–1.839) and recessive (CC vs. AA?AC:

p = 0.001; OR 1.429, 95 % CI 1.151–1.774) genetic

models also demonstrated risk of developing cancer. This

meta-analysis suggested that XPD A751C polymorphism

likely contribute to cancer susceptibility in Indian

population. Further studies about gene–gene and gene–

environment interactions are required.

Keywords DNA repair gene � Nucleotide excision

repair � Meta-analysis � Cancer � Polymorphism

Introduction

Human genome constantly damaged by exogenous and

endogenous stresses [1]. DNA disruptions can lead to gene

rearrangements, translocations, amplifications, and dele-

tions, which can in turn contribute to cancer development

[2]. DNA repair pathways play a critical role in main-

taining the genomic integrity, as well as in the prevention

of carcinogenesis, and therefore defect in these genes can

lead to higher susceptibility to multiple cancers [3].

Molecular epidemiology studies have also documented that

genetic variants of DNA repair genes and reduced DNA

repair capacity (DRC) are thought to contribute higher risk

of developing cancers [4, 5].

Xeroderma pigmentosum group D (XPD or ERCC2) is a

key gene of nucleotide excision repair (NER) pathway and

the gene product play a major role in repair to bulky DNA

lesions and genetic damage induced by tobacco, UV

induced photolesions and other chemical carcinogens [6,

7]. The XPD protein has an ATP-dependent DNA helicase

activity and essential part of the basal transcription factor

BTF2/TFIIH complex [8]. Mutations in the XPD gene can

prevent the DNA strand opening and dual incision steps,

resulting in a defect in NER, in transcription, and in an

abnormal response to apoptosis [9]. It has been docu-

mented that polymorphism in XPD gene is associated with

reduced DRC because of a possible reduction in helicase

activity [10]. Several single nucleotide polymorphisms

R. K. Mandal (&)

Department of Urology and Renal Transplantation, Sanjay

Gandhi Post Graduate Institute of Medical Sciences,

Raibareli Road, Luknow, India

e-mail: rajmandalbiot@gmail.com

S. S. Yadav

Department of Pharmacology, King George Medical University,

Lucknow, India

A. K. Panda

Department of Infectious Disease Biology, Institute of Life

Sciences, Bhubaneswar, India

123

Mol Biol Rep (2014) 41:713–719

DOI 10.1007/s11033-013-2910-y

(SNPs) have been described in the XPD gene, among them

codon 751 (A[C substitution at position 35931, exon 23,

Lys[Gln, rs1052559) polymorphism, located in the

C-terminal region, undergoes a major change in the con-

formation of the respective amino acid [11]. Individuals

with XPD 751 CC genotype have been revealed to have

suboptimal DRC to remove UV photoproducts when

compared to the 751Lys/Lys and Lys/Gln genotypes [12].

Having known the functional significance of this genetic

variant in DRC, several molecular epidemiological studies

investigated the impact of XPD exon 23 A[C polymor-

phism on the susceptibility to various cancers in Indian

population (Table 1) [13–25]. However, the findings from

these studies remain inconsistent. To clarify the role of

XPD exon 23 A[C polymorphism and susceptibility to

cancer risk in Indian population, we performed this meta-

analysis based on published case–control studies to make a

more comprehensive and compelling evaluation of the

overall cancer risk associated with this polymorphism, as

well as to evaluate this polymorphism as potential marker

for screening of cancer in Indian population.

Materials and methods

Identification of eligible studies

Literature search was conducted within in the PubMed

(Medline) and EMBASE database up to February 2013,

using the keywords ‘‘XPD’’ or ‘‘ERCC2’’ polymorphism

and cancer or carcinoma in Indian population. Addition-

ally, we also used the ‘‘Related Articles’’ option in PubMed

to identify additional studies on the same topic.

Criteria for inclusion and exclusion

To minimize heterogeneity and facilitate the proper elucidation

of results, all eligible studies had to fulfill all the following

criteria: (a) original research article evaluated XPD exon 23

A[C and cancer risk, (b) use of case–control or cohort studies

of Indian population, (c) recruited pathologically confirmed

cancer patients and cancer free controls, (d) have available

genotype frequency in case and control. Also, when the case–

control study was included by more than one article using the

same case series, we selected the study that included the largest

number of individuals. The major reasons for exclusion of

studies were, (a) overlapping of data, (b) case-only studies,

(c) review articles, (d) editorials, (e) animal studies.

Data extraction and quality assessment

For each publication, the methodological quality assessment

and data extraction was independently abstracted in duplicate

by two independent investigators using a standard protocol.

Data accuracy was ensured using data-collection form

according to the inclusion criteria listed above. In case of

disagreement on any item of the data collected from the

retrieved studies, the problem would be fully discussed to

reach a consensus. Data extracted from these studies included

the name of first author, year of publication, type of cancer,

number of cases and controls, types of study and genotyping

methods and frequencies.

Evaluations of statistical associations

Hardy–Weinberg equilibrium (HWE) was examined in the

control subjects using a goodness of fit chi-square test for

Table 1 Main characteristics of all thirteen studies included in the meta-analysis

First authors and year Types of cancer Study design Genotyping method Control Cases

Kumar et al. 2012 [13] SCCHN HB PCR–RFLP 278 278

Sobti et al. 2012 [14] Bladder HB PCR–RFLP 252 270

Sobti et al. 2012 [15] Prostate HB PCR–RFLP 150 150

Samson et al. 2011 [16] Breast HB Taq Man 500 250

Wang et al. 2010 [17] Colorectal HB PCR–RFLP 291 302

Mandal et al. 2010 [18] Prostate HB PCR–RFLP 200 171

Srivastava et al. 2010 [19] Gallbladder HB PCR–RFLP 230 230

Syamala et al. 2009 [20] Breast HB PCR–RFLP 367 359

Gangwar et al. 2009 [21] Bladder HB PCR–RFLP 250 206

Mitra et al. 2009 [22] Breast HB PCR–RFLP 215 155

Mitra et al. 2009 [22] SCCHN HB PCR–RFLP 385 275

Sreeja et al. 2008 [23] Lung HB PCR–RFLP 211 211

Sobti et al. 2007 [24] Esophageal HB PCR–RFLP 160 120

Ramachandran et al. 2006 [25] Oral HB PCR–RFLP 110 110

SCCHN squamous cell carcinomas of the head and neck, HB hospital based

714 Mol Biol Rep (2014) 41:713–719

123

each study, Odds ratio (OR) with 95 % confidence inter-

vals (CI) was used to assess the strength of association

between the XPD exon 23 A[C gene polymorphism and

cancer risk. Heterogeneity was assessed with standard

Q-statistic test. If heterogeneity existed, the random effects

model was adopted to calculate the overall OR value [26].

Otherwise, the fixed effect model was used [27]. Begg’s

funnel plots and Egger’s regression test were undertaken to

assess the potential publication bias [28]. p value less than

0.05 was judged significant. All the data analysis was

performed using a comprehensive meta-analysis (CMA)

V2 software (Biostat, USA).

Results

Characteristics of published studies

A total of thirteen articles were retrieved through literature

search from the PubMed (Medline) and EMBASE data-

base. All retrieved articles were examined by reading the

titles, abstracts and the full texts for the potentially relevant

publications. Articles were further checked for their suit-

ability for this meta-analysis. In addition to the database

search, the reference lists of the retrieved articles were also

screened for other potential relevant articles. Studies

comprising XPD polymorphism to predict survival in

cancer patients or considering XPD variant as an indicator

for response to therapy were excluded. Studies related to

investigation of the levels of XPD mRNA or protein

expression or review articles were also excluded. Strict

criteria were followed in article search, only case–control

or cohort design studies having frequency of all the three

genotypes were included. Following the careful screening

and strict inclusion and exclusion criteria, thirteen eligible

original published studies were achieved and included in

the study (Table 1). Distribution of genotypes, Minor allele

frequency (MAF) and HWE p values has been tabulated in

the Table 2.

Publication bias

Begg’s funnel plot and Egger’s test were performed to

evaluate the publication bias among the included studies

for this meta-analysis. The shape of funnel plots did not

reveal any evidence of obvious asymmetry in all compar-

isons, and the Egger’s test was used to provide statistical

evidence of funnel plot. The results did not show any

evidence of publication bias in all genetic models

(Table 3).

Test of heterogeneity

Q-test and I2 statistics were used to test for heterogeneity

among the studies. Heterogeneity was observed in all the

models, such as allele (C vs. A), homozygous (CC vs. AA),

heterozygous (AC vs. AA), recessive (CC vs. AA?AC)

and dominant (CC?AC vs. AA) models, which was

included for this analysis. Thus, we applied random effect

model to calculate the pooled OR and 95 % CI (Table 3).

Table 2 Genotypic distribution of XPD A751C (rs1052559) gene polymorphism included in meta-analysis

Authors and year Controls Cancer cases HWE

Genotype Minor allele Genotype Minor allele

AA AC CC MAF AA AC CC MAF p value

Kumar et al. 2012 [13] 129 110 39 0.44 92 125 61 0.33 0.05

Sobti et al. 2012 [14] 104 81 67 0.53 74 104 92 0.42 \0.0001

Sobti et al. 2012 [15] 67 69 14 0.36 62 67 21 0.32 0.53

Samson et al. 2011 [16] 235 214 51 0.36 107 102 41 0.316 0.82

Wang et al. 2010 [17] 137 117 37 0.32 138 130 34 0.32 0.13

Mandal et al. 2010 [18] 89 94 17 0.32 73 84 14 0.32 0.25

Srivastava et al. 2010 [19] 113 90 27 0.37 93 103 34 0.31 0.17

Syamala et al. 2009 [20] 247 98 22 0.36 148 161 50 0.19 0.005

Gangwar et al. 2009 [21] 110 121 19 0.33 86 104 16 0.31 0.06

Mitra et al. 2009 [22] 84 98 33 0.57 30 73 52 0.38 0.61

Mitra et al. 2009 [22] 163 179 43 0.41 88 148 39 0.34 0.55

Sreeja et al. 2008 [23] 139 61 11 0.27 109 89 13 0.19 0.21

Sobti et al. 2007 [24] 63 77 20 0.31 52 61 7 0.36 0.63

Ramachandran et al. 2006 [25] 71 31 8 0.34 49 46 15 0.21 0.09

MAF Minor allele frequency, HWE Hardy–Weinberg equilibrium

Mol Biol Rep (2014) 41:713–719 715

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Overall effects of XPD exon 23 A[C polymorphism

and cancer susceptibility

All the thirteen studies were pooled together which resulted

into 3,599 controls and 3,087 cancer cases was used to

assess the overall association between the XPD exon 23

A[C polymorphism and risk of cancer. The pooled data

indicated an evidence for a significant association between

the XPD exon 23 A[C polymorphism and susceptibility to

cancer in all the models. Variant allele C demonstrated

significant risk of developing cancer in terms of the fre-

quency with wild allele (A) comparison (C vs. A:

p = 0.001; OR 1.372, 95 % CI 1.172–1.605). Similarly,

homozygous mutant CC (CC vs. AA; p = 0.001; OR

1.691, 95 % CI 1.280–2.233) and heterozygous AC (AC

vs. AA: p = 0.001; OR 1.453, 95 % CI 1.215–1.737)

Table 3 Statistics to test publication bias and heterogeneity in meta-analysis

Comparisons Egger’s regression analysis Heterogeneity analysis Model used for

meta-analysisIntercept 95 % CI p value Q value pheterogeneity I2 (%)

C vs. A -1.30 -8.72 to 6.11 0.70 58.36 \0.0001 77.72 Random

CC vs. AA -2.11 -6.25 to 2.02 0.28 37.65 \0.0001 65.47 Random

AC vs. AA -0.25 -6.28 to 5.78 0.92 35.71 0.001 63.60 Random

CC?AC vs. AA -0.73 -7.64 to 6.16 0.81 48.29 \0.0001 73.08 Random

CC vs. AA?AC -1.79 -4.91 to 1.33 0.23 26.39 0.01 50.74 Random

Fig. 1 Forest plot of a meta-analysis of the association between XPD exon 23 A[C polymorphism (C vs. A; AC vs. AA; CC vs. AA) and overall

cancer risk

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genotypes revealed significantly increased risk for the

occurrence of cancer as compared with the homozygous

AA genotype (Fig. 1). Additionally, analysis of recessive

(CC vs. AA?AC: p = 0.001; OR 1.429, 95 % CI

1.151–1.774) and dominant (CC?AC vs. AA: p = 0.001;

OR 1.512, 95 % CI 1.244–1.839) genetic models indicated

1.4- and 1.5-fold increased risk of developing cancer

(Fig. 2).

Discussion

Common genetic polymorphisms or mutation in the DNA

repair genes may alter protein function and play a major

role in carcinogenesis. In the recent years, interest in the

genetic susceptibility to cancers has led to a growing

attention to the study of polymorphisms of genes involved

in carcinoma. Several studies has been supported an

important role for genetics in determining the risk for

cancer, and association studies are apposite for searching

susceptibility genes involved in cancer [29]. Till date,

series of epidemiological studies have been performed to

explore the role of XPD exon 23 A[C polymorphism on

cancer susceptibility in worldwide and in Indian popula-

tion, but the results remain controversial. Some studies are

limited by their sample size and subsequently suffer from

too low power to detect effects that may exist. Meta-ana-

lysis is a powerful tool for summarizing the results from

different studies and gives more reliable results than a

single case–control study, where individual sample sizes

are small and inadequate statistical power [30]. Combining

data from many studies has the advantage of reducing

random error [31]. Hence, in order to improve the statis-

tical power and determine the effect size of XPD exon 23

A[C polymorphism, we performed this meta- analysis

with thirteen eligible studies to provide the more compre-

hensive and reliable association between XPD exon 23

A[C polymorphism and overall cancer risk for Indian

population.

Results of the present meta-analysis showed that XPD

exon 23 A[C polymorphism is significantly associated

with increased cancer risk in Indian population. Subjects

Fig. 2 Forest plot of a meta-analysis of the association between XPD exon 23 A[C (CC?AC vs. AA; CC vs. AA?AC) and overall cancer risk

Mol Biol Rep (2014) 41:713–719 717

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with C allele and variants homozygous CC had 1.3- and

1.6-fold increased risk of developing cancer as compared

with the wild A allele and homozygous AA genotype,

respectively. Similarly, heterozygous, dominant and

recessive models have shown increased risk of cancer.

Based upon the above results and importance of XPD’s role

in the pathogenesis of cancer, it is biologically plausible

that XPD exon 23 A[C polymorphism may modulate the

risk of cancer and could be a genetic factor for inter-indi-

vidual differences in susceptibility to cancer disease. It has

been suggested that functional and common sequence

variations of DNA repair genes may be potential cancer

susceptibility factors in the general population exposed to

environmental carcinogens such as polycyclic aromatic

hydrocarbons (PAHs) [12, 32]. Earlier, Lunn et al. studied

the functional significance of XPD polymorphisms with

respect to chromosome aberrations and Hou et al. also

reported that common variant alleles of codon 751 of XPD

gene was associated with reduced repair of aromatic DNA

adducts [33, 34]. Genome wide association study suggested

that XPD exon 23 A[C polymorphism has reduced DRC

and contribute to increase risk of cancer [35].

It is of a great concern; that genetic susceptibility to

cancer is polygenic type [36]; hence single genetic variant

is usually inadequate to predict the risk of this deadly

disease. Some limitations should be addressed which may

affect the result, i.e., first, in this meta-analysis we found

inter-study heterogeneity. Many factors might contribute to

this heterogeneity, because regional lifestyle varied among

populations from different parts of India [37], another

recruitment of control group the controls were not uni-

formly defined, some studies used a healthy population as

the reference group where as other selected hospital

patients without cancer as the reference group. Second, the

present meta-analysis was based primarily on unadjusted

effect estimates and CIs. Third, the gene–gene and gene–

environment interactions were not addressed.

In spite of these limitations, our meta-analysis has some

advantages. First, we did not detect publication bias,

indicated that the results are statistically robust. Second, we

performed strict data extraction and analysis to make sat-

isfactory and reliable conclusion.

In conclusion, this meta-analysis indicates that, XPD

exon 23 A[C polymorphism would be a risk factor for

cancer susceptibility in Indian population. The importance

of this polymorphism as a predictor of the risk of cancer is

very high and the screening utility of this genetic variant in

symptomatic individuals may be warranted. Future well

designed large scale studies in the same NER pathway with

gene-environment interaction might be necessary to

investigate the association between DNA repair gene SNPs

and risk of cancer.

Conflict of interest None.

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