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Carcinogenesis Advance Access originally published online on October 17, 2006
Carcinogenesis 2007 28(3):672-676; doi:10.1093/carcin/bgl181
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Polymorphism in the ERCC2 codon 751 is associated with arsenic-induced premalignant hyperkeratosis and significant chromosome aberrations

Mayukh Banerjee1, Jyotirmoy Sarkar1, Jayanta K. Das2, Angshuman Mukherjee3, Ajoy K. Sarkar4, Lakshmikanta Mondal5 and Ashok K. Giri1,*

1 Molecular and Human Genetics Division, Indian Institute of Chemical Biology Kolkata, India
2 West Bank Hospital, Howrah India
3 Vivekananda Institute of Medical Sciences, Kolkata India
4 Peerless Hospital and B.K Roy Research Centre Kolkata, India
5 Regional Institute of Ophthalmology, Calcutta Medical College Kolkata, India

*To whom correspondence should be addressed at: Molecular and Human Genetics Division, Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700 032, India Tel: +91 33 2473 3491/0492/6793; Fax: +91 33 2473 5197; E-mail: akgiri15{at}yahoo.com; akgiri{at}iicb.res.in


   Abstract
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 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
In West Bengal, India more than 6 million people are exposed to high levels of arsenic through drinking water. Since, only 15–20% of the exposed individuals show arsenic-induced skin lesions, it is assumed that genetic variation might play an important role in arsenic toxicity and carcinogenicity. Arsenic exposure often leads to the development of hyperkeratosis, the precursor of arsenic-induced skin cancer. ERCC2 (excision repair cross-complementing rodent repair deficiency, complementation group 2) is a nucleotide excision repair pathway gene, and its SNPs have been implicated in several types of epithelial cancers. We investigated the possible association of ERCC2 codon 751 A->C polymorphism (lysine to glutamine) with arsenic-induced hyperkeratosis and correlated ERCC2 genotypes with increased frequencies of chromosomal aberration to ascertain whether any genotype leads to sub-optimal DNA repair. For this association study, 318 unrelated arsenic exposed subjects (165 with hyperkeratosis and 153 without any arsenic-induced skin lesions), drinking water contaminated with arsenic to a similar extent, were recruited. Genotyping was done through PCR–RFLP procedure. Lys/Lys genotype was significantly over-represented in the arsenic-induced hyperkeratosis-exhibiting group [odds ratio (OR) = 4.77, 95% confidence interval (CI) = 2.75–8.23]. A statistically significant increase in both CA/cell and percentage of aberrant cells was observed in the individuals with AA genotype compared to those with AC or CC genotype combined (P < 0.01) in each of the two study groups, as also, in the total study population. This study indicates that ERCC2 codon 751 Lys/Lys genotype is significantly associated with arsenic-induced premalignant hyperkeratosis and is possibly due to sub-optimal DNA repair capacity of the ERCC2 codon 751 Lys/Lys genotype.

Abbreviations: CA, chromosomal aberrations; ERCC2, excision repair cross-complementing rodent repair deficiency, complementation group 2; NER, nucleotide excision repair; XPD, xeroderma pigmentosum group D


   Introduction
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 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Ground water in 9 out of 18 districts of West Bengal, India, is contaminated with arsenic, concentrations ranging from 55 to 625 µg/l, much higher than the current permissible maximum contamination level (1,2). More than 300 000 people show arsenic-induced skin lesions in these districts. This is regarded as the greatest arsenic calamity in the world. Chronic arsenicosis is associated with a wide array of dermatological symptoms including palmo-planter hyperkeratosis, raindrop pigmentation and hyperpigmentation. Hyperkeratosis of skin is considered as a precursor of arsenic-induced skin cancer (3,4), as skin cancers often appear at the sites of existing hyperkeratosis (5). A strong relationship between arsenic level in water with the prevalence of hyperkeratosis and hyperpigmentation in the exposed individuals has been reported earlier (6). Long-term exposure to arsenic contaminated water causes a wide range of adverse health effects including skin pigmentations, hyperkeratosis, vascular diseases, conjunctivitis in the eyes, neuropathy, lung diseases and non-melanocytic cancer of skin and different internal organs (6). Strikingly enough, of the huge number of people exposed to arsenic contaminated drinking water, only 15–20% exhibit arsenic-specific skin lesions (7). This fact suggests that genetic variability might play a key role in arsenic-induced toxicity and carcinogenicity.

Many studies have shown that arsenic can cause DNA damage both in vitro and in vivo (8,9). ERCC2 protein, encoded by the gene ERCC2 (excision repair cross-complementing rodent repair deficiency, complementation group 2), also known as xeroderma pigmentosum group D (XPD), has a helicase activity and plays a key role in nucleotide excision repair (NER) pathway. The NER system is one of the best defence weapons employed by cells to combat genotoxic insults, especially those induced by exposure to chemical carcinogens. Defects in NER systems have been shown to be associated with several human diseases, such as xeroderma pigmentosum (XP), Cockayne's syndrome (CS) and trichothiodystrophy (TTD). The primary prerequisite for normal NER function is the unwinding of DNA double helix, and this step is mediated by the transcription factor TFIIH. TFIIH is a nine subunit complex, whose helicase activity depends, to a large extent, on the subunit known as XPD. Thus, polymorphisms in this XPD gene are likely to result in altered DNA repair and subsequent disorders that might ultimately culminate in cancer. Till date six exonic single nucleotide polymorphisms (SNPs) have been reported in ERCC2 (10), and of them, A->C polymorphism at codon 751 on exon 23 has been studied most widely. This A->C change results in amino acid substitution from lysine to glutamine. Thus codon 751 variant leads to total rearrangement of the electronic configuration of the amino acid. This is a major change, located in the important domain of interaction between XPD and its helicase activator, p44 protein, inside the TFIIH complex (11), and hence, theoretically, this should be the most important polymorphism as far as XPD activity is concerned (12). Previous reports show the association of this polymorphism with different types of cancers (13,14).

Genotoxic end-points such as chromosomal aberrations (including both chromosome-type aberrations as well as chromatid type aberrations) have been utilized successfully as biomarkers as these are considered to be markers of early biological effects of carcinogen exposure (15). Genotoxic effects of arsenic have been implicated in the carcinogenic outcomes (5). Higher incidence of chromosomal aberrations (CA) has been reported from the human populations exposed to arsenic through drinking water in various countries such as Mexico (16), Finland (17), Argentina (18), Taiwan (15), as also by our group in India (19). It has also been reported that the genotoxic effects of arsenic is mainly due its inhibitory effects in DNA repair synthesis (20). In the present paper, we have made an attempt to find out the possible association of ERCC2 codon 751 polymorphism with arsenic-induced hyperkeratosis. Attempts have also been made to study the CA frequency in the different genotypic groups in both the subclasses (individuals with arsenic-induced hyperkeratosis, and individuals with no arsenic-specific skin lesions) to ascertain whether the extent of CA could be correlated to the level of DNA repair as indicated by the genotype–phenotype association study.


   Materials and methods
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 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Study area and selection of subjects
Two of the affected districts viz. North 24 Parganas and Nadia were selected as our study sites and the details of the selection of study subjects has been described previously (7,21). Physicians examined the study participants for detection of various types of arsenic-related skin lesions. As we were interested in the association study of ERCC2 polymorphisms with arsenic-induced hyperkeratosis, individuals with hyperkeratosis and the individuals with no skin lesions, drinking similar arsenic contaminated water, were selected as study participants. We have selected the individuals with hyperkeratosis, irrespective of having any other arsenic-induced skin lesions like hyper pigmentation, raindrop pigmentation etc. Water and other biological samples such as blood, urine, nail and hair were collected from all the participants. The selected subjects provided informed consent to participate and fulfilled the inclusion criteria (21). We recruited 318 unrelated individuals; among whom 165 had arsenic-induced hyperkeratosis and 153 had no arsenic-induced skin lesion. This study was conducted in accordance with the Helsinki II Declaration and was approved by our Institutional Ethics Committee.

Arsenic exposure assessment
Study participants were provided with acid-washed [nitric acid:water (1:1)] plastic bottles for collection of drinking water samples (~100 ml) into which nitric acid (1.0 ml/l) was added as preservative (21). First morning voids (~100 ml) were collected in pre-coded polypropylene bottles for arsenic estimation. Samples of water, urine, nail (~250–500 mg) and hair (~300–500 mg) were collected and arsenic was estimated as described earlier (7,21). Flow injection-hydride generation-atomic absorption spectrometry (FI-HG-AAS) was used for estimation of arsenic content in different biological samples (urine, nail and hair) and drinking water, as described previously (21).

ERCC2 genotyping
DNA extraction from blood was carried out using standard protocol (22). Polymerase chain reaction (PCR) was performed in a 25 µl reaction volume using standard buffer, MgCl2 (1.5 mM), deoxyribonucleotides (200 µM) and Taq polymerase supplied by Life Technologies (USA) with the following primers: ERCC2Fe, 5'-GAC TCC CTA GCT GGC TCC TC -3'; and ERCC2 Re 5'-TGG TGG ATA GCT GCC TTC TC-3' (MWG Biotech, Germany) to generate a 450 bp product. Cycling was performed as follows: a pre PCR step of 5 min denaturation at 94°C followed by 30 cycles of 30 s denaturation at 94°C, 30 s annealing at 56°C, 60 s extension at 72°C, and finally 5 min incubation at 72°C.

PCR products, as appropriate, were subjected to restriction digestion with EarI (New England Biolabs Inc. Beverly, MA) in a 20 µl digestion mixture at 37°C for 4 h. EarI restricted products of XPD codon 751 Lys/Lys, genotypes had band sizes of 262/188, and while Gln/Gln genotype had band size of 450 bp due to loss of restriction site. Heterozygote Lys/Gln genotype showed all the three bands of sizes 450, 262 and 188 bp. Digested products were separated in 6% polyacrylamide gels, stained with ethidium bromide and photographed under UV (Figure 1A). Genotyping of 10% of the samples were reconfirmed by DNA sequencing (Figure 1B–D).


Figure 1
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  		Fig. 1 (A) RFLP analysis of ERCC2 codon 751 polymorphism. Lane 1, represents genotype CC, lanes 2–4 and 6 represent AA genotype, lanes 5 and 7 represent the genotype AC. Lane 8 contains a PCR product (undigested) and lane M is for PBS HaeIII marker. Representative chromatograms for the genotypes CC (B), AA (C) and AC (D).

 
Chromosomal aberrations assay
From each subject 5–7 ml venous blood was drawn and lymphocyte culture was carried out following standard protocol as described earlier (19). Whole blood (0.7 ml) was added to 7 ml of RPMI-1640 supplemented with L-glutamine, 15% FCS (fetal calf serum), penicillin (100 IU/ml), streptomycin (100 µg/ml) and 2% PHA-M form. Duplicate cultures were maintained for each sample. The cultures were incubated at 37°C and harvested at 72 h. All the slides of CA assay were coded and from each individual subject, depending on the availability of good scoring metaphase plates, 50–100 metaphases were randomly scored for CA (7). Gaps were not included in the aberrations per cell. Results were expressed as CA per cell and also as percentage of aberrant cells.

Statistical analyses
Odd's ratio (OR) and 95% confidence intervals (CI) were calculated using Microsoft Excel, whereas, mean, standard deviation and two-tailed P-values for arsenic estimation parameters and CA analyses were calculated by using GraphPad InStat Software (Graphpad Software Inc., San Diego, CA). OR was adjusted for age, gender and smoking.


   Results
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 Abstract
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 Materials and methods
 Results
Discussion
 References
 
Demographic characteristics of the study population are summarized in Table I, which shows that the two study groups are well-matched as far as age, gender, environmental arsenic exposure (arsenic content in drinking water) and urinary arsenic excretion are concerned. Individuals with hyperkeratosis, however, showed significantly greater arsenic retention in body, in their nails and hairs. Genotype frequencies for each of the two sub populations were calculated (Table II). In our study population, A allele had a frequency of 0.4, while that of C allele was 0.6. Lys/Lys (AA) genotype was significantly over-represented in individuals with arsenic-induced hyperkeratosis (OR = 4.77, 95% CI = 2.75–8.23). OR has been calculated against subjects with combined Gln/Gln (CC) and Lys/Gln (AC) genotypes and has been adjusted for age, gender and smoking habit.


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  		Table I Demographic characteristics of the study population exposed to arsenic through drinking water

 


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  		Table II Association between XPD genotype and arsenic-induced hyperkeratosis

 
Frequency of CA in the individuals exhibiting hyperkeratosis and those devoid of any arsenic-specific skin lesion has been compared in Table III. Individuals with hyperkeratosis were seen to exhibit a significantly higher frequency of both CA/cell and percentage of aberrant cells compared to the no skin lesion group (P < 0.01). Frequency of CA in the two different genotypic groups (AA and AC/CC), in each of the two study groups (with hyperkeratosis and without arsenic-induced skin lesions), as also in the total study population (comprising the two study groups combined) has been documented in Table IV. A statistically significant increase in both the parameters (CA/cell and percentage of aberrant cells) was observed in the individuals with AA genotype compared with those with either AC or CC genotype combined (P < 0.01) in either of the two study groups as also in the total study population.


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  		Table III Frequency of chromosomal aberrations (CA/cell) and percentage of aberrant cells in the individuals without skin lesions and in the individuals with arsenic-induced hyperkeratosis

 


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  		Table IV Frequency of chromosomal aberrations (CA/cell) and percentage of aberrant cells in the different genotypic groups of ERCC2 codon 751 polymorphism (AA & AC/CC combined) in both the study groups

 

   Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
Arsenic is considered to be a ‘paradoxical human carcinogen’, as it can alone induce cancerous growth in humans, but not in any other animal model. In human ex-vivo system, inorganic arsenic induces chromosomal aberrations, heightened oxidative stress and impairment of DNA repair, which in the long run leads to a multitude of multisystemic non-cancerous, as well as, cancerous developments (23). The most widely noted arsenic-induced precancerous skin lesion is hyperkeratosis, and, it has been reported previously, that skin cancers most often appear at the sites of existing hyperkeratosis (5).

There is convincing evidence that, reactive oxygen species, particularly hydroxyl radicals, play an important causal role in the genotoxicity of arsenical compounds in mammalian cells (24). Arsenic induces DNA adducts through calcium-mediated production of peroxynitrite, hypochlorous acid and hydroxyl radicals (25). There is also evidence to show that, a large portion of arsenite-induced DNA strand breaks come from excision of oxidative DNA adducts and DNA–protein cross-links (25). All these damages induced by arsenic are corrected by excision repair system and involves both the NER system as also the base excision repair (BER) system. However, this apart, arsenic also acts as a carcinogen through inhibition of DNA repair mechanisms, leading indirectly to increased mutations from other DNA damaging agents (26). Arsenic has been shown to down regulate genes playing key roles in NER pathway (26).

In the present study, individuals exhibiting hyperkeratosis have been compared with the individuals without any arsenic-induced skin lesion, with respect to ERCC2 codon 751 polymorphism. There is only one report available on the association study of this polymorphism with arsenic-specific hyperkeratosis (3). That study on Bangladesh population, however, found no statistically significant association (OR = 1.7, 95% CI = 0.7–4.3), probably due to very small sample size (29 individuals with arsenic-induced hyperkeratosis, and 105 controls), but the trend was similar to our findings. The point to be noted is that, the minor allele frequency in our study group (0.4) is higher than in Caucasian population (0.29), but lower than that in Bangladesh population (close to 0.5), as reported by Shen et al. (10) and Ahsan et al. (3) respectively. Also, we have found A allele to be the minor allele, unlike that reported in the Bangladesh population (3). Thus, in this study, we have found a strong association between arsenic-induced premalignant hyperkeratosis and ERCC2 codon 751 polymorphism. Individuals with Lys/Lys codon 751 ERCC2 genotype are considerably at higher risk (OR = 4.77; 95% CI = 2.75–8.23) of developing arsenic-specific hyperkeratosis that is considered to be precursor lesion of arsenic-induced skin cancer. This might be due to the fact that, the A->C variation in exon 23 gives rise to the amino acid substitution Lys to Gln, which is a change from a basic to a acidic amino acid. The nucleotide variation is located ~50 bp upstream from the poly (A) signal, and could possibly improve the function of the XPD protein (13). There is also ample evidence that mutations in the XPD C-terminal domain might prevent its interaction with p44, thus explaining decrease in ERCC2 helicase activity, and consequent NER defect, leading to diseases like XPD and TTD (11). Our studies indicate that AA genotype might play a similar role in decreasing the NER efficiency, which might be the ultimate explanation for ERCC2 codon 751 AA genotype-mediated susceptibility to arsenic toxicity.

From the foregoing discussion, it logically follows that ERCC2 codon 751 Lys/Lys genotype is associated with sub-optimal DNA repair, which is also well documented in the existing literature (27,28). Hence, it is to be expected that, CA frequency in individuals with ERCC2 codon 751 Lys/Lys genotype will be substantially higher than that of individuals with either Lys/Gln or Gln/Gln genotype. Our data are consistent with this hypothesis and provide significant evidence that individuals with AA genotype are more susceptible to develop premalignant hyperkeratosis, when faced with arsenic challenge. We have also seen that the individuals with arsenic-induced hyperkeratosis have significantly higher CA frequency, and this observation is also consistent with our earlier findings (7). Again, this group consists of a large proportion of individuals having ERCC2 Lys/Lys genotype. Hence, we speculate that, may be, it is the contribution of the ERCC2 Lys/Lys genotype individuals that is responsible for increased CA frequency in the arsenic-induced hyperkeratotic group.

The significance of this report lies in the fact, that it is the first study of its kind on the highly arsenic affected West Bengal population with respect to ERCC2 codon 751 polymorphism along with CA status, and paves the way for further functional studies in this direction.


   Acknowledgments
 
Authors are extremely grateful to Dr Kunal Ray, Molecular and Human Genetics Division of IICB for his help and suggestion for SNP study and to Dr Susanta Roychowdhury, of the same Division for his help and the use of sequencing facilities in his laboratory. This study is supported by grants (CMM-0003) and research fellowship to M.B. from Council of Scientific and Industrial Research (CSIR), Govt. of India.

Conflict of Interest Statement: None declared.


   References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received June 30, 2006; revised September 13, 2006; accepted September 20, 2006.


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