Browse Subject Areas

Click through the PLOS taxonomy to find articles in your field.

For more information about PLOS Subject Areas, click here.

  • Loading metrics

Homozygous Wildtype of XPD K751Q Polymorphism Is Associated with Increased Risk of Nasopharyngeal Carcinoma in Malaysian Population

  • Munn-Sann Lye ,

    Affiliation Department of Community Health, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia

  • Shaneeta Visuvanathan,

    Affiliation Department of Community Health, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia

  • Pei-Pei Chong,

    Affiliation Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia

  • Yoke-Yeow Yap,

    Affiliation Department of Surgery, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia

  • Chin-Chye Lim,

    Affiliation National Cancer Institute, Ministry of Health Malaysia, Putrajaya, Malaysia

  • Eng-Zhuan Ban

    Affiliation Department of Community Health, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia

Homozygous Wildtype of XPD K751Q Polymorphism Is Associated with Increased Risk of Nasopharyngeal Carcinoma in Malaysian Population

  • Munn-Sann Lye, 
  • Shaneeta Visuvanathan, 
  • Pei-Pei Chong, 
  • Yoke-Yeow Yap, 
  • Chin-Chye Lim, 
  • Eng-Zhuan Ban


The xeroderma pigmentosum group D (XPD) gene encodes a DNA helicase, an important component in transcription factor IIH (TFIIH) complex. XPD helicase plays a pivotal role in unwinding DNA at the damaged region during nucleotide excision repair (NER) mechanism. Dysfunctional XPD helicase protein from polymorphic diversity may contribute to increased risk of developing cancers. This study aims to determine the association between XPD K751Q polymorphism (rs13181) and risk of nasopharyngeal carcinoma (NPC) in the Malaysian population. In this hospital-based matched case-control study, 356 controls were matched by age, gender and ethnicity to 356 cases. RFLP-PCR was used to genotype the XPD K751Q polymorphism. A significant association was observed between XPD K751Q polymorphism and the risk of NPC using conditional logistic regression. Subjects with homozygous Lys/Lys (wildtype) genotype have 1.58 times higher odds of developing NPC compared to subjects with recessive combination of heterozygous Lys/Gln and homozygous Gln/Gln genotypes (OR = 1.58, 95% CI = 1.05–2.38 p = 0.028) adjusted for cigarette smoking, alcohol and salted fish consumption. Our data suggests that Lys/Lys (wildtype) of XPD K751Q contributes to increased risk of NPC in the Malaysian population.


Nasopharyngeal carcinoma (NPC) originates from the epithelial lining of the nasopharynx. In most parts of the world, NPC is an uncommon cancer. The incidence proportion of NPC in the United States is as low as 1 per 100,000 population [1] whereas in Southeast Asia (mainly in Malaysia, Singapore and Indonesia) it averages 6.5 per 100,000 population [2]. According to the National Cancer Statistics Malaysia 2007, incidence proportion of NPC in Malaysia was 6.4 per 100,000 population in males and 2.3 per 100,000 population in females [3]. Several postulations have been made to explain this disparity in NPC incidence in different parts of the world. Etiological factors such as genetic susceptibility, consumption of high-salt-content-preserved food and cigarette smoking were associated with increased risk of NPC [46]. Exposures to nitrosamines from salted fish could lead to the formation of harmful DNA adducts [7]. Accumulation of DNA adducts in normal healthy cells without proper DNA repair could result in genomic instability [8]. DNA repair systems play an important role in preserving the human genome from genotoxic stress exerted by both exogenous as well as endogenous carcinogens such as reactive oxygen species and DNA single strand breaks [9]. Single nucleotide polymorphisms (SNPs) in DNA repair genes have been extensively studied in relation to cancer development due to their potential effect on the maintenance of genomic integrity [10] and some of these have been found to be associated with increased risk of developing cancers. However, the role of these SNPs remains largely unknown in relation to NPC carcinogenesis.

Human XPD gene is an important component in transcription factor IIH (TFIIH) complex and is responsible for encoding an ATP-dependent 5’-3’ DNA helicase protein, which is 761 amino acids long in sequence and has a molecular weight of 86,909 Da [11]. XPD helicase consists of 4 domains namely helicase domains 1 and 2 (where carboxy terminal domain, CTD is located), Arch and FeS cluster-containing domains [12]. TFIIH is the main protein complex involved in eukaryotic NER mechanism [13] and is made up of XPD helicase and 2 sub-complexes involving 9 subunits, namely XPB, p62, p52, p44, p34 and p8 combined that form the core, and also cdk7, cdk-activating kinase assembly factor 1 (MAT1) and cyclin H bound together forming another sub-complex known as cdk-activating kinase (CAK). XPD helicase is an indispensable member of TFIIH complex because the helicase bridges both sub-complexes of TFIIH together [14]. XPD links p44 and MAT1 [1517] via the binding of MAT1 to the XPD helicase’s Arch domain while p44 interacts with CTD of the same helicase. With XPD bridging both of the sub-complexes, functional TFIIH plays a pivotal role in DNA repair [1819]. The role of NER mechanism in the removal of helix-distorting bulky DNA adducts is important in maintaining a low level of DNA damage in human cells. Smaller DNA adducts such as cisplatin and ultra-violet exposure-related photoproducts are also removed by NER [20]. The binding of XPD to CAK complex negatively regulates its helicase activity whereas interaction with p44 enhances the aforementioned activity of XPD [2122]. XPD gene polymorphisms have been observed in almost every region of the helicase structure [23]. R156R (rs238406), D312N (rs1799793) as well as K751Q (rs13181) are examples of notable cancer-associated polymorphisms and they are located in HD1, Arch and CTD domains of XPD helicase respectively [24]. These single nucleotide polymorphisms (SNPs) have been studied extensively and been implicated in candidate gene studies. While several studies reported significant associations of these SNPs in cancer development [2531], others did not [3234]. We focused on K751Q polymorphism because this SNP is located in the XPD-p44 interacting C terminus region, and interaction with p44 is important for XPD helicase activity.

Materials and Methods

Ethics Statement

This study was conducted with approval from both the Medical Research Ethics Committees of the Ministry of Health, Malaysia and the Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Malaysia. Written informed consent was obtained from each of the study participants.

Study population

Sample size was calculated using the formula adopted by Schlesselman [35] on matched case-control study using a power (1-β) of 90 percent with α set at 0.05. Estimated proportion of exposed cases and controls in target population were adapted from Huang et al [36]. To detect a minimum effect size of odds ratio of 2, at least 310 matched pairs were needed. Inclusion criteria for cases include those who were histologically confirmed NPC patients diagnosed from year 2007 onwards in two public hospitals. Cases below 18 years of age or who were seropositive for Hepatitis B and C were excluded. Individuals without prior history of cancers were recruited as controls from the same hospitals and were age, sex and ethnicity matched to the cases. Only individuals recruited from the same public hospitals as the cases are eligible controls. 356 case-control pairs were available for analysis using conditional logistic regression.

Isolation of genomic DNA and genotyping

Each subject donated 2.0 mL of whole blood stored in EDTA tubes at -70°C. Genomic DNA was later extracted from the blood samples using QIAamp DNA Mini and Blood Mini kit (QIAgen, USA). Polymorphism of XPD K751Q (rs13181) was detected using polymerase chain reaction—restriction fragment length polymorphism (PCR-RFLP) assay. The sequences of primers used to amplify the polymorphism of XPD K751Q were adopted from Duell et al [37]. Forward and reverse primers used were 5′-CCC CCT CTC CCT TTC CTC TG-3′ and 5′-AAC CAG GGC CAG GCA AGA C-3′ respectively. PCR-RFLP assay for the selected polymorphism is shown in Table 1. Digested PCR products were resolved on 3.0% (w/v) agarose gel. As shown in Fig 1, samples were identified as homozygous Lys/Lys (wildtype) if two PCR bands were observed at 102 bp and 82 bp. For heterozygous Lys/Gln genotype, three PCR bands were observed at 184 bp, 102 bp and 82 bp. Homozygous Gln/Gln (variant) genotype was recorded if a single PCR band was observed at 184 bp. 10% of the total samples were randomly chosen for DNA sequencing analysis to verify the PCR-RFLP results.

Fig 1. Gel electrophoresis of PCR-RFLP products for representative blood samples for the XPD Lys751Gln polymorphism.

Lane M represents low range DNA ladder marker (Fermentas), lanes 1 and 4 represent Lys/Lys genotype (102 bp and 82 bp), lanes 2 and 5 represent Lys/Gln genotype (184bp, 102 bp and 82 bp), lanes 3 and 6 represent Gln/Gln genotype (184 bp), lane 7 represents negative control (RFLP reaction without PCR product) and lane 8 represents negative control (RFLP reaction without restriction enzyme, MboII).

Statistical analysis

Relative frequencies were used to describe variables studied including socio-demographic and exposure data using SPSS version 21. Deviation from Hardy-Weinberg equilibrium (HWE) was tested using Court Lab Calculator on controls [38]. The association between potential confounders (gender, ethnicity, cigarette smoking, salted fish and alcohol consumption) and genotype was explored for cases and controls using χ2 analysis. Conditional logistic regression using STATA 10 was used to estimate adjusted odds ratios and their 95% confidence intervals to determine association between XPD K751Q polymorphism and risk of NPC, controlling for cigarette smoking, salted fish and alcohol consumption.


Distributions of age, gender and ethnicity were equal in both cases and controls. The mean age for both cases and controls was 53.17 years while the male to female ratio was 3.44: 1. 70.2% were ethnic Chinese while 28.4% were Malays. The distribution of cigarette smoking, salted fish and alcohol consumption among study subjects are shown in Table 2. Genotype frequencies of XPD K751Q polymorphism in cases were 305 (85.7%) homozygous Lys/Lys, 49 (13.8%) heterozygous Lys/Gln and 2 (0.5%) homozygous Gln/Gln. As for the controls, genotype frequencies were 283 (79.5%), 64 (18.0%), and 9 (2.5%) respectively. Lys/Lys genotype was more prevalent in both cases (85.7%) and controls (79.5%) compared to Gln/Gln genotype. This finding is consistent with the NCBI SNP database (rs13181) indicating that Lys/Lys is the wildtype [39]. None of the associations between factors (cigarette smoking, salted fish and alcohol consumption, gender and ethnicity) and XPD genotypes are significant. NPC cases were more likely to ever consume salted fish compared to controls (OR = 1.75, 95% CI = 1.23–2.51, p = 0.002). Individuals with previous history of smoking were also at higher risk of NPC (OR = 1.74, 95% CI = 1.20–2.52, p = 0.003). No significant difference was found between NPC cases and controls for alcohol consumption.

Table 2. Characteristics of the nasopharyngeal carcinoma cases and controls.

Genotype and allelic frequencies of XPD K751Q polymorphism of controls were in Hardy-Weinberg equilibrium (p>0.05) (Table 3). There was 100% concordance of the 10% of samples sent for DNA sequencing with results obtained from PCR-RFLP assay. Partial chromatograms showing exact XPD K751Q polymorphism are presented in Fig 2. To determine the effect of K751Q polymorphism on NPC risk, a recessive model (combination of heterozygous Lys/Gln and homozygous Gln/Gln) was used due to small numbers in the Gln/Gln genotype. Homozygous Lys/Lys was compared against the combined recessive model as reference group and was found to significantly increase odds of NPC (OR = 1.58, 95% CI = 1.05–2.38, p = 0.028) after adjusting for cigarette smoking, salted fish and alcohol consumption (Table 4).

Fig 2. Partial sequence chromatograms of Lys751Gln polymorphism from study subjects.

Arrow indicates the location of the nucleotide changes. Partial sequence chromatogram (A) represents Lys/Lys genotype, partial sequence chromatogram (B) represents Lys/Gln genotype and partial sequence chromatogram (C) represents Gln/Gln genotype.

Table 3. Allelic and genotype frequencies of XPD K751Q polymorphism (Hardy-Weinberg equilibrium test).

Table 4. Frequency of XPD K751Q recessive model genotypes and association with NPC.


In Malaysia, NPC was the 4th most frequent cancer in 2011 [3]. In general, Cantonese-speaking individuals from Southern China have higher incidence rate of NPC compared to other ethnic groups [40]. Although offspring of Chinese origin who have migrated to western countries were observed to have progressively lower risk of NPC, incidence of NPC remained higher in these migrants compared to indigenous populations [40]. Similarly, results from the present study showed that majority of cases were of Chinese origin (70.2%). NPC cases in this study showed male to female ratio of 3.44:1 consistent with previous reports of males having 2–3 fold higher incidence of NPC compared to females [2]. Genetic susceptibility alone may be inadequate to explain the incidence of NPC. Inclusion of environmental factors in the causal model is crucial to better understand NPC carcinogenesis [41].

Salted fish consumption was implicated in increasing NPC risk in past studies [4244]. In our study, subjects who consumed salted fish were found to be more susceptible to NPC (OR = 1.75, 95% CI = 1.23–2.51, p = 0.002). The causal role of cigarette smoking in carcinogenesis of various cancers has long been implicated in previous studies. Individuals who smoked were more susceptible to lung, bladder and nasopharyngeal carcinoma [4547]. Subjects with smoking history in our study have a higher risk of NPC (OR = 1.74, 95% CI = 1.20–2.52, p = 0.003). Both these environmental factors mentioned are capable of inducing DNA damage [4849]. Cigarette smoking-related carcinogens including polycyclic aromatic hydrocarbons (PAH) and N-nitrosamines have been shown to cause bulky DNA adducts [50]. Salted fish bought from regions with highest NPC mortality also contained high levels of N-nitrosamines [51]. NER is the main DNA repair mechanism responsible for removing bulky DNA adducts induced by the aforementioned environmental carcinogens [48]; optimal NER activity protects living cells from DNA damage. Lower than average NER activity due to interference by DNA polymorphisms in NER-related genes with constant challenges from environmental carcinogens could lead to higher NPC incidence [52].

After adjusting for effects of environmental factors, XPD homozygous wildtype Lys/Lys genotype was associated with higher odds of NPC (OR = 1.58, 95% CI = 1.05–2.38, p = 0.028). This observation contradicts some of the conclusions drawn by previous studies, in which homozygous Gln/Gln was the genotype implicating risk of various cancers. Benascu et al. [53] reported that homozygous Gln/Gln was associated with higher risk of chronic myeloid leukemia (OR = 2.37; 95% CI = 1.20–4.67, p value = 0.016). Huang et al. [36] showed that Gln allele was associated with a significantly higher risk of esophageal squamous cell carcinoma while Gln/Gln genotype carriers are associated with increased risk of digestive tract cancer. However, evidence from other studies showed that the Lys allele increased risk in various cancers. Yang et al. [54] found Lys allele to be associated with increased risk of NPC in Sichuan population. In another study in West Bengal by Banerjee et al. [55], Lys/Lys genotype was shown to be associated with increased risk (OR = 4.77, 95% CI = 2.75–8.23) of developing arsenic-induced premalignant hyperkeratosis, which is a precursor lesion of arsenic-induced skin cancer. Lys allele was also implicated in increasing risk of oral leukoplakia and cancer (OR = 1.6, 95% CI = 1.1–2.3) [56]. Ozcan et al. [57] found the Lys/Lys genotype increased risk of early relapse in hematological malignancies (OR = 13.12, 95% CI = 1.09–157.76). Lunn et al. [58] compared 61 Caucasian women with and without a family history of breast cancer and showed that Lys/Lys genotype was associated with impaired repair of X-ray-induced DNA damage as evidenced by a higher level of chromatid aberrations compared to individuals with Gln alleles.

Several postulations have been put forward in order to explain the effect of XPD K751Q polymorphism on NPC risk. Firstly, Friedberg E. [59] proposed that an A to C nucleotide change at XPD codon 751 causes an amino acid substitution from Lysine to Glutamine that results in alteration of the electronic configuration of amino acid from acidic to basic. Kuper et al. [13] showed that XPD helicase activity is deficient without proper XPD-p44 interaction leading to impaired unwinding of DNA during NER process. Secondly, Sturgis et al. [60] reported that XPD protein expression might be altered due to the close proximity of K751Q polymorphism’s location to the poly (A) signal made up of AAUAAA hexamer, which is recognized by components of cleavage and polyadenylation complex [61] and is the key trigger for pre-mRNA 3’ end processing. Polyadenylation is an important process in living cells because poly (A) tail protects RNA from enzymatic degradation. A nucleotide change in K751Q could lead to failure in recognizing poly (A) signal by polyadenylation complex resulting in a lower than normal DNA repair capacity from diminished XPD gene expression due to less XPD mRNA that will escape the highly active enzymatic degradation [62].

The molecular basis of the association between XPD K751Q polymorphism and NPC needs to be further elucidated. Differences in the integrity and functionality of TFIIH complex between Lys/Lys and Gln/Gln genotype and involvement of other genes in NER mechanism (p44 protein) could provide evidence needed to explain the association. Other DNA repair pathways (base excision repair, BER) and other cell signaling pathways such as Wnt, MAPK and PI3K-Akt pathway are also implicated in NPC carcinogenesis [63]. Future research investigating crosstalk between DNA repair and other pathways are warranted to better understand NPC carcinogenesis.

Supporting Information


The authors of this article are grateful to all hospital staff for their assistance. In addition, we thank all the participants, enumerators and research assistants who were involved in this study.

Author Contributions

Conceived and designed the experiments: MSL. Performed the experiments: SV EZB. Analyzed the data: MSL SV EZB. Contributed reagents/materials/analysis tools: MSL PPC YYY CCL. Wrote the paper: MSL SV EZB.


  1. 1. Parkin DM, Whelan SL, Ferlay J, Teppo L, Thomas DB. (1997) Cancer incidence in five continents, vol. 7. International Agency for Research on Cancer, Lyon. 334–337.
  2. 2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. (2011) Global cancer statistics. CA: A Cancer Journal for Clinicians. 61: 69–90. pmid:21296855
  3. 3. Zainal AO, Nor SIT. (2011) National Cancer Report 2011 Malaysia: Ministry of Health.
  4. 4. Gallicchio L, Matanoski G, Tao XG. (2006) Adulthood consumption of preserved and nonpreserved vegetables and the risk of nasopharyngeal carcinoma: A systemic review. Int J Cancer 119: 1125–1135. pmid:16570274
  5. 5. Ng CC, Yew PY, Puah SM, Krishnan J, Yap LF, Teo SH, et al. (2009) A genome-wide association study identifies ITAG9 conferring risk of nasopharyngeal carcinoma. Journal of Human Genetics 54: 392–397. pmid:19478819
  6. 6. Yu MC, Yuan JM. (2002) Epidemiology of nasopharyngeal carcinoma. Seminars in Cancer Biology 12: 421–429. pmid:12450728
  7. 7. Tardiff RG, Lohman PHM, Wogan GN. (1994) Methods to access DNA damage and repair: interspecies comparisons. Chichester: John Wiley & Sons. 30p.
  8. 8. Jackson SP, Bartek J. (2009) The DNA-damage response in human biology and disease. Nature Reviews 461: 1071–1078. pmid:19847258
  9. 9. Hoeijmakers JHJ. (2001) Genome maintenance mechanisms for preventing cancer. Nature 411: 366–374. pmid:11357144
  10. 10. Yin Z, Su M, Li X, Li M, Ma R, He Q, et al. (2009) ERCC2, ERCC1 polymorphisms and haplotypes, cooking oil fume and lung adenocarcinoma risk in Chinese non-smoking females. Journal of Experimental & Clinical Cancer Research 28(153): 1–7.
  11. 11. Sung P, Bailly V, Weber C, Thompson LH, Prakash L, Prakash S. (1993) Human xeroderma pigmentosum group D gene encodes a DNA helicase. Nature 365: 852–855. pmid:8413672
  12. 12. Wolski SC, Kuper J, Hanzelmann P, Truglio JJ, Croteau DL, Houten BV, et al. (2008) Crystal structure of the FeS cluster-containing nucleotide excision repair helicase XPD. PLoS Biol 6(6): e149. pmid:18578568
  13. 13. Kuper J, Braun C, Elias A, Michels G, Sauer F, Schmitt DR, et al. (2014) In TFIIH, XPD Helicase Is Exclusively Devoted to DNA Repair. PLoS Biol 12(9): e1001954. pmid:25268380
  14. 14. Lainé JP, Mocquet V, Egly JM. (2006) TFIIH enzymatic activities in transcription and nucleotide excision repair. Methods Enzymol 408:246–263. pmid:16793373
  15. 15. Schaeffer L, Moncollin V, Roy R, Staub A, Mezzina M, Sarasin A, et al. (1994) The ERCC2/DNA repair protein is associated with the class II BTF2/TFIIH transcription factor. EMBO J 13: 2388–2392. pmid:8194528
  16. 16. Compe E, Egly J-M. (2012) TFIIH: when transcription met DNA repair. Nat Rev Mol Cell Biol 13: 343–354. pmid:22572993
  17. 17. Coin F, Oksenych V, Egly J-M. (2007) Distinct roles for the XPB/p52 and XPD/p44 subcomplexes of TFIIH in damaged DNA opening during nucleotide excision repair. Mol Cell 26: 245–256. pmid:17466626
  18. 18. Liu H, Rudolf J, Johnson KA, McMahon SA, Oke M, Carter L, et al. (2008) Structure of the DNA repair helicase XPD. Cell 133: 801–812. pmid:18510925
  19. 19. Abdulrahman W, Iltis I, Radu L, Braun C, Maglott-Roth A, Giraudon C, et al. (2013) ARCH domain of XPD, an anchoring platform for CAK that conditions TFIIH DNA repair and transcription activities. Proc Natl Acad Sci USA 110(8): E633–E642. pmid:23382212
  20. 20. Sancar A. (1994) Mechanisms of DNA excision repair. Science 266: 1954–1956. pmid:7801120
  21. 21. Araujo SJ, Tirode F, Coin F, Pospiech H, Syvaoja JE, Stucki M, et al. (2000) Nucleotide excision repair of DNA with recombinant human proteins: definition of the minimal set of factors, active forms of TFIIH, and modulation by CAK. Genes Dev 14: 349–359. pmid:10673506
  22. 22. 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. pmid:9771713
  23. 23. Benhamou Simone, Sarasin Alain. (2005) ERCC2/XPD gene polymorphisms and lung cancer: a HuGE review. Am. J. Epidemiol. 161(1):1–14. pmid:15615908
  24. 24. Fan L, Fuss JO, Cheng QJ, Arvai AS, Hammel M, Roberts VA, et al. (2008) XPD Helicase Structures and Activities: Insights into the Cancer and Aging Phenotypes from XPD Mutations. Cell 133(5): 789–800. pmid:18510924
  25. 25. Du Y, He Y, Mei Z, Qian L, Shi J, Jie Z. (2014) Association between genetic polymorphisms in XPD and XRCC1 genes and risks of non-small cell lung cancer in East Chinese Han population. Clin Respir J.
  26. 26. Wang T, Wang H, Guo H, Yang S, Zhu G, Guo H, et al. (2014) Polymorphisms in DNA Repair Gene ERCC2/XPD and Breast Cancer Risk: A HapMap-Based Case-Control Study Among Han Women in a Chinese Less-Developed Area. Genetic Testing and Molecular Biomarkers 18(10): 703–710. pmid:25117088
  27. 27. Aneta M, Katarzyna PS, Rodney JS, Bohdan G, Thierry VDW, Dominika W, et al. (2014) Common variants of xeroderma pigmentosum genes and prostate cancer risk. Gene 546(2): 156–161. pmid:24933002
  28. 28. Zhou C, Xie LP, Lin YW, Yang K, Mao QQ, Cheng Y. (2013) Susceptibility of XPD and hOGG1 genetic variants to prostate cancer. Biomedical Reports 1: 679–683. pmid:24649009
  29. 29. Bo Y, Wei-hua C, Xiao-fei W, Hui L, Feng L. (2013) Role of DNA Repair-related Gene Polymorphisms in Susceptibility to Risk of Prostate Cancer. Asian Pac J Cancer Prev 14(10): 5839–5842. pmid:24289586
  30. 30. Du H, Guo N, Shi B, Zhang Q, Chen Z, Lu K, et al. (2014) The Effect of XPD Polymorphisms on Digestive Tract Cancers Risk: A Meta-Analysis. PLoS ONE 9(5): e96301. pmid:24787743
  31. 31. Xue H, Lu Y, Lin B, Chen J, Tang F, Huang G. (2012) The Effect of XPD/ERCC2 Polymorphisms on Gastric Cancer Risk among Different Ethnicities: A Systematic Review and Meta-Analysis. PLoS ONE 7(9): e43431. pmid:23028453
  32. 32. Hu YY, Yuan H, Jiang GB, Chen N, Wen L, Leng W, et al. (2012) Associations between XPD Asp312Asn Polymorphism and Risk of Head and Neck Cancer: A Meta-Analysis Based on 7,122 Subjects. PLoS ONE 7(4): e35220. pmid:22536360
  33. 33. Fatima ZM, Meriem SA, Valerie LM, Lotfi L, Ricardo B, Abdelkader B, et al. (2014) No association between XRCC3 Thr241Met and XPD Lys751Gln polymorphisms and the risk of colorectal cancer in West Algerian population: a case-control study. Med Oncol 31: 942. pmid:24687779
  34. 34. Mi Y, Zhang L, Feng N, Wu S, You X, Shao H, et al. (2012) Impact of Two Common Xeroderma Pigmentosum Group D (XPD) Gene Polymorphisms on Risk of Prostate Cancer. PLoS ONE 7(9): e44756. pmid:23028604
  35. 35. Schlesselman JJ. (1982) Case-control studies: design, conduct, analysis. Oxford University Press, New York.
  36. 36. Huang CG, Liu T, Lv GD, Liu Q, Feng JG, Lu XM. (2012) Analysis of XPD genetic polymorphisms of esophageal squamous cell carcinoma in a population of Yili Prefecture, in Xinjiang, China. Mol Biol Rep 39(1): 709–714. pmid:21553048
  37. 37. Duell EJ, Wiencke JK, Cheng T, Varkonyi A, Zuo ZF, Ashok TD, et al. (2000) Polymorphisms in the DNA repair genes XRCC1 and ERCC2 and biomarkers of DNA damage in human blood mononuclear cells. Carcinogenesis 21(5): 965–971. pmid:10783319
  38. 38. Court M: Court Lab Calculator. 2008. Available:
  39. 39. NLM. Database of Single Nucleotide Polymorphisms (dbSNP). Bethesda (MD): National Center for Biotechnology Information, National Library of Medicine. dbSNP accession:{rs13181} Available:
  40. 40. Sun LM, Epplein M, Li CI, Vaughan TL, Weiss NS. (2005) Trends in the incidence rates of nasopharyngeal carcinoma among Chinese Americans living in Los Angeles county and the San Francisco metropolitan area, 1992–2002. Am J Epidemiology 162(12): 1174–1178. pmid:16282240
  41. 41. Guo X, Johnson RC, Deng H, Liao J, Guan L, Nelson GW, et al. (2009) Evaluation of non-viral risk factors for nasopharyngeal carcinoma in a high-risk population of Southern China. Int J Cancer 124(12):2942–2947. pmid:19296536
  42. 42. Ning JP, Yu MC, Wang QS, Henderson BE. (1990) Consumption of salted fish and other risk factors for nasopharyngeal carcinoma (NPC) in Tianjin, a low-risk region for NPC in the People’s Republic of China. J Natl Cancer Inst 82(4): 291–296. pmid:2299678
  43. 43. Yu MC, Ho JHC, Lai SH, Henderson BE (1986) Cantonese–style Salted Fish as a Cause of Nasopharyngeal Carcinoma: Report of a Case-Control Study in Hong Kong. Cancer Res 46: 956–961. pmid:3940655
  44. 44. Armstrong RW, Imrey PB, Lye MS, Armstrong MJ, Yu MC, Sani S. (1998) Nasopharyngeal carcinoma in Malaysian Chinese: salted fish and other dietary exposures. Int J Cancer 77:228–235. pmid:9650558
  45. 45. Hartge P, Silverman D, Hoover R, Schairer C, Altman R, Austin D, el at. (1987) Changing cigarette habits and bladder cancer risk: a case-control study. J Natl Cancer Inst 78: 1119–1925. pmid:3473252
  46. 46. Cheng YJ, Hildesheim A, Hsu MM, Chen IH, Brinton LA, Levine PH, et al. (1999) Cigarette smoking, alcohol consumption and risk of nasopharyngeal carcinoma in Taiwan. Cancer Causes Control 10(3): 201–207. pmid:10454065
  47. 47. Pesch B, Kendzia B, Gustavsson P, Jockel KH, Johnen G, Pohlabeln H, et al. (2012) Cigarette smoking and lung cancer–relative risk estimates for the major histological types from a pooled analysis of case-control studies. Int J Cancer 131(5): 1210–1219. pmid:22052329
  48. 48. Denissenko MF, Pao A, Tang M, Pfeifer GP. (1996) Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53. Science 274(5286): 430–432. pmid:8832894
  49. 49. Bartsch H, Montesano R. (1984) Relevance of nitrosamines to human cancer. Carcinogenesis 5(11): 1381–1393. pmid:6386215
  50. 50. Pfeifer GP, Denissenko MF, Olivier M, Tretyakova N, Hecht SS, Hainaut P. (2002) Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene 21: 7435–7451. pmid:12379884
  51. 51. Zou X, Li J, Lu S, Song X, Wang X, Guo L, et al. (1992) Volatile N-nitrosamines in salted fish samples from high- and low-risk areas for NPC in China. Chin Med Sci J 7: 201–204. pmid:1307494
  52. 52. Hoeijmakers JH. (2001) Genome maintenance mechanisms for preventing cancer. Nature 411: 366–374. pmid:11357144
  53. 53. Banescu C, Trifa AP, Demain S, Lazar EB, Dima D, Duicu C, et al. (2014) Polymorphism of XRCC1, XRCC3, and XPD Genes and Risk of Chronic Myeloid Leukemia. BioMed Research International 2014: 213790. pmid:24955348
  54. 54. Yang ZH, Du B, Wei YS, Zhang JH, Zhou B, Liang WB, et al. (2007) Genetic polymorphisms of DNA repair gene and risk of nasopharyngeal carcinoma. DNA & Cell Biology 26: 491–496.
  55. 55. Banerjee M, Sarkar J, Das JK, Mukherjee A, Sarkar AK, Mondal L, et al. (2007) Polymorphism in the ERCC2 codon 751 is associated with arsenic-induced premalignant hyperkeratosis and significant chromosome aberrations. Carcinogenesis 28(3): 672–676. pmid:17050553
  56. 56. Majumder M, Sikdar N, Ghosh S, Bidyut R. (2007) Polymorphisms at XPD and XRCC1 DNA repair loci and increase risk of oral leukoplakia and cancer among NAT2 slow acetylators. International Journal Cancer 120: 2148–2156. pmid:17290401
  57. 57. Ozcan A, Pehlivan M, Tomatir AG, Karaca E, Ozkinay C, Ozdemir F, et al. (2011) Polymorphisms of the DNA repair gene XPD (751) and XRCC1 (399) correlates with risk of hematological malignancies in Turkish population. African Journal of Biotechnology 10(44): 8860–8870.
  58. 58. Lunn RM, Helzlsouer KJ, Parshad R, Umbach DM, Harris EL, Sanford KK, et al. (2000) XPD polymorphisms: Effects on DNA repair proficiency. Carcinogenesis 21(4): 551–555. pmid:10753184
  59. 59. Friedberg E. (2001) How nucleotide excision repair protects against cancer. Nature Rev Cancer 1: 22–33. pmid:11900249
  60. 60. Sturgis EM, Zheng R, Li L, Castillo EJ, Eicher SA, Chen M, et al. (2000) XPD/ERCC2 polymorphisms and risk of head and neck cancer: A case-control analysis. Carcinogenesis 21(12): 2219–2223. pmid:11133811
  61. 61. Guo J, Garrett M, Micklem G, Brogna S. (2011) Poly (A) Signals Located near the 5’ End of Genes Are Silenced by a General Mechanism That Prevents Premature 3’-End Processing. Molecular and Cellular Biology 31(4): 639–651. pmid:21135120
  62. 62. Proudfoot NJ. (2001) Genetic dangers in poly (A) signals. EMBO 2(10): 891–892.
  63. 63. Tulalamba W and Janvilisri T. (2012) Nasopharyngeal Carcinoma Signaling Pathway: An Update on Molecular Biomarkers. International Journal of Cell Biology 2012: 594681–594691. pmid:22500174