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Egyptian Journal of Medical Human Genetics
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Gene-environment and gene-gene interactions between CHRNA3 rs1051730, XRCC1 rs25487, and ERCC1 rs735482 variants highly elevate the risk of lung cancer

Egyptian Journal of Medical Human Genetics volume 20, Article number: 23 (2019) Cite this article

Abstract

Background

Gene-gene and gene-environment interactions play an important role in cancer susceptibility. In this work, we studied the association of XRCC1 rs25487, ERCC1 rs735482, and CHRNA3 rs1051730 variants with lung cancer and assessed the modulatory effect of potential interaction between these variants on disease risk.

Results

In this study, 86 primary lung cancer patients and 64 control subjects were genotyped for CHRNA3 rs1051730, XRCC1 rs25487, and ERCC1 rs735482 by real-time PCR. The frequency of the three studied variants was higher among lung cancer patients than in control subjects, but with no statistical significance. ERCC1 rs735482 variant was associated with 6.9-fold increased risk to develop lung cancer among smokers (p = 0.03). Concomitant presence of CHRNA3 and ERCC1 wild alleles was associated with 2.7-fold elevated risk of lung cancer (p < 0.0001), while concomitant presence of CHRNA3 rs1051730 variant allele with ERCC1 wild allele was associated with 20-fold elevated risk (p < 0.000). Concomitant presence of both variants, ERCC1 rs735482 and CHRNA3 rs1051730, was associated with 9.9-fold elevated risk (p < 0.0001). Meanwhile, the concomitant presence of XRCC1 rs25487 with either ERCC1 rs735482 or CHRNA3 rs1051730 or both was not associated with increased risk of the disease.

Conclusion

Our results emphasize the role of gene-gene interaction in the pathogenesis of lung cancer. Large-scale further studies to clarify the underlying mechanisms are needed.

Background

Lung cancer is a leading cause of death with a poor survival rate worldwide [1]. Although smoking is the main cause of lung cancer, yet it cannot fully elucidate the epidemiologic incidences of disease among nonsmokers [2]. Gene-gene and gene-environment interactions are currently believed to play a major role in individual’s susceptibility to lung cancer [3, 4].

Polymorphisms of DNA repair genes have been reported as potential markers for disease susceptibility and prognosis [5]. Subjects with low expression and/or activity of DNA repair enzymes have impaired ability to remove tobacco-induced DNA damage and are more likely to develop lung cancer. Excision repair cross complementing group 1 (ERCC1) and X-ray repair cross-complementing group 1 (XRCC1) enzymes are needed to clear DNA damage and have been highlighted as potential biomarkers of clinical outcome in cancer [6,7,8,9,10].

XRCC1 gene is involved in base excision repair (BER) and single-stranded break repair (SSBR) [11] and helps in removing oxidative DNA damage induced by exposures to ionizing radiation or alkylating agents [12]. XRCC1 rs25487 variant is a single-nucleotide polymorphism resulting from a nucleotide substitution at codon 399 with an amino acid change from arginine (Arg) to glutamine (Gln) and has been associated with an altered DNA repair activity [13]. Previous studies on this variant and its role in susceptibility to lung cancer gave inconsistent results among different ethnic groups [14,15,16,17].

On the other hand, ERCC1 protein functions in nucleotide excision repair (NER) and DNA inter strand crosslinks (ICL) repair pathways; therefore, it was hypothesized that polymorphisms which alter the expression and/or function of ERCC1 may play a role in cancer pathogenesis [18,19,20].

Also, cholinergic receptor nicotinic α3 (CHRNA3) gene coding for nicotinic acetylcholine receptor subunits (nAChRs) harbors another candidate variant, rs1051730 that has been associated with elevated risk of lung cancer in genome-wide association studies (GWAS) [21, 22].

In this study, we aim to examine the association of XRCC1 rs25487, ERCC1 rs735482, and CHRNA3 rs1051730 variants with lung cancer and to assess the modulatory effect of the potential interaction between these variants on disease risk in Egyptian patients.

Methods

Subjects

This study is a case-control study that included 86 unrelated adult patients with primary lung cancer and 64 apparently healthy unrelated controls. Patients were presented to the Chest Diseases clinic of the National Research Center (NRC) from different governorates of Egypt. All subjects gave written informed consent and the study was approved by the local ethics committee. Medical history was obtained from all participants via questionnaire including demographic data, smoking and occupational history, as well as family history of malignancy. Thorough clinical examination and chest radiography were conducted. Exclusion criteria were pulmonary fibrosis, pneumonia, and any anti-cancer medication.

Genotyping analysis

Genomic DNA was extracted from whole peripheral blood using QIAamp DNA extraction kit (Qiagen Hilden, Germany, Cat No. 51304) according to the manufacturer’s protocol. XRCC1 rs25487, ERCC1 rs735482, and CHRNA3 rs1051730 variants were genotyped using TaqMan® SNP Genotyping Assays. All primers and probes were designed by Applied Biosystems (Foster City, CA, USA) and genotyping analyses were performed on ABI 7500 real-time PCR system (Applied Biosystems) according to the manufacturer’s protocol. Negative controls were included in all assays and 10% of samples were randomly selected and analyzed in duplicates and the concordance rate was 100%.

Statistical analysis

Data were analyzed using IBM SPSS version 20.0 software (Statistical Package for Social Science). Quantitative data were expressed as mean values ± standard deviation (SD) and qualitative data were expressed as frequency (%). Normally distributed data were compared using Student’s t test. The significance of differences between proportions was tested by the Chi-square test (χ2). Differences were considered significant with p value < 0.05. Genotype and allele frequencies between groups were compared by Chi-square test. Univariate logistic regression analysis was used to test the association between studied polymorphisms and diseases and were presented as unadjusted odds ratios (OR) with confidence interval (95% CI).

Results

Both patients and control groups were age matched (p = 0.08). Male gender was more frequent among lung cancer patients (81.4%) and associated with 6.4 times higher risk of lung cancer occurrence than female gender (p < 0.001). The frequency of smokers was significantly higher among patients than among control subjects (69.7% vs. 21.8%, p < 0.0001), and were at 8.2 times higher risk to develop lung cancer than nonsmokers. There was a significant association between the number of pack-year and the occurrence of lung cancer among smokers (p = 0.03). General characteristics of patients and control subjects are shown in Table 1.

Table 1 General characteristics of the studied lung cancer patients and control subjects
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The frequency of the three studied variants was higher in lung cancer patients than in control subjects, but none was of statistical significance under any genetic model (Tables 2 and 3). All studied genotypes were in agreement with Hardy–Weinberg equilibrium in both lung cancer patients and control groups (p > 0.05) (Figs. 1, 2, and 3).

Table 2 Genotypes and alleles frequencies of the studied SNP in lung cancer patients and control subjects
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Table 3 Association of studied SNPs with lung cancer under different genetic models of inheritance
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Fig. 1
figure 1

Percentage of rs1051730 genotypes frequency in lung cancer patients and controls

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Fig. 2
figure 2

Percentage of rs25487 genotypes frequency in lung cancer patients and controls

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Fig. 3
figure 3

Percentage of rs735482 genotypes frequency in lung cancer patients and controls

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Analysis of genotypes and variant alleles frequency in respect to histological types showed that the frequency of variant alleles was higher in non-small cell lung cancer (NSCLC) than in small cell lung cancer (SCLC) but of no statistical significance (Table 4). In respect to smoking status, ERCC1 rs735482 variant (G allele) associated with 6.9 times higher risk to develop lung cancer among smokers compared to non-smokers (p = 0.03) (Table 5).

Table 4 Genotypes frequency in different histological types of lung cancer
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Table 5 Association between different genotypes and lung cancer in respect to smoking status
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Only 5% of lung cancer patients carried the wild alleles of the three studied genes together, while 95% carried at least one of the three variants. Studying the synergistic effect of XRCC1 rs25487, ERCC1 rs735482, and CHRNA3 rs1051730 variants on the risk of lung cancer showed that concomitant presence of CHRNA3 and ERCC1 wild alleles was associated with 2.7-fold increased risk (p < 0.0001). While concomitant presence of CHRNA3 rs1051730 variant with ERCC1 wild allele was associated with 20-fold elevated risk (p < 0.0001). Meanwhile, concomitant presence of both variants, ERCC1 rs735482 and CHRNA3 rs1051730, elevated the risk by 9.9-fold (p < 0.0001). However, concomitant presence of XRCC1 rs25487 with either ERCC1 rs735482 or CHRNA3 rs1051730 or both was not associated with increased risk of the disease (Table 6).

Table 6 Gene-gene interaction in lung cancer patients
Full size table

Discussion

In this work, we studied the association of XRCC1 rs25487, ERCC1 rs735482, and CHRNA3 rs1051730 variants with lung cancer and assessed the modulatory effect of the potential interaction between these variants on disease risk.

To our knowledge, this is the first work to study the three variants together in lung cancer patients. Our results showed higher frequency of the three studied variants among lung cancer patients but with no statistical significance. ERCC1 rs735482 variant was associated with 6.9-fold increased risk to develop lung cancer among smokers emphasizing the role of gene-environment interaction. We demonstrated for the first time that concomitant presence of CHRNA3 and ERCC1 wild alleles was associated with 2.7-fold elevated risk of lung cancer, while concomitant presence of CHRNA3 rs1051730 variant allele with ERCC1 wild allele was associated with 20-fold elevated risk. In addition, concomitant presence of both variants, ERCC1 rs735482 and CHRNA3 rs1051730, was associated with 9.9-fold increased disease risk. Our results confirming the role of gene-gene interaction and indicating variations in more than one gene may play a role in the susceptibility to lung cancer.

Our results support the results of previous studies that have reported lack of association between CHRNA3 rs1051730 and lung cancer [23,24,25,26,27,28]. In contrast, CHRNA3 rs1051730 has been reported to be significantly associated with elevated risk for lung cancer among Caucasians, Asians, Japanese, and in European ancestry [21, 29,30,31,32,33,34,35].

Mechanisms of elevated lung cancer risk independent of smoking in individuals with rs1051730 variant is not entirely clear. While David et al. found that rs1051730 was associated with cigarette per day (CPD) and lung cancer in African-Americans [36], other studies have reported associations between rs1051730 and lung cancer in nonsmokers [33, 37,38,39].

In our study, XRCC1 rs25487 was not associated with lung cancer and concomitant presence with either ERCC1 or CHRNA3 variants was not associated with elevated risk for the disease in our population. The association of rs25487 with lung cancer in different ethnic groups gave inconsistent results [40,41,42,43,44,45,46,47], while some studies reported significant association between the variant allele and lung cancer [40,41,42], other studies reported lack of such association [43, 44].

In the present study, ERCC1 rs735482 variant was associated with 6.9-fold elevated risk of lung cancer among smokers. In Chinese population, rs735482 was associated with lung cancer risk [48]. In contrast, Azad et al. reported lack of association with squamous cell carcinoma, the overall survival (OS), or the disease-free survival (DFS) [49]; however, in a Korean study, rs735482 was associated with poor survival in NSCLC patients [50]. In contrast, better prognosis was associated with the variant allele in lung adenocarcinoma patients [20]. The inconsistent results were attributed to the inconformity to Hardy–Weinberg equilibrium or to the small sample size.

Conclusion

Gene-environment interaction involving ERCC1 rs735482 variant elevates the risk of lung cancer among smokers. Concomitant presence of CHRNA3 rs1051730 and ERCC1 rs735482 variants augments the risk of lung cancer. Our results emphasize the role of gene-gene interaction in the pathogenesis of lung cancer and the underlying mechanisms need to be clarified in future studies.

Availability of data and materials

All data generated and/or analyzed during this study are available from the corresponding author upon reasonable request.

Abbreviations

Arg:

Arginine

BER:

Base excision repair

CHRNA3:

Cholinergic receptor nicotinicα3

CPD:

Cigarette per day

DFS:

Disease-free survival

DSB:

Double strand breaks

ERCC1:

Excision repair cross complementing group 1

Gln:

Glutamine

GWAS:

Genome-wide association studies

ICL:

Inter strand crosslinks

nAChRs:

Nicotinic acetylcholine receptor subunits

NER:

Nucleotide excision repair

NSCLC:

Non-small cell lung cancer

OS:

Overall survival

SCLC:

Small cell lung cancer

SNPs:

Single-nucleotide polymorphisms

SSBR:

Single-stranded break repair

UV:

Ultraviolet

XRCC1:

X-ray repair cross-complementing group 1

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90

    Article  PubMed  Google Scholar 

  2. Herbst RS, Heymach JV, Lippman SM (2008) Lung cancer. N Engl J Med 359:1367–1380

    Article  CAS  PubMed  Google Scholar 

  3. Hoeijmakers JH (2009) DNA damage, aging, and cancer. N Engl J Med 361:1475–1485

    Article  CAS  PubMed  Google Scholar 

  4. Negrini S, Gorgoulis VG, Halazonetis TD (2010) Genomic instability-an evolving hallmark of cancer. Nat Rev Mol Cell Biol 11:220–228

    Article  CAS  PubMed  Google Scholar 

  5. Dai Q, Luo H, Li XP, Huang J, Zhou TJ, Yang ZH (2015) XRCC1 and ERCC1 polymorphisms are related to susceptibility and survival of colorectal cancer in the Chinese population. Mutagenesis 30(3):441–449

    Article  CAS  PubMed  Google Scholar 

  6. Lopes-Aguiar L, Costa EFD, Nogueira GAS, Lima TRP, Visacri MB, Pincinato EC et al (2016) XPD c.934G>A polymorphism of nucleotide excision repair pathway in outcome of head and neck squamous cell carcinoma patients treated with cisplatin chemoradiation. Oncotarget 8:16190–16201

    PubMed Central  Google Scholar 

  7. Nanda SS, Gandhi AK, Rastogi M, Khurana R, Hadi R, Sahni K et al (2018) Evaluation of XRCC1 gene polymorphism as a biomarker in head and neck cancer patients undergoing chemoradiation therapy. Int J Radiat Oncol Biol Phys 101:593–601

    Article  CAS  PubMed  Google Scholar 

  8. Liu H, Qi B, Guo X, Tang LQ, Chen QY, Zhang L et al (2013) Genetic variations in radiation and chemotherapy drug action pathways and survival in locoregionally advanced nasopharyngeal carcinoma treated with chemoradiotherapy. PLoS One 8:e82750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tengström M, Mannermaa A, Kosma VM, Hirvonen A, Kataja V (2014) XRCC1 rs25487 polymorphism predicts the survival of patients after postoperative radiotherapyand adjuvant chemotherapy for breast cancer. Anticancer Res 34(6):3031–3037

    PubMed  Google Scholar 

  10. Senghore T, Chien HT, Wang WC, Chen YX, Young CK, Huang SF et al (2019) Polymorphisms in ERCC5 rs17655 and ERCC1 rs735482 genes associated with the survival of male patients with postoperative oral squamous cell carcinoma treated with adjuvant concurrent chemoradiotherapy. J Clin Med 8(1):E33

    Article  PubMed  Google Scholar 

  11. Caldecott KW (2003) XRCC1 and DNA strand break repair. DNA Repair (Amst) 2(9):955–969

    Article  CAS  Google Scholar 

  12. Wong HK, Kim D, Hogue BA, McNeill DR, Wilson DM (2005) DNA damage levels and biochemical repair capacities associated with XRCC1 deficiency. Biochemistry 44:14335–14343

    Article  CAS  PubMed  Google Scholar 

  13. Slyskova J, Dusinska M, Kuricova M, Soucek P, Vodickova L, Susova S et al (2007) Relationship between the capacity to repair 8-oxoguanine, biomarkers of genotoxicity and individual susceptibility in styrene-exposed workers. Mutat Res 634:101–111

    Article  CAS  PubMed  Google Scholar 

  14. Park JY, Lee SY, Jeon HS, Bae NC, Chae SC, Joo S et al (2002) Polymorphism of the DNA repair gene XRCC1 and risk of primary lung cancer. Cancer Epidemiol Biomark Prev 11:23–27

    CAS  Google Scholar 

  15. Schneider J, Classen V, Bernges U, Philipp M (2005) XRCC1 polymorphism and lung cancer risk in relation to tobacco smoking. Int J Mol Med 16:709–716

    CAS  PubMed  Google Scholar 

  16. Schneider J, Classen V, Helmig S (2008) XRCC1 polymorphism and lung cancer risk. Expert Rev Mol Diagn 8:761–780

    Article  CAS  PubMed  Google Scholar 

  17. Zhu DQ, Zou Q, Hu CH, Su JL, Zhou GH, Liu P (2015) XRCC1 genetic polymorphism acts a potential biomarker for lung cancer. Tumour Biol 36:3745–3750

    Article  CAS  PubMed  Google Scholar 

  18. Ahmad A, Robinson AR, Duensing A, van Drunen E, Beverloo HB, Weisberg DB et al (2008) ERCC1-XPF endonuclease facilitates DNA double-strand break repair. Mol Cell Biol 28(16):5082–5092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Vaezi A, Feldman CH, Niedernhofer LJ (2011) ERCC1 and XRCC1 as biomarkers for lung and head and neck cancer. Pharmacogenomics and Personalized Medicine:447–463

  20. Pintarelli G, Cotroneo CE, Noci S, Dugo M, Galvan A, Carpini D et al (2017) Genetic susceptibility variants for lung cancer: replication study and assessment as expression quantitative trait loci. Sci Rep 7(1-2):42185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Amos CI, Wu X, Broderick P, Gorlov IP, Gu J, Eisen T et al (2008) Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet 40:616–622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wei S, Wang LE, McHugh MK, Han Y, Xiong M, Amos CI et al (2012) Genome-wide gene-environment interaction analysis for asbestos exposure in lung cancer susceptibility. Carcinogenesis 33:1531–1537

    Article  CAS  PubMed  Google Scholar 

  23. Wu C, Hu Z, Yu D, Huang L, Jin G, Liang J et al (2009) Genetic variants on chromosome 15q25 associated with lung cancer risk in Chinese populations. Cancer Res 69:5065–5072

    Article  CAS  PubMed  Google Scholar 

  24. Sinha P, Logan HL, Mendenhall WM (2012) Human papillomavirus, smoking, and head and neck cancer. Am J Otolaryngol 33:130–136

    Article  PubMed  Google Scholar 

  25. Gu M, Dong X, Zhang X, Wang X, Qi Y, Yu J et al (2012) Strong association between two polymorphisms on 15q25.1 and lung cancer risk: a meta-analysis. PLoS One 7:e37970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. He P, Yang X, He XQ, Chen J, Li FX, Gu X et al (2014) CHRNA3 polymorphism modifies lung adenocarcinoma risk in the Chinese Han population. Int J Mol Sci 15:5446–5457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hansen HM, Xiao Y, Rice T, Bracci PM, Wrensch MR, Sison JD et al (2010) Fine mapping of chromosome 15q25.1 lung cancer susceptibility in African-Americans. Hum Mol Genet 19(18):3652–3661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hu B, Huang Y, Yu RH, Mao HJ, Guan C, Zhao J (2014) Quantitative assessment of the influence of common variations (rs8034191 and rs1051730) at 15q25 and lung cancer risk. Tumour Biol 35:2777–2785

    Article  PubMed  Google Scholar 

  29. Liu P, Yang P, Wu X, Vikis HG, Lu Y, Wang Y et al (2010) Second genetic variant on chromosome 15q24-25.1 associates with lung cancer. Cancer Res 70(8):3128–3135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kaur-Knudsen D, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG (2011) Nicotinic acetylcholine receptor polymorphism, smoking behavior, and tobacco-related cancer and lung and cardiovascular diseases: a cohort study. J Clin Oncol 29:2875–2882

    Article  CAS  PubMed  Google Scholar 

  31. Kaur-Knudsen D, Nordestgaard BG, Bojesen SE (2012) CHRNA3 genotype, nicotine dependence, lung function and disease in the general population. Eur Respir J 40:1538–1544

    Article  PubMed  Google Scholar 

  32. Thorgeirsson TE, Geller F, Sulem P, Rafnar T, Wiste A, Magnusson KP et al (2008) A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature 452:638–642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Shiraishi K, Kohno T, Kunitoh H, Watanabe S, Goto K, Nishiwaki Y et al (2009) Contribution of nicotine acetylcholine receptor polymorphisms to lung cancer risk in a smoking-independent manner in the Japanese. Carcinogenesis 30(1):65–70

    Article  CAS  PubMed  Google Scholar 

  34. Zhan P, Song Y (2019) CHRNA3 rs1051730 polymorphism and lung cancer susceptibility in Asian population: a meta-analysis. Transl Lung Cancer Res 4:104–108

    Google Scholar 

  35. Yang IA, Holloway JW, Fong KM (2013) Genetic susceptibility to lung cancer and co-morbidities. J Thorac Dis 5(Suppl 5):S454–S462

    PubMed  PubMed Central  Google Scholar 

  36. David SP, Wang A, Kapphahn K, Hedlin H, Desai M, Henderson M et al (2016) Gene by Environment Investigation of Incident Lung Cancer Risk in African-Americans. EBioMedicine 4:153–161

    Article  PubMed  PubMed Central  Google Scholar 

  37. Hung RJ, McKay JD, Gaborieau V, Boffetta P, Hashibe M, Zaridze D et al (2008) Susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature 452:633–637

    Article  CAS  PubMed  Google Scholar 

  38. Ren JH, Jin M, He WS, Liu CW, Jiang S, Chen WH et al (2013) Association between CHRNA3 rs1051730 genotype and lung cancer risk in Chinese Han population: a case-control study. J Huazhong Univ Sci Technolog Med Sci 33:897–901

    Article  CAS  PubMed  Google Scholar 

  39. Ayesh BM, Al-Masri R, Abed AA (2018) CHRNA5 and CHRNA3 polymorphism and lung cancer susceptibility in Palestinian population. BMC Res Notes 11(1):218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zheng H, Wang Z, Shi X, Wang Z (2009) XRCC1 polymorphisms and lung cancer risk in Chinese populations: a meta-analysis. Lung Cancer 65:268–273

    Article  PubMed  Google Scholar 

  41. Li Y, Huang Y, Cao YS, Zeng J, Tong WN, Xu SL, Zhuo AS (2013) Assessment of the association between XRCC1 Arg399Gln polymorphism and lung cancer in Chinese. Tumour Biol 34:3681–3685

    Article  CAS  PubMed  Google Scholar 

  42. Tasnim T, Al-Mamun MMA, Nahid NA, Islam MR, Apu MNH, Bushra MU et al (2017) Genetic variants of SULT1A1 and XRCC1 genes and risk of lung cancer in Bangladeshi population. Tumour Biol 39(11):1010428317729270

    Article  CAS  PubMed  Google Scholar 

  43. Hou SM, Ryk C, Kannio A, Angelini S, Falt S, Nyberg F et al (2003) Influence of common XPD and XRCC1 variant alleles on p53 mutations in lung tumors. Environ Mol Mutagen 41:37–42

    Article  CAS  PubMed  Google Scholar 

  44. Hou WM, Romkes M, Day RD, Siegfried JM, Luketich JD, Mady HH et al (2003) Association of the DNA repair gene XPD Asp312Asn polymorphism with p53 gene mutations in tobacco-related non-small cell lung cancer. Carcinogenesis 24:1671–1676

    Article  Google Scholar 

  45. Kiyohara C, Takayama K, Nakanishi Y (2006) Association of genetic polymorphisms in the base excision repair pathway with lung cancer risk: a meta-analysis. Lung Cancer 54:267–283

    Article  PubMed  Google Scholar 

  46. Chen L, Zhuo D, Chen J, Yuan H (2015) XRCC1 polymorphisms and lung cancer risk in Caucasian populations: a meta-analysis. Int J Clin Exp Med 8:14969–14976

    PubMed  PubMed Central  Google Scholar 

  47. Yoo SS, Jin C, Jung DK, Choi YY, Choi JE, Lee WK et al (2015) Putative functional variants of XRCC1 identified by RegulomeDB were not associated with lung cancer risk in a Korean population. Cancer Gene Ther 208:19–24

    Article  CAS  Google Scholar 

  48. Yin J, Wang H, Vogel U, Wang C, Wang C, Hou W et al (2016) Fine-mapping markers of lung cancer susceptibility in a sub-region of chromosome 19q13.3 among Chinese. Oncotarget. 7(38):60929–60939

    Article  PubMed  PubMed Central  Google Scholar 

  49. Azad AK, Bairati I, Samson E, Cheng D, Mirshams M, Qiu X et al (2012) Validation of genetic sequence variants as prognostic factors in early-stage head and neck squamous cell cancer survival. Clin Cancer Res 18(1):196–206

    Article  CAS  PubMed  Google Scholar 

  50. Lee Y, Kyong-Ah Yoon K, Joo J, Lee D, Bae K, Han J et al (2013) Prognostic implications of genetic variants in advanced non-small cell lung cancer: a genome-wide association study. Carcinogenesis 34:307–313

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Chest Diseases, Department of Internal Medicine, Medical Division, National Research Center, Cairo, Egypt

    Nada Ezzeldin

  2. Department of Clinical and Chemical Pathology, Medical Research Division, National Research Center, Al-Bohouth Street, Dokki, P.O. Box 12311, Cairo, Egypt

    Dalia El-Lebedy

  3. Department of Environmental and Occupational Medicine, National Research Center, Cairo, Egypt

    Asmaa Mohammed

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Contributions

All authors contributed to the present study. NE and DE designed the study, NE collected the samples and clinic pathological data, DE performed the molecular analysis, and AM analyzed the data. NE and DE wrote the manuscript. All authors have read, revised, and approved the final version of the manuscript.

Corresponding author

Correspondence to Dalia El-Lebedy.

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Ethics approval and consent to participate

The study protocol was approved by Medical Research Ethics Committee (MREC) of the National Research Center of Egypt prior to the study commencement (Ref. no. 14008). All subjects were aware of the study protocol and gave written informed consent.

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Ezzeldin, N., El-Lebedy, D. & Mohammed, A. Gene-environment and gene-gene interactions between CHRNA3 rs1051730, XRCC1 rs25487, and ERCC1 rs735482 variants highly elevate the risk of lung cancer. Egypt J Med Hum Genet 20, 23 (2019). https://doi.org/10.1186/s43042-019-0034-1

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Keywords

  • Lung cancer
  • Smoking
  • XRCC1
  • ERCC1
  • CHRNA3
  • Polymorphism