Association between superoxide dismutase 2, glutathione peroxidase 1, xeroderma pigmentosum group d gene variations, and head and neck squamous cell cancer susceptibility


  • Gülçin Köse Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Ankara University, Ankara, Turkey
  • Merve Demirbugen Oz Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Ankara University, Ankara, Turkey
  • Ela Cömert Department of Otorhinolaryngology, Faculty of Medicine, Kırıkkale University, Kırıkkale, Turkey
  • Halit Sinan Süzen Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Ankara University, Ankara, Turkey



Head and neck squamous cell cancer, gene polymorphism, GPX1, SOD2, XPD


Paper description:

  • Oxidative stress and reactive oxygen species (ROS) are implicated in the pathogenesis of head and neck squamous cell cancer (HNSCC). The functions of antioxidant enzyme systems and DNA-repair proteins are critical in the occurrence of HNSCC.
  • SOD2-Val16Ala, GPX1-Pro198Leu, and DNA-repair XPD-Lys751Gln polymorphisms were analyzed in additive, dominant, recessive genetic models, individually and in an interaction model, in a case-control study.
  • These polymorphisms modify the risk individually but are significantly higher when functioning and evaluated together.
  • The antioxidant defense system and DNA repair against ROS-induced lesions are targets for HNSCC susceptibility.

Abstract: As oxidative stress is implicated in the pathogenesis of head and neck squamous cell cancer (HNSCC), the functions of antioxidant enzyme systems and DNA repair proteins are critical in the development of cancer. To investigate the role of genetic polymorphisms of the antioxidant superoxide dismutase 2 (SOD2) Val16Ala, glutathione peroxidase 1 (GPX1) Pro198Leu, and the DNA repair Xeroderma Pigmentosum Group D (XPD) Lys751Gln genes under exogenous risk factors, including smoking and alcohol consumption, in HNSCC carcinogenesis, we conducted a case-control study on 139 unrelated cases and 265 non-cancer controls. Polymorphisms were analyzed in additive, dominant and recessive genetic models, individually and in an interaction model. Carriers of the T allele of SOD2 were associated with an increased risk for HNSCC in the overall subgroups of males and smokers; similarly, the T allele of GPX1 was associated with elevated risk in the overall and smoker subgroup. A 12.47-fold increased risk was observed for the carriers of GPX1 TT, SOD2 CT and XPD CC genotypes for HNSCC. This is the first study presenting the potential roles of SOD2, GPX1 and XPD polymorphisms in interaction and under three genetic models in the development of HNSCC. The results suggest that these polymorphisms slightly modify the risk in HNSCC development individually but are significantly higher when they functioned and were evaluated together.


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Johnson DE, Burtness B, Leemans CR, Lui VWY, Bauman JE, Grandis JR. Head and neck squamous cell carcinoma. Nat Rev Dis Primers. 2020;6(1):92.

Lacko M, Oude Ophuis MB, Peters WH, Manni JJ. Genetic polymorphisms of smoking-related carcinogen detoxifying enzymes and head and neck cancer susceptibility. Anticancer Res. 2009;29(2):753-61.

Suzen HS, Guvenc G, Turanli M, Comert E, Duydu Y, Elhan A. The role of GSTM1 and GSTT1 polymorphisms in head and neck cancer risk. Oncol Res. 2007;16(9):423-9.

Okezie IA, Kyung-Sun K, Theeshan B, Mi-Kyung S, Irfan R. Oxidative Damage and Chronic Inflammation Induced by Smoking: Potential Antioxidant and Peripheral Biomarker Considerations. J Cancer Prev. 2005;10(3):149-58.

Dequanter D, Dok R, Nuyts S. Basal oxidative stress ratio of head and neck squamous cell carcinomas correlates with nodal metastatic spread in patients under therapy. Onco Targets Ther. 2017;10:259-63.

Milonski J, Zielinska-Blizniewska H, Olszewski J, Majsterek I, Mrowicka M. DNA damage and oxidant-antioxidant status in blood of patients with head and neck cancer. DNA Cell Biol. 2015;34(3):213-9.

Teimoori B, Moradi-Shahrebabak M, Razavi M, Rezaei M, Harati-Sadegh M, Salimi S. The effect of GPx-1 rs1050450 and MnSOD rs4880 polymorphisms on PE susceptibility: a case- control study. Mol Biol Rep. 2019;46(6):6099-104.

Zhang T, Zhang DM, Zhao D, Hou XM, Ma SC, Liu XJ. Lack of association between the XPD Lys751Gln polymorphism and colorectal cancer risk: a meta-analysis. Onco Targets Ther. 2014;7:1255-60.

Grasbon-Frodl EM, Kosel S, Riess O, Muller U, Mehraein P, Graeber MB. Analysis of mitochondrial targeting sequence and coding region polymorphisms of the manganese superoxide dismutase gene in German Parkinson disease patients. Biochem Biophys Res Commun. 1999;255(3):749-52.

Mitra AK, Singh N, Garg VK, Chaturvedi R, Sharma M, Rath SK. Statistically significant association of the single nucleotide polymorphism (SNP) rs13181 (ERCC2) with predisposition to Squamous Cell Carcinomas of the Head and Neck (SCCHN) and Breast cancer in the north Indian population. J Exp Clin Cancer Res. 2009;28:104.

Suzen HS, Gucyener E, Sakalli O, Uckun Z, Kose G, Ustel D, Duydu Y. CAT C-262T and GPX1 Pro198Leu polymorphisms in a Turkish population. Mol Biol Rep. 2010;37(1):87-92.

Valavanidis A, Vlachogianni T, Fiotakis K. Tobacco smoke: involvement of reactive oxygen species and stable free radicals in mechanisms of oxidative damage, carcinogenesis and synergistic effects with other respirable particles. Int J Environ Res Public Health. 2009;6(2):445-62.

Jethwa AR, Khariwala SS. Tobacco-related carcinogenesis in head and neck cancer. Cancer Metastasis Rev. 2017;36(3):411-23.

Jalal S, Earley JN, Turchi JJ. DNA repair: from genome maintenance to biomarker and therapeutic target. Clin Cancer Res. 2011;17(22):6973-84.

Wen M, Zhou B, Lin X, Chen Y, Song J, Li Y, Zacksenhaus E, Ben-David Y, Hao X. Associations Between XPD Lys751Gln Polymorphism and Leukemia: A Meta-Analysis. Front Genet. 2018;9:218.

Buch S, Zhu B, Davis AG, Odom D, Siegfried JM, Grandis JR, Romkes M. Association of polymorphisms in the cyclin D1 and XPD genes and susceptibility to cancers of the upper aero-digestive tract. Mol Carcinog. 2005;42(4):222-8.

Kumar A, Pant MC, Singh HS, Khandelwal S. Associated risk of XRCC1 and XPD cross talk and life style factors in progression of head and neck cancer in north Indian population. Mutat Res. 2012;729(1-2):24-34.

Lin H, Lin D, Zheng C. Association of XPD Lys751Gln polymorphism with head and neck cancer susceptibility: evidence from 11,443 subjects. Diagn Pathol. 2014;9:15.

Ji YB, Tae K, Lee YS, Lee SH, Kim KR, Park CW, Park BL, Shin HD. XPD Polymorphisms and Risk of Squamous Cell Carcinoma of the Head and Neck in a Korean Sample. Clin Exp Otorhinolaryngol. 2010;3(1):42-7.

Crawford A, Fassett RG, Geraghty DP, Kunde DA, Ball MJ, Robertson IK, Coombes JS. Relationships between single nucleotide polymorphisms of antioxidant enzymes and disease. Gene. 2012;501(2):89-103.

Yahya MJ, Ismail PB, Nordin NB, Akim ABM, Yusuf WSBM, Adam NLB, Zulkifli NF. CNDP1, NOS3, and MnSOD Polymorphisms as Risk Factors for Diabetic Nephropathy among Type 2 Diabetic Patients in Malaysia. J Nutr Metab. 2019:8736215.

Sutton A, Imbert A, Igoudjil A, Descatoire V, Cazanave S, Pessayre D, Degoul F. The manganese superoxide dismutase Ala16Val dimorphism modulates both mitochondrial import and mRNA stability. Pharmacogenet Genomics. 2005;15(5):311-9.

Liu Y, Zha L, Li B, Zhang L, Yu T, Li L. Correlation between superoxide dismutase 1 and 2 polymorphisms and susceptibility to oral squamous cell carcinoma. Exp Ther Med. 2014;7(1):171-8.

Ogunro PS, Bolarinde AA, Owa OO, Salawu AA, Oshodi AA. Antioxidant status and reproductive hormones in women during reproductive, perimenopausal and postmenopausal phase of life. Afr J Med Med Sci. 2014;43(1):49-57.

Vina J, Gambini J, Lopez-Grueso R, Abdelaziz KM, Jove M, Borras C. Females live longer than males: role of oxidative stress. Curr Pharm Des. 2011;17(36):3959-65.

Arsova-Sarafinovska Z, Matevska N, Eken A, Petrovski D, Banev S, Dzikova S, Georgiev V, Sikole A, Erdem O, Sayal A, Aydın A, Dimovski A. Glutathione peroxidase 1 (GPX1) genetic polymorphism, erythrocyte GPX activity, and prostate cancer risk. Int Urol Nephrol. 2009;41(1):63-70.

Hu YJ, Dolan ME, Bae R, Yee H, Roy M, Glickman R, Kiremidjian-Schumacher L, Diamon AM. Allelic loss at the GPx-1 locus in cancer of the head and neck. Biol Trace Elem Res. 2004;101(2):97-106.

Wu SH, Lee KW, Chen CH, Lin CC, Tseng YM, Ma H, Tsai SM, Tsai LY. Epistasis of oxidative stress-related enzyme genes on modulating the risks in oral cavity cancer. Clin Chim Acta. 2010;411(21-22):1705-10.

Ravn-Haren G, Olsen A, Tjonneland A, Dragsted LO, Nexo BA, Wallin H, Overvad K, Raaschou-Nielsen O, Vogel U. Associations between GPX1 Pro198Leu polymorphism, erythrocyte GPX activity, alcohol consumption and breast cancer risk in a prospective cohort study. Carcinogenesis. 2006;27(4):820-5.

Salimi S, Harati-Sadegh M, Eskandari M, Heidari Z. The effects of the genetic polymorphisms of antioxidant enzymes on susceptibility to papillary thyroid carcinoma. IUBMB Life. 2020;72(5):1045-53.

di Martino E, Hardie LJ, Wild CP, Gong YY, Olliver JR, Gough MD, Bird NC. The NAD(P)H:quinone oxidoreductase I C609T polymorphism modifies the risk of Barrett esophagus and esophageal adenocarcinoma. Genet Med. 2007;9(6):341-7.

Murphy SJ, Hughes AE, Patterson CC, Anderson LA, Watson RG, Johnston BT, Comber H, McGuigan J, Reynolds JV, Murray LJ. A population-based association study of SNPs of GSTP1, MnSOD, GPX2 and Barrett's esophagus and esophageal adenocarcinoma. Carcinogenesis. 2007;28(6):1323-8.

Visuvanathan S, Chong PP, Yap YY, Lim CC, Tan MK, Lye MS. Distribution and haplotype associations of XPD Lys751Gln, XRCC1 Arg280His and XRCC1 Arg399Gln polymorphisms with nasopharyngeal carcinoma in the Malaysian population. Asian Pac J Cancer Prev. 2014;15(6):2747-51.

Yuan H, Li H, Ma H, Niu Y, Wu Y, Zhang S, Hu Z, Shen H, Chen N. Genetic polymorphisms in key DNA repair genes and risk of head and neck cancer in a Chinese population. Exp Ther Med. 2012;3(4):719-24.

Jelonek K, Gdowicz-Klosok A, Pietrowska M, Borkowska M, Korfanty J, Rzeszowska-Wolny J, Widlak P. Association between single-nucleotide polymorphisms of selected genes involved in the response to DNA damage and risk of colon, head and neck, and breast cancers in a Polish population. J Appl Genet. 2010;51(3):343-52.

An J, Liu Z, Hu Z, Li G, Wang LE, Sturgis EM, El-Naggar AK, Spitz MR, Wei Q. Potentially functional single nucleotide polymorphisms in the core nucleotide excision repair genes and risk of squamous cell carcinoma of the head and neck. Cancer Epidemiol Biomarkers Prev. 2007;16(8):1633-8.

Rydzanicz M, Wierzbicka M, Gajecka M, Szyfter W, Szyfter K. The impact of genetic factors on the incidence of multiple primary tumors (MPT) of the head and neck. Cancer Lett. 2005;224(2):263-78.

Huang WY, Olshan AF, Schwartz SM, Berndt SI, Chen C, Llaca V, Chanock SJ, Fraumeni Jr JF, Hayes RB. Selected genetic polymorphisms in MGMT, XRCC1, XPD, and XRCC3 and risk of head and neck cancer: a pooled analysis. Cancer Epidemiol Biomarkers Prev. 2005;14(7):1747-53.

Sturgis EM, Zheng R, Li L, Castillo EJ, Eicher SA, Chen M, Strom SS, Spitz MR, Wei Q. XPD/ERCC2 polymorphisms and risk of head and neck cancer: a case-control analysis. Carcinogenesis. 2000;21(12):2219-23.




How to Cite

Köse G, Demirbugen Oz M, Cömert E, Süzen HS. Association between superoxide dismutase 2, glutathione peroxidase 1, xeroderma pigmentosum group d gene variations, and head and neck squamous cell cancer susceptibility. Arch Biol Sci [Internet]. 2022Jun.27 [cited 2024Jul.20];74(2):181-9. Available from: