Cancer Causes & Control

, Volume 30, Issue 12, pp 1365–1375 | Cite as

Polymorphisms in oxidative stress pathway genes and prostate cancer risk

  • Zhenzhen Zhang
  • Duo Jiang
  • Chi Wang
  • Mark Garzotto
  • Ryan Kopp
  • Beth Wilmot
  • Philippe Thuillier
  • Andy Dang
  • Amy Palma
  • Paige E. Farris
  • Jackilen ShannonEmail author
Original Paper



Age-related factors including oxidative stress play an important role in prostate carcinogenesis. We hypothesize that germline single-nucleotide polymorphisms (SNPs) in oxidative stress pathway are associated with prostate cancer (PCa) risk. In this study, we aim to examine which of these SNPs is associated with PCa.


Participants included in this analyses came from the “Genetic Susceptibility, Environment and Prostate Cancer Risk Study” conducted at the Veterans Affairs Portland Health Care System. After applying exclusion criteria, 231 PCa cases and 382 prostate biopsy-negative controls who had genotyping data on twenty-two single-nucleotide polymorphisms (SNPs) in six genes (MAPK14, NRF2, CAT, GPX1, GSTP1, SOD2, and XDH) associated with oxidative stress pathway were included in the analyses. The genotyping of SNPs was conducted by the Illumina BeadXpress VeraCode platform. We investigated these SNPs in relation to overall and aggressive PCa risk using logistic regression models controlling for relevant covariates.


One SNP in the MAPK14 (rs851023) was significantly associated with incident PCa risk. Compared to men carrying two copies of allele A, the presence of one or two copies of the G allele was associated with decreased risk of PCa [OR (95% CI) 0.19 (0.06–0.51)]. There was no statistically significant association between other SNPs in the NRF2, CAT, GPX1, GSTP1, SOD2, and XDH genes and PCa risk.


The MAPK14 gene SNP rs851023 was associated with PCa and aggressive PCa risk after multiple comparison adjustment. Further studies in other populations or functional studies are needed to validate the finding.


Prostate cancer SNP Oxidative stress genes 



Analysis of variance


Bayesian information criterion


Body mass index

95% CI

95% confidence interval


Genetic Susceptibility, Environment and Prostate Cancer Risk


National Cancer Institute


Oregon Health & Science University


Prostatic intraepithelial neoplasia


Prostate-specific antigen


Prostate-specific antigen density


Standard Error


VA Portland Health Care System



We greatly appreciate all the veterans and their family members who contributed their time and effort to join the Genetic Susceptibility, Environment and Prostate Cancer Risk (GSEP) study. Gratitude is expressed to our large list of collaborators and providers of tools to make this project successful; use of Case Western University’s Genetic Risk Easy Assessment Tool (GREAT) was provided by Dr. Louise Acheson; Oregon Clinical and Translational Research Institute’s (OCTRI) Biomedical Informatics Program was instrumental in tying all of our electronic questionnaires together into one HIPAA-compliant portal; VAPHCS phlebotomy staff helped us collect research specimens and allowing laboratory space for saliva collection; OCTRI’s Clinical and Translational Research Center (CTRC) Core Laboratory processed, analyzed, and stored subjects’ biological specimens; genotyping was conducted by iGenix in Seattle, Washington. Dr. Shannon’s current and previous research coordinators spent large amounts of time with our numerous in-person and over-the-phone participants in support of this study, assuring quality data collection as well as close, personal attention to our nation’s veterans and their family members choosing to join this study. We are also grateful to VAPHCS Urology Nurses and Operative Care staff for supporting coordinators’ recruitment of research participants.


Research reported in this publication was supported by the Veterans Affairs’ Biomedical Laboratory Research and Development Merit Review Award, VA Portland Health Care System (VAPHCS), and by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR000128. Clinical Trial Registration’s identifier: NCT01013129. This work was directly supported by the Veterans Affairs’ Biomedical Laboratory Research and Development Merit Review Award, and Oregon Health & Science University/Oregon State University Cancer Prevention and Control Initiative (2017-Horizon-Knight-11).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

10552_2019_1242_MOESM1_ESM.docx (31 kb)
Supplementary material 1 (DOCX 30 kb)


  1. 1.
    Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. CA Cancer J Clin 66:7–30CrossRefGoogle Scholar
  2. 2.
    Udensi UK, Tchounwou PB (2016) Oxidative stress in prostate hyperplasia and carcinogenesis. J Exp Clin Cancer Res 35:139CrossRefGoogle Scholar
  3. 3.
    Oh B, Figtree G, Costa D et al (2016) Oxidative stress in prostate cancer patients: a systematic review of case control studies. Prostate Int 4:71–87CrossRefGoogle Scholar
  4. 4.
    Kregel KC, Zhang HJ (2007) An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations. Am J Physiol Regul Integr Comp Physiol 292:R18–R36CrossRefGoogle Scholar
  5. 5.
    Roumeguere T, Sfeir J, El Rassy E et al (2017) Oxidative stress and prostatic diseases. Mol Clin Oncol 7:723–728CrossRefGoogle Scholar
  6. 6.
    Arsova-Sarafinovska Z, Eken A, Matevska N et al (2009) Increased oxidative/nitrosative stress and decreased antioxidant enzyme activities in prostate cancer. Clin Biochem 42:1228–1235CrossRefGoogle Scholar
  7. 7.
    Desideri E, Vegliante R, Cardaci S, Nepravishta R, Paci M, Ciriolo MR (2014) MAPK14/p38alpha-dependent modulation of glucose metabolism affects ROS levels and autophagy during starvation. Autophagy 10:1652–1665CrossRefGoogle Scholar
  8. 8.
    Abrigo J, Elorza AA, Riedel CA et al (2018) Role of oxidative stress as key regulator of muscle wasting during cachexia. Oxid Med Cell Longev 2018:2063179CrossRefGoogle Scholar
  9. 9.
    Eeles RA, Kote-Jarai Z, Giles GG et al (2008) Multiple newly identified loci associated with prostate cancer susceptibility. Nat Genet 40:316–321CrossRefGoogle Scholar
  10. 10.
    Thomas G, Jacobs KB, Yeager M et al (2008) Multiple loci identified in a genome-wide association study of prostate cancer. Nat Genet 40:310–315CrossRefGoogle Scholar
  11. 11.
    Geybels MS, van den Brandt PA, van Schooten FJ, Verhage BA (2015) Oxidative stress-related genetic variants, pro- and antioxidant intake and status, and advanced prostate cancer risk. Cancer Epidemiol Biomark Prev 24:178–186CrossRefGoogle Scholar
  12. 12.
    Hu J, Feng F, Zhu S et al (2015) Catalase C-262T polymorphism and risk of prostate cancer: evidence from meta-analysis. Gene 558:265–270CrossRefGoogle Scholar
  13. 13.
    Ntais C, Polycarpou A, Ioannidis JP (2005) Association of GSTM1, GSTT1, and GSTP1 gene polymorphisms with the risk of prostate cancer: a meta-analysis. Cancer Epidemiol Biomark Prev 14:176–181Google Scholar
  14. 14.
    Martignano F, Gurioli G, Salvi S et al (2016) GSTP1 methylation and protein expression in prostate cancer: diagnostic implications. Dis Mark 2016:4358292Google Scholar
  15. 15.
    Men T, Zhang X, Yang J et al (2014) The rs1050450 C > T polymorphism of GPX1 is associated with the risk of bladder but not prostate cancer: evidence from a meta-analysis. Tumour Biol 35:269–275CrossRefGoogle Scholar
  16. 16.
    Geybels MS, van den Brandt PA, Schouten LJ et al (2014) Selenoprotein gene variants, toenail selenium levels, and risk for advanced prostate cancer. J Natl Cancer Inst 106:dju003CrossRefGoogle Scholar
  17. 17.
    Kang SW (2015) Superoxide dismutase 2 gene and cancer risk: evidence from an updated meta-analysis. Int J Clin Exp Med 8:14647–14655PubMedPubMedCentralGoogle Scholar
  18. 18.
    de Jong K, Vonk JM, Imboden M et al (2017) Genes and pathways underlying susceptibility to impaired lung function in the context of environmental tobacco smoke exposure. Respir Res 18:142CrossRefGoogle Scholar
  19. 19.
    Son Y, Cheong YK, Kim NH, Chung HT, Kang DG, Pae HO (2011) Mitogen-activated protein kinases and reactive oxygen species: how can ROS activate MAPK pathways? J Signal Transduct 2011:792639CrossRefGoogle Scholar
  20. 20.
    Mulholland DJ, Kobayashi N, Ruscetti M et al (2012) Pten loss and RAS/MAPK activation cooperate to promote EMT and metastasis initiated from prostate cancer stem/progenitor cells. Cancer Res 72:1878–1889CrossRefGoogle Scholar
  21. 21.
    Rodriguez-Berriguete G, Fraile B, Martinez-Onsurbe P, Olmedilla G, Paniagua R, Royuela M (2012) MAP kinases and prostate cancer. J Signal Transduct 2012:169170CrossRefGoogle Scholar
  22. 22.
    Jiang Y, Chen C, Li Z et al (1996) Characterization of the structure and function of a new mitogen-activated protein kinase (p38beta). J Biol Chem 271:17920–17926CrossRefGoogle Scholar
  23. 23.
    Huang X, Chen S, Xu L et al (2005) Genistein inhibits p38 map kinase activation, matrix metalloproteinase type 2, and cell invasion in human prostate epithelial cells. Cancer Res 65:3470–3478CrossRefGoogle Scholar
  24. 24.
    Ricote M, Garcia-Tunon I, Bethencourt F et al (2006) The p38 transduction pathway in prostatic neoplasia. J Pathol 208:401–407CrossRefGoogle Scholar
  25. 25.
    Zheng Q, Ye J, Wu H, Yu Q, Cao J (2014) Association between mitogen-activated protein kinase kinase kinase 1 polymorphisms and breast cancer susceptibility: a meta-analysis of 20 case-control studies. PLoS ONE 9:e90771CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Zhenzhen Zhang
    • 1
  • Duo Jiang
    • 2
  • Chi Wang
    • 3
    • 4
  • Mark Garzotto
    • 5
    • 6
  • Ryan Kopp
    • 5
    • 6
  • Beth Wilmot
    • 7
    • 8
  • Philippe Thuillier
    • 9
    • 10
  • Andy Dang
    • 2
  • Amy Palma
    • 10
  • Paige E. Farris
    • 10
  • Jackilen Shannon
    • 10
    Email author
  1. 1.Division of Hematology and OncologyOregon Health & Science UniversityPortlandUSA
  2. 2.Department of StatisticsOregon State UniversityCorvallisUSA
  3. 3.Department of BiostatisticsUniversity of KentuckyLexingtonUSA
  4. 4.Markey Cancer CenterUniversity of KentuckyLexingtonUSA
  5. 5.Urology SectionVeterans Affairs Portland Health Care SystemPortlandUSA
  6. 6.Department of UrologyOregon Health & Science UniversityPortlandUSA
  7. 7.Oregon Clinical and Translational Research InstituteOregon Health & Science UniversityPortlandUSA
  8. 8.Department of Medical and Clinical InformaticsOregon Health & Science UniversityPortlandUSA
  9. 9.Department of DermatologyOregon Health & Science UniversityPortlandUSA
  10. 10.OHSU-PSU School of Public HealthOregon Health & Science UniversityPortlandUSA

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