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Clinical Research

Genetic factors regulating inflammation and DNA methylation associated with prostate cancer

Prostate Cancer and Prostatic Diseases volume 16, pages 56–61 (2013)Cite this article

Subjects

Abstract

Background:

Prostate cancer (PCa) displays a strong familiarity component and genetic factors; genes regulating inflammation may have a pivotal role in the disease. Epigenetic changes control chromosomal integrity, gene functions and ultimately carcinogenesis. The enzyme glycine-N-methyltransferase (GNMT) contributes to S-adenosylmethionine level regulation and, by affecting DNA methylation, influences gene expression. The genotype and allele distribution of single-nucleotide polymorphisms (SNPs) in the promoter regions of vascular endothelial growth factor (VEGF), interleukin (IL)-10, IL-1β, alpha-1-antichymotrypsin (ACT) and GNMT genes, the level of global DNA methylation and the influence of GNMT SNP upon DNA methylation in a PCa case–control study have been investigated.

Methods:

SNPs of VEGF (rs699947), ACT (rs1884082), IL-1β (rs16944), IL-10 (rs1800896) and GNMT (rs9462856) genes were assessed by PCR or by real-time PCR methods. DNA methylation was assessed by an ELISA assay.

Results:

Frequencies of the VEGF AA genotype, the IL-10 A allele and GNMT T allele were higher in PCa. The concomitant presence of the AA genotype of VEGF, the A allele of IL-10 and T allele of GNMT increased the risk of PCa. Total DNA methylation was decreased in PCa; control GNMT T carriers (T+) showed the highest level of DNA methylation.

Conclusions:

SNPs in VEGF, IL-10 and GNMT genes might have a synergistic role in the development of PCa. The GNMT T allele may influence PCa risk by affecting DNA methylation and prostate gene expression. Our observations might help implement the screening of unaffected subjects with an increased susceptibility to develop PCa.

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References

  1. Quinn M, Babb P . Patterns and trends in prostate cancer incidence, survival, prevalence and mortality. Part I: international comparisons. BJU Int 2002; 90: 162–173.

    Article  CAS  Google Scholar 

  2. Holman CD, Wisniewski ZS, Semmens JB, Rouse IL, Bass AJ . Mortality and prostate cancer risk in 19 598 men after surgery for benign prostatic hyperplasia. BJU Int 1999; 84: 37–42.

    Article  CAS  Google Scholar 

  3. Schröder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 2009; 360: 1320–1328.

    Article  Google Scholar 

  4. Koul HK, Kumar B, Koul S, Deb AA, Hwa JS, Maroni P et al. The role of inflammation and infection in prostate cancer: importance in prevention, diagnosis and treatment. Drugs Today (Barc) 2010; 46: 929–943.

    Article  CAS  Google Scholar 

  5. Mantovani A, Allavena P, Sica A, Balkwill F . Cancer-related inflammation. Nature 2008; 454: 436–444.

    Article  CAS  Google Scholar 

  6. De Nunzio C, Kramer G, Marberger M, Montironi R, Nelson W, Schröder F et al. The controversial relationship between benign prostatic hyperplasia and prostate cancer: the role of inflammation. Eur Urol 2011; 60: 106–117.

    Article  CAS  Google Scholar 

  7. Omabe M, Ezeani M . Infection, inflammation and prostate carcinogenesis. Infect Genet Evol 2011; 11: 1195–1198.

    Article  Google Scholar 

  8. McCarron SL, Edwards S, Evans PR, Gibbs R, Dearnaley DP, Dowe A et al. Influence of cytokine gene polymorphisms on the development of prostate cancer. Cancer Res 2002; 62: 3369–3372.

    CAS  PubMed  Google Scholar 

  9. Michaud DS, Daugherty SE, Berndt SI, Platz EA, Yeager M, Crawford ED et al. Genetic polymorphisms of interleukin-1B (IL-1B), IL-6, IL-8, and IL-10 and risk of prostate cancer. Cancer Res 2006; 66: 4525–4530.

    Article  CAS  Google Scholar 

  10. Shao N, Xu B, Mi YY, Hua LX . IL-10 polymorphisms and prostate cancer risk: a meta-analysis. Prostate Cancer Prostatic Dis 2011; 14: 129–135.

    Article  CAS  Google Scholar 

  11. Sfar S, Saad H, Mosbah F, Chouchane L . Combined effects of the angiogenic genes polymorphisms on prostate cancer susceptibility and aggressiveness. Mol Biol Rep 2009; 36: 37–45.

    Article  CAS  Google Scholar 

  12. Jain L, Vargo CA, Danesi R, Sissung TM, Price DK, Venzon D et al. The role of vascular endothelial growth factor SNPs as predictive and prognostic markers for major solid tumors. Mol Cancer Ther 2009; 8: 2496–2508.

    Article  CAS  Google Scholar 

  13. VanCleave TT, Moore JH, Benford ML, Brock GN, Kalbfleisch T, Baumgartner RN et al. Interaction among variant vascular endothelial growth factor (VEGF) and its receptor in relation to prostate cancer risk. Prostate 2010; 70: 341–352.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Langsenlehner T, Langsenlehner U, Renner W, Krippl P, Mayer R, Wascher TC et al. Single nucleotide polymorphisms and haplotypes in the gene for vascular endothelial growth factor and risk of prostate cancer. Eur J Cancer 2008; 44: 1572–1576.

    Article  CAS  Google Scholar 

  15. Jacobs EJ, Hsing AW, Bain EB, Stevens VL, Wang Y, Chen J et al. Polymorphisms in angiogenesis-related genes and prostate cancer. Cancer Epidemiol Biomarkers Prev 2008; 17: 972–977.

    Article  CAS  Google Scholar 

  16. Solinas G, Germano G, Mantovani A, Allavena P . Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol 2009; 86: 1065–1073.

    Article  CAS  Google Scholar 

  17. Niwa T, Ushijima T . Induction of epigenetic alterations by chronic inflammation and its significance on carcinogenesis. Adv Genet 2010; 71: 41–56.

    Article  CAS  Google Scholar 

  18. Kelavkar UP, Harya NS, Hutzley J, Bacich DJ, Monzon FA, Chandran U et al. DNA methylation paradigm shift: 15-lipoxygenase-1 upregulation in prostatic intraepithelial neoplasia and prostate cancer by atypical promoter hypermethylation. Prostaglandins Other Lipid Mediat 2007; 82: 185–197.

    Article  CAS  Google Scholar 

  19. Pierconti F, Martini M, Pinto F, Cenci T, Capodimonti S, Calarco A et al. Epigenetic silencing of SOCS3 identifies a subset of prostate cancer with an aggressive behavior. Prostate 2011; 71: 318–325.

    Article  CAS  Google Scholar 

  20. Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature 2009; 457: 910–914.

    Article  CAS  Google Scholar 

  21. Luka Z, Mudd SH, Wagner C . Glycine N-methyltransferase and regulation of S-adenosylmethionine levels. J Biol Chem 2009; 284: 22507–22511.

    Article  CAS  Google Scholar 

  22. Huang YC, Lee CM, Chen M, Chung MY, Chang YH, Huang WJ et al. Haplotypes, loss of heterozygosity, and expression levels of glycine N-methyltransferase in prostate cancer. Clin Cancer Res 2007; 13: 1412–1420.

    Article  CAS  Google Scholar 

  23. Hatziapostolou M, Iliopoulos D . Epigenetic aberrations during oncogenesis. Cell Mol Life Sci 2011; 68: 1681–1702.

    Article  CAS  Google Scholar 

  24. Partin AW, Brawer MK, Bartsch G, Horninger W, Taneja SS, Lepor H et al. Complexed prostate specific antigen improves specificity for prostate cancer detection: results of a prospective multicenter clinical trial. J Urol 2003; 170: 1787–1791.

    Article  Google Scholar 

  25. Licastro F, Chiappelli M, Porcellini E, Campo G, Buscema M, Grossi E et al. Gene-gene and gene - clinical factors interaction in acute myocardial infarction: a new detailed risk chart. Curr Pharm Des 2010; 16: 783–788.

    Article  CAS  Google Scholar 

  26. Epstein JI, Allsbrook Jr WC, Amin MB, Egevad LL . The 2005 International Society of Urological Pathology (ISUP) consensus conference on gleason grading of prostatic carcinoma. Am J Surg Pathol 2005; 29: 228–1242.

    Google Scholar 

  27. Ravaglia G, Forti P, Maioli F, Chiappelli M, Montesi F, Tumini E et al. Blood inflammatory markers and risk of dementia: The Conselice Study of brain aging. Neurobiol Aging 2007; 28: 1810–1820.

    Article  CAS  Google Scholar 

  28. Licastro F, Chiappelli M, Grimaldi LM, Morgan K, Kalsheker N, Calabrese E et al. A new promoter polymorphism in the alpha-1-antichymotrypsin gene is a disease modifier of Alzheimer's disease. Neurobiol Aging 2005; 26: 449–453.

    Article  CAS  Google Scholar 

  29. Chiappelli M, Borroni B, Archetti S, Calabrese E, Corsi MM, Franceschi M et al. VEGF gene and phenotype relation with Alzheimer's disease and mild cognitive impairment. Rejuvenation Res 2006; 9: 485–493.

    Article  CAS  Google Scholar 

  30. Benecchi L, Pieri AM, Pastizzaro CD, Potenzoni M . Evaluation of prostate specific antigen acceleration for prostate cancer diagnosis. J Urol 2011; 185: 821–826.

    Article  CAS  Google Scholar 

  31. Rajarubendra N, Lawrentschuk N, Bolton DM, Klotz L, Davis ID . Prostate cancer immunology - an update for urologists. BJU Int 2011; 107: 1046–1051.

    Article  CAS  Google Scholar 

  32. Vasto S, Carruba G, Candore G, Italiano E, Di Bona D, Caruso C . Inflammation and prostate cancer. Future Oncol 2008; 4: 637–645.

    Article  Google Scholar 

  33. McCarron SL, Edwards S, Evans PR, Gibbs R, Dearnaley DP, Dowe A et al. Influence of cytokine gene polymorphisms on the development of prostate cancer. Cancer Res 2002; 62: 3369–3372.

    CAS  PubMed  Google Scholar 

  34. Wang MH, Helzlsouer KJ, Smith MW, Hoffman-Bolton JA, Clipp SL, Grinberg V et al. Association of IL10 and other immune response- and obesity-related genes with prostate cancer in CLUE II. Prostate 2009; 69: 874–885.

    Article  CAS  Google Scholar 

  35. Michaud DS, Daugherty SE, Berndt SI, Platz EA, Yeager M, Crawford ED et al. Genetic polymorphisms of interleukin-1B (IL-1B), IL-6, IL-8, and IL-10 and risk of prostate cancer. Cancer Res 2006; 66: 4525–4530.

    Article  CAS  Google Scholar 

  36. Mateo I, Llorca J, Infante J, Rodríguez-Rodríguez E, Sánchez-Quintana C, Sánchez-Juan P et al. Case-control study of vascular endothelial growth factor (VEGF) genetic variability in Alzheimer's disease. Neurosci Lett 2006; 401: 171–173.

    Article  CAS  Google Scholar 

  37. Crawley E, Kay R, Sillibourne J, Patel P, Hutchinson I, Woo P . Polymorphic haplotypes of the interleukin-10 5′ flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis. Arthritis Rheum 1999; 42: 1101–1108.

    Article  CAS  Google Scholar 

  38. Esteller M . Epigenetics in cancer. N Engl J Med 2008; 358: 1148–1159.

    Article  CAS  Google Scholar 

  39. Kim SJ, Kelly WK, Fu A, Haines K, Hoffman A, Zheng T et al. Genome-wide methylation analysis identifies involvement of TNF-α mediated cancer pathways in prostate cancer. Cancer Lett 2011; 302: 47–53.

    Article  CAS  Google Scholar 

  40. Yang B, Sun H, Lin W, Hou W, Li H, Zhang L et al. Evaluation of global DNA hypomethylation in human prostate cancer and prostatic intraepithelial neoplasm tissues by immunohistochemistry. Urol Oncol 2011 (e-pub ahead of print 23 June 2011).

  41. Aps JK, Van den MK, Delanghe JR, Martens LC . Flow cytometry as a new method to quantify the cellular content of human saliva and its relation to gingivitis. Clin Chim Acta 2002; 321: 35–41.

    Article  CAS  Google Scholar 

  42. Zhou Y, Li S, Zhou J, Wang L, Song X, Lu X et al. DNA profiling in blood, buccal swabs and hair follicles of patients after allogeneic peripheral blood stem cells transplantation. Leg Med 2011; 13: 47–51.

    Article  CAS  Google Scholar 

  43. Grolleau-Julius A, Ray D, Yung RL . The role of epigenetics in aging and autoimmunity. Clin Rev Allergy Immunol 2010; 39: 42–50.

    Article  CAS  Google Scholar 

  44. Wilson VL, Smith RA, Ma S, Cutler RG . Genomic 5-methyldeoxycytidine decreases with age. J Biol Chem 1987; 262: 9948–9951.

    CAS  PubMed  Google Scholar 

  45. Jaenisch R, Bird A . Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 2003; 33 (Suppl): 245–254.

    Article  CAS  Google Scholar 

  46. McArdle PA, Qayyum T, McMillan DC . Systemic inflammatory response and survival in patients with localised prostate cancer: 10-year follow-up. Urol Int 2010; 85: 482.

    Article  Google Scholar 

  47. Lin HC, Liu CC, Kang WY, Yu CC, Wu TT, Wang JS et al. Influence of cytokine gene polymorphisms on prostate-specific antigen recurrence in prostate cancer after radical prostatectomy. Urol Int 2009; 83: 463–470.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Dr Stefania Bitonte for technical assistance. We thank Dr Christine M Betts for kindly grammatical editing the manuscript.

Funding: Research partially supported by Italian Pallotti Grants and Cassa di Risparmio Foundation in Bologna.

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Authors and Affiliations

  1. Department of Experimental Pathology, School of Medicine, University of Bologna, Bologna, Italy

    M Ianni, E Porcellini, I Carbone & F Licastro

  2. Department of Urology, Fidenza Hospital, Parma, Italy

    M Potenzoni, A M Pieri, C D Pastizzaro & L Benecchi

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  1. M Ianni
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Correspondence to F Licastro.

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Ianni, M., Porcellini, E., Carbone, I. et al. Genetic factors regulating inflammation and DNA methylation associated with prostate cancer. Prostate Cancer Prostatic Dis 16, 56–61 (2013). https://doi.org/10.1038/pcan.2012.30

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