Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Clinical Research

Association between metformin medication, genetic variation and prostate cancer risk

Prostate Cancer and Prostatic Diseases volume 24, pages 96–105 (2021)Cite this article

Subjects

Abstract

Background

The relationship between metformin use and prostate cancer risk remains controversial. Genetic variation in metformin metabolism pathways appears to modify metformin glycemic control and the protective association with some cancers. However, no studies to date have examined this pharmacogenetic interaction and prostate cancer chemoprevention.

Methods

Clinical data and germline DNA were collected from our prostate biopsy database between 1996 and 2014. In addition to a genome-wide association study (GWAS), 27 single nucleotide polymorphisms (SNPs) implicated in metformin metabolism were included on a custom SNP array. Associations between metformin use and risk of high-grade (Grade Group ≥ 2) and overall prostate cancer were explored using a case-control design. Interaction between the candidate/GWAS SNPs and the metformin-cancer association was explored using a case-only design.

Results

Among 3481 men, 132 (4%) were taking metformin at diagnosis. Metformin users were older, more likely non-Caucasian, and had higher body mass index, Gleason score, and number of positive cores. Overall, 2061 (59%) were diagnosed with prostate cancer, of which 922 (45%) were high-grade. After adjusting for baseline characteristics, metformin use was associated with higher risk of high-grade prostate cancer (OR = 1.76, 95% CI 1.1–2.9, p = 0.02) and overall prostate cancer (OR = 1.77, 95% CI 1.1–2.9, p = 0.03). None of the 27 candidate SNPs in metformin metabolic pathways had significant interaction with the metformin-cancer association. Among the GWAS SNPs, one SNP (rs149137006) had genome-wide significant interaction with metformin for high-grade prostate cancer, and another, rs115071742, for overall prostate cancer. They were intronic and intergenic SNPs, respectively, with largely uncharacterized roles in prostate cancer chemoprevention.

Conclusions

In our cohort, metformin use was associated with increased risk of being diagnosed with prostate cancer. While SNPs involved in metformin metabolism did not have modifying effects on the association with disease risk, one intronic and one intergenic SNP from the GWAS study did, and these require further study.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Manhattan plot of the high-grade prostate cancer case only and all prostate cancer case-only analysis.

Similar content being viewed by others

References

  1. American Cancer Society. Key statistics for prostate cancer. Atlanta, Georgia, United: American Cancer Society; 2019.

    Google Scholar 

  2. Carlson LE, Angen M, Cullum J, Goodey E, Koopmans J, Lamont L, et al. High levels of untreated distress and fatigue in cancer patients. Br J Cancer. 2004;90:2297–304.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Balderson N, Towell T. The prevalence and predictors of psychological distress in men with prostate cancer who are seeking support. Br J Health Psychol. 2003;8(Pt 2):125–34.

    PubMed  Google Scholar 

  4. Resnick MJ, Koyama T, Fan KH, Albertsen PC, Goodman M, Hamilton AS, et al. Long-term functional outcomes after treatment for localized prostate cancer. N. Engl J Med. 2013;368:436–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Saenz A, Fernandez-Esteban I, Mataix A, Ausejo M, Roque M, Moher D. Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2005;3:CD002966.

    Google Scholar 

  6. Ben Sahra I, Laurent K, Giuliano S, Larbret F, Ponzio G, Gounon P, et al. Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells. Cancer Res. 2010;70:2465–75.

    PubMed  Google Scholar 

  7. Ben Sahra I, Laurent K, Loubat A, Giorgetti-Peraldi S, Colosetti P, Auberger P, et al. The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene. 2008;27:3576–86.

    PubMed  Google Scholar 

  8. Tsutsumi Y, Nomiyama T, Kawanami T, Hamaguchi Y, Terawaki Y, Tanaka T, et al. Combined treatment with Exendin-4 and metformin attenuates prostate cancer growth. PLoS ONE. 2015;10:e0139709.

    PubMed  PubMed Central  Google Scholar 

  9. Zaidi S, Gandhi J, Joshi G, Smith NL, Khan SA. The anticancer potential of metformin on prostate cancer. Prostate Cancer Prostatic Dis. 2019;3:351–61.

    Google Scholar 

  10. Murtola TJ, Tammela TL, Lahtela J, Auvinen A. Antidiabetic medication and prostate cancer risk: a population-based case-control study. Am J Epidemiol. 2008;168:925–31.

    PubMed  Google Scholar 

  11. Wright JL, Stanford JL. Metformin use and prostate cancer in Caucasian men: results from a population-based case-control study. Cancer Causes Control. 2009;20:1617–22.

    PubMed  PubMed Central  Google Scholar 

  12. Ruiter R, Visser LE, van Herk-Sukel MP, Coebergh JW, Haak HR, Geelhoed-Duijvestijn PH, et al. Lower risk of cancer in patients on metformin in comparison with those on sulfonylurea derivatives: results from a large population-based follow-up study. Diabetes Care. 2012;35:119–24.

    CAS  PubMed  Google Scholar 

  13. Preston MA, Riis AH, Ehrenstein V, Breau RH, Batista JL, Olumi AF, et al. Metformin use and prostate cancer risk. Eur Urol. 2014;66:1012–20.

    CAS  PubMed  Google Scholar 

  14. Margel D, Urbach D, Lipscombe LL, Bell CM, Kulkarni G, Austin PC, et al. Association between metformin use and risk of prostate cancer and its grade. J Natl Cancer Inst. 2013;105:1123–31.

    PubMed  Google Scholar 

  15. Azoulay L, Dell’Aniello S, Gagnon B, Pollak M, Suissa S. Metformin and the incidence of prostate cancer in patients with type 2 diabetes. Cancer Epidemiol Biomark Prev. 2011;20:337–44.

    CAS  Google Scholar 

  16. Feng T, Sun X, Howard LE, Vidal AC, Gaines AR, Moreira DM, et al. Metformin use and risk of prostate cancer: results from the REDUCE study. Cancer Prev Res. 2015;8:1055–60.

    CAS  Google Scholar 

  17. Wang DS, Jonker JW, Kato Y, Kusuhara H, Schinkel AH, Sugiyama Y. Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J Pharmacol Exp Ther. 2002;302:510–5.

    CAS  PubMed  Google Scholar 

  18. Shu Y, Brown C, Castro RA, Shi RJ, Lin ET, Owen RP, et al. Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin Pharm Ther. 2008;83:273–80.

    CAS  Google Scholar 

  19. Zhou K, Donnelly LA, Kimber CH, Donnan PT, Doney AS, Leese G, et al. Reduced-function SLC22A1 polymorphisms encoding organic cation transporter 1 and glycemic response to metformin: a GoDARTS study. Diabetes. 2009;58:1434–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Becker ML, Visser LE, van Schaik RH, Hofman A, Uitterlinden AG, Stricker BH. Genetic variation in the multidrug and toxin extrusion 1 transporter protein influences the glucose-lowering effect of metformin in patients with diabetes: a preliminary study. Diabetes. 2009;58:745–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Stocker SL, Morrissey KM, Yee SW, Castro RA, Xu L, Dahlin A, et al. The effect of novel promoter variants in MATE1 and MATE2 on the pharmacokinetics and pharmacodynamics of metformin. Clin Pharmacol Ther. 2013;93:186–94.

    CAS  PubMed  Google Scholar 

  22. Choi JH, Yee SW, Ramirez AH, Morrissey KM, Jang GH, Joski PJ, et al. A common 5’-UTR variant in MATE2-K is associated with poor response to metformin. Clin Pharmacol Ther. 2011;90:674–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Dong M, Gong ZC, Dai XP, Lei GH, Lu HB, Fan L, et al. Serine racemase rs391300 G/A polymorphism influences the therapeutic efficacy of metformin in Chinese patients with diabetes mellitus type 2. Clin Exp Pharmacol Physiol. 2011;38:824–9.

    CAS  PubMed  Google Scholar 

  24. GoDarts, Group UDPS, Wellcome Trust Case Control Consortium, Zhou K, Bellenguez C, Spencer CC, et al. Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nat Genet. 2011;43:117–20.

    Google Scholar 

  25. Pacanowski MA, Hopley CW, Aquilante CL. Interindividual variability in oral antidiabetic drug disposition and response: the role of drug transporter polymorphisms. Expert Opin Drug Metab Toxicol. 2008;4:529–44.

    CAS  PubMed  Google Scholar 

  26. Clarke GM, Morris AP. A comparison of sample size and power in case-only association studies of gene-environment interaction. Am J Epidemiol. 2010;171:498–505.

    PubMed  PubMed Central  Google Scholar 

  27. Kote-Jarai Z, Olama AA, Giles GG, Severi G, Schleutker J, Weischer M, et al. Seven prostate cancer susceptibility loci identified by a multi-stage genome-wide association study. Nat Genet. 2011;43:785–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Kote-Jarai Z, Easton DF, Stanford JL, Ostrander EA, Schleutker J, Ingles SA, et al. Multiple novel prostate cancer predisposition loci confirmed by an international study: the PRACTICAL Consortium. Cancer Epidemiol Biomark Prev. 2008;17:2052–61.

    CAS  Google Scholar 

  29. Akinyeke T, Matsumura S, Wang X, Wu Y, Schalfer ED, Saxena A, et al. Metformin targets c-MYC oncogene to prevent prostate cancer. Carcinogenesis. 2013;34:2823–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Dowling RJ, Goodwin PJ, Stambolic V. Understanding the benefit of metformin use in cancer treatment. BMC Med. 2011;9:33.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Cusi K, Consoli A, DeFronzo RA. Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1996;81:4059–67.

    CAS  PubMed  Google Scholar 

  32. Frasca F, Pandini G, Sciacca L, Pezzino V, Squatrito S, Belfiore A, et al. The role of insulin receptors and IGF-I receptors in cancer and other diseases. Arch Physiol Biochem. 2008;114:23–37.

    CAS  PubMed  Google Scholar 

  33. Lima GA, Correa LL, Gabrich R, Miranda LC, Gadelha MR. IGF-I, insulin and prostate cancer. Arq Bras Endocrinol Metab. 2009;53:969–75.

    Google Scholar 

  34. Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003;115:577–90.

    CAS  PubMed  Google Scholar 

  35. Markman B, Atzori F, Perez-Garcia J, Tabernero J, Baselga J. Status of PI3K inhibition and biomarker development in cancer therapeutics. Ann Oncol. 2010;21:683–91.

    CAS  PubMed  Google Scholar 

  36. Sarker D, Reid AH, Yap TA, de Bono JS. Targeting the PI3K/AKT pathway for the treatment of prostate cancer. Clin Cancer Res. 2009;15:4799–805.

    CAS  PubMed  Google Scholar 

  37. Colquhoun AJ, Venier NA, Vandersluis AD, Besla R, Sugar LM, Kiss A, et al. Metformin enhances the antiproliferative and apoptotic effect of bicalutamide in prostate cancer. Prostate Cancer Prostatic Dis. 2012;15:346–52.

    CAS  PubMed  Google Scholar 

  38. Wu GF, Zhang XL, Luo ZG, Yan JJ, Pan SH, Ying XR, et al. Metformin therapy and prostate cancer risk: a meta-analysis of observational studies. Int J Clin Exp Med. 2015;8:13089–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Suissa S, Azoulay L. Metformin and cancer: mounting evidence against an association. Diabetes Care. 2014;37:1786–8.

    CAS  PubMed  Google Scholar 

  40. Segawa T, Nau ME, Xu LL, Chilukuri RN, Makarem M, Zhang W, et al. Androgen-induced expression of endoplasmic reticulum (ER) stress response genes in prostate cancer cells. Oncogene. 2002;21:8749–58.

    CAS  PubMed  Google Scholar 

  41. Schmitt AM, Chang HY. Long noncoding RNAs in cancer pathways. Cancer Cell. 2016;29:452–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Wang D, Ding L, Wang L, Zhao Y, Sun Z, Karnes RJ, et al. LncRNA MALAT1 enhances oncogenic activities of EZH2 in castration-resistant prostate cancer. Oncotarget. 2015;6:41045–55.

    PubMed  PubMed Central  Google Scholar 

  43. Marques Howarth M, Simpson D, Ngok SP, Nieves B, Chen R, Siprashvili Z, et al. Long noncoding RNA EWSAT1-mediated gene repression facilitates Ewing sarcoma oncogenesis. J Clin Invest. 2014;124:5275–90.

    PubMed  PubMed Central  Google Scholar 

  44. Agrelo R, Souabni A, Novatchkova M, Haslinger C, Leeb M, Komnenovic V, et al. SATB1 defines the developmental context for gene silencing by Xist in lymphoma and embryonic cells. Dev Cell. 2009;16:507–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Ling H, Spizzo R, Atlasi Y, Nicoloso M, Shimizu M, Redis RS, et al. CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer. Genome Res. 2013;23:1446–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Wang Y, Wang Z, Xu J, Li J, Li S, Zhang M, et al. Systematic identification of non-coding pharmacogenomic landscape in cancer. Nat Commun. 2018;9:3192.

    PubMed  PubMed Central  Google Scholar 

  47. Parasramka M, Yan IK, Wang X, Nguyen P, Matsuda A, Maji S, et al. BAP1 dependent expression of long non-coding RNA NEAT-1 contributes to sensitivity to gemcitabine in cholangiocarcinoma. Mol Cancer. 2017;16:22.

    PubMed  PubMed Central  Google Scholar 

  48. Prensner JR, Chen W, Iyer MK, Cao Q, Ma T, Han S, et al. PCAT-1, a long noncoding RNA, regulates BRCA2 and controls homologous recombination in cancer. Cancer Res. 2014;74:1651–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Bester AC, Lee JD, Chavez A, Lee YR, Nachmani D, Vora S, et al. An integrated genome-wide CRISPRa approach to functionalize lncRNAs in drug resistance. Cell. 2018;173:649–64 e620.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

RJH funding from CCSRI (Grant#702108) and PCC (Grant#D2013-17) and CUASF Career Development for Research Grant 2017-2018.

Author information

Authors and Affiliations

  1. Division of Urology, Department of Surgery, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada

    Min Joon Lee, Viranda H. Jayalath, Neil E. Fleshner, Girish S. Kulkarni, Antonio Finelli & Robert J. Hamilton

  2. Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada

    Wei Xu & Lin Lu

  3. Division of Urology, Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Stephen J. Freedland

  4. Division of Urology, Veterans Affairs Medical Center, Durham, NC, USA

    Stephen J. Freedland

  5. Department of Pathology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada

    Theodorus H. van der Kwast

Authors
  1. Min Joon Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Viranda H. Jayalath
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lin Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stephen J. Freedland
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Neil E. Fleshner
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Girish S. Kulkarni
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Antonio Finelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Theodorus H. van der Kwast
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Robert J. Hamilton
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert J. Hamilton.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, M.J., Jayalath, V.H., Xu, W. et al. Association between metformin medication, genetic variation and prostate cancer risk. Prostate Cancer Prostatic Dis 24, 96–105 (2021). https://doi.org/10.1038/s41391-020-0238-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41391-020-0238-y

This article is cited by

Search

Advanced search

Quick links