Interaction between single nucleotide polymorphisms in selenoprotein P and mitochondrial superoxide dismutase determines prostate cancer risk.

Selenium may affect prostate cancer risk via its plasma carrier selenoprotein P which shows dramatically reduced expression in prostate cancer tumors and cell lines. The selenoprotein P (SEPP1) Ala234 single nucleotide polymorphism (SNP) allele is associated with lower plasma selenoprotein P in men, reducing the concentration/activity of other antioxidant selenoproteins. Selenium status also modifies the effect of the mitochondrial superoxide dismutase (SOD2) SNP Ala16Val on prostate cancer risk. We investigated the relationship of these SNPs with prostate cancer risk. DNA from 2,975 cases and 1,896 age-matched controls from the population-based Prostate Cancer in Sweden study were genotyped using TaqMan assays. Cases were designated aggressive or nonaggressive prostate cancers at diagnosis by clinical criteria. Association with prostate cancer was investigated by logistic regression; gene-gene interaction using a general linear model. The mean plasma selenium concentration measured in 169 controls was relatively low (76.0 +/- 17.2 microg/L). SNP genotype distributions were in Hardy-Weinberg equilibrium. SOD2-Ala16+ men were at a greater risk of prostate cancer [odds ratios (OR), 1.19; 95% confidence intervals (CI), 1.03-1.37] compared with SOD2-Val16 homozygotes. Men homozygous for SEPP1-Ala234 who were also SOD2-Ala16+ had a higher risk of prostate cancer (OR, 1.43; 95% CI, 1.17-1.76) and aggressive prostate cancer (OR, 1.60; 95% CI, 1.22-2.09) than those who were SOD2-Val16 homozygotes (interaction, prostate cancer P = 0.05; aggressive prostate cancer P = 0.01). This interaction was stronger in ever-smokers: SOD2-Ala16+ men homozygous for SEPP1-Ala234 had an almost doubled risk of prostate cancer (OR, 1.97; 95% CI, 1.33-2.91; interaction P = 0.001). In a low-selenium population, SOD2-Ala16+ men homozygous for SEPP1-Ala234 are at an increased risk of prostate cancer/aggressive prostate cancer especially if ever-smokers, because they are likely to produce more mitochondrial H(2)O(2) that they cannot remove, thereby promoting prostate tumor cell proliferation and migration.

[1]  L. Ekström,et al.  The UGT2B17 gene deletion is not associated with prostate cancer risk , 2008, The Prostate.

[2]  W. Willett,et al.  Multiple loci identified in a genome-wide association study of prostate cancer , 2008, Nature Genetics.

[3]  Kevin M. Bradley,et al.  Common sequence variants on 2p15 and Xp11.22 confer susceptibility to prostate cancer , 2008, Nature Genetics.

[4]  Ali Amin Al Olama,et al.  Multiple newly identified loci associated with prostate cancer susceptibility , 2008, Nature Genetics.

[5]  L. Schomburg,et al.  Hepatic selenoprotein P (SePP) expression restores selenium transport and prevents infertility and motor-incoordination in Sepp-knockout mice. , 2008, The Biochemical journal.

[6]  J. Carpten,et al.  Two genome-wide association studies of aggressive prostate cancer implicate putative prostate tumor suppressor gene DAB2IP. , 2007, Journal of the National Cancer Institute.

[7]  J. Mathers,et al.  Genetic polymorphisms in the human selenoprotein P gene determine the response of selenoprotein markers to selenium supplementation in a gender‐specific manner (the SELGEN study) , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[8]  D. Thurnham,et al.  Monitoring micronutrients in cigarette smokers. , 2007, Clinica chimica acta; international journal of clinical chemistry.

[9]  V. Ray,et al.  Selenoprotein deficiency accelerates prostate carcinogenesis in a transgenic model. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[10]  C. Davis,et al.  Both selenoproteins and low molecular weight selenocompounds reduce colon cancer risk in mice with genetically impaired selenoprotein expression , 2006, The Journal of nutrition.

[11]  Evangelia Papadimitriou,et al.  Hydrogen Peroxide Stimulates Proliferation and Migration of Human Prostate Cancer Cells through Activation of Activator Protein-1 and Up-regulation of the Heparin Affin Regulatory Peptide Gene* , 2005, Journal of Biological Chemistry.

[12]  M. Rayman.  Selenium in cancer prevention: a review of the evidence and mechanism of action , 2005, Proceedings of the Nutrition Society.

[13]  D. Pessayre,et al.  The manganese superoxide dismutase Ala16Val dimorphism modulates both mitochondrial import and mRNA stability , 2005, Pharmacogenetics and genomics.

[14]  D. Byrne,et al.  Effectiveness of selenium supplements in a low-selenium area of China. , 2005, The American journal of clinical nutrition.

[15]  P. Kantoff,et al.  Manganese superoxide dismutase polymorphism, prediagnostic antioxidant status, and risk of clinical significant prostate cancer. , 2005, Cancer research.

[16]  F. Marshall,et al.  Increased Nox1 and hydrogen peroxide in prostate cancer , 2005, The Prostate.

[17]  Pär Stattin,et al.  H6D polymorphism in macrophage-inhibitory cytokine-1 gene associated with prostate cancer. , 2004, Journal of the National Cancer Institute.

[18]  W. Willett,et al.  A prospective study of plasma selenium levels and prostate cancer risk. , 2004, Journal of the National Cancer Institute.

[19]  J. Crapo,et al.  Superoxide dismutases in malignant cells and human tumors. , 2004, Free radical biology & medicine.

[20]  M. Scheurlen,et al.  Expression Profiling and Genetic Alterations of the Selenoproteins GI-GPx and SePP in Colorectal Carcinogenesis , 2004, Nutrition and cancer.

[21]  R. Goldbohm,et al.  Toenail selenium levels and the subsequent risk of prostate cancer: a prospective cohort study. , 2003, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[22]  D. Albanes,et al.  Manganese superoxide dismutase (MnSOD) polymorphism, α-tocopherol supplementation and prostate cancer risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (Finland) , 2003, Cancer Causes & Control.

[23]  J. F. Atkins,et al.  Deletion of Selenoprotein P Alters Distribution of Selenium in the Mouse* , 2003, The Journal of Biological Chemistry.

[24]  B. Turnbull,et al.  Selenium supplementation, baseline plasma selenium status and incidence of prostate cancer: an analysis of the complete treatment period of the Nutritional Prevention of Cancer Trial , 2003, BJU international.

[25]  L. Flohé,et al.  Gene disruption discloses role of selenoprotein P in selenium delivery to target tissues. , 2003, The Biochemical journal.

[26]  D. Pessayre,et al.  The Ala16Val genetic dimorphism modulates the import of human manganese superoxide dismutase into rat liver mitochondria. , 2003, Pharmacogenetics.

[27]  D. Albanes,et al.  Toenail selenium concentration and lung cancer in male smokers (Finland) , 2002, Cancer Causes & Control.

[28]  Cheryl Jorcyk,et al.  Alterations in gene expression profiles during prostate cancer progression: functional correlations to tumorigenicity and down-regulation of selenoprotein-P in mouse and human tumors. , 2002, Cancer research.

[29]  B. Turnbull,et al.  Baseline characteristics and the effect of selenium supplementation on cancer incidence in a randomized clinical trial: a summary report of the Nutritional Prevention of Cancer Trial. , 2002, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[30]  L. Oberley,et al.  Activation of Matrix Metalloproteinase-2 by Overexpression of Manganese Superoxide Dismutase in Human Breast Cancer MCF-7 Cells Involves Reactive Oxygen Species* , 2002, The Journal of Biological Chemistry.

[31]  J. S. Morris,et al.  Association Between α-Tocopherol, γ-Tocopherol, Selenium, and Subsequent Prostate Cancer , 2000 .

[32]  G. Combs,et al.  Serum selenium and subsequent risk of prostate cancer. , 2000, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[33]  Sheila M. Williams,et al.  An estimation of selenium requirements for New Zealanders. , 1999, The American journal of clinical nutrition.

[34]  E. Rimm,et al.  Study of prediagnostic selenium level in toenails and the risk of advanced prostate cancer. , 1998, Journal of the National Cancer Institute.

[35]  E. Constant,et al.  Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. , 1998 .

[36]  Bruce W. Turnbull,et al.  Effects of Selenium Supplementation for Cancer Prevention in Patients With Carcinoma of the Skin: A Randomized Controlled Trial , 1996 .

[37]  B Chance,et al.  Hydroperoxide metabolism in mammalian organs. , 1979, Physiological reviews.

[38]  K. Flegal,et al.  Serum selenium levels in the US population , 2007, Biological Trace Element Research.

[39]  A. Prentice,et al.  Selenium status and its correlates in a British national diet and nutrition survey: people aged 65 years and over. , 2002, Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements.

[40]  M. Moschos.  Selenoprotein P , 2000, Cellular and Molecular Life Sciences CMLS.

[41]  E. Larsen,et al.  The application of inductively coupled plasma dynamic reaction cell mass spectrometry for measurement of selenium isotopes, isotope ratios and chromatographic detection of selenoamino acids , 2000 .

[42]  H. Delves,et al.  Determination of total selenium in serum, whole blood and erythrocytes by ICP-MS , 1999 .

[43]  B W Turnbull,et al.  Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. , 1996, JAMA.