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Genetic Variability of the Forkhead Box O3 and Prostate Cancer Risk in the European Prospective Investigation on Cancer

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Genetic Variability of the Forkhead Box O3 and Prostate Cancer Risk in the European Prospective Investigation on Cancer ONCOLOGY REPORTS 26: 979-986, 2011 Genetic variability of the forkhead box O3 and prostate cancer risk in the European Prospective Investigation on Cancer DANIELE CAMPA1, ANIKA HÜSING1, LUCIE DOSTAL1, ANGELIKA STEIN1, DAGMAR DROGAN2, HEINER BOEING2, ANNE TJØNNELAND3, NINA ROSWALL3, JANE NAUTRUP ØSTERGAARD4,5, KIM OVERVAD4,5, LAUDINA RODRÍGUEZ6, CATALINA BONET7, MARIA-JOSÉ SÁNCHEZ8,9, NEREA LARRAÑAGA9,10, JOSÉ MARÍA HUERTA9,11, EVA ARDANAZ9,12, KAY-TEE KHAW13, NICHOLAS WAREHAM14, RUTH C. TRAVIS15, NAOMI E. ALLEN15, ANTONIA TRICHOPOULOU16,17, DIMOSTHENIS ZYLIS17, TINA KARAPETYAN17, DOMENICO PALLI18, SABINA SIERI19, ROSARIO TUMINO20, PAOLO VINEIS21,22, H. BAS BUENO-DE-MESQUITA23, PER LENNER24, MATTIAS JOHANSSON25,26, MAZDA JENAB26, DAVID COX27, AFSHAN SIDDIQ27, RUDOLF KAAKS1 and FEDERICO CANZIAN1 1German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg; 2Department of Epidemiology, Deutsches Institut für Ernährungsforschung, Arthur-Scheunert-Allee 114-116, D-14558 Potsdam-Rehbrücke, Germany; 3The Danish Cancer Society, Institute of Cancer Epidemiology, Strandboulevarden 49, DK-2100 Copenhagen; 4Department of Cardiology, Center for Cardiovascular Research, Aalborg Hospital, Aarhus University Hospital, Sdr. Skovvej 15, Box 365, DK-9100 Aalborg; 5Department of Epidemiology, School of Public Health, Aarhus University, Sdr. Skovvej 15, Box 365, DK-9100 Aalborg, Denmark; 6Public Health and Participation Directorate, Health and Health Care Services Council, Asturias, C/General Elorza 32, 33001 Oviedo; 7Department of Epidemiology, Catalan Institute of Oncology, Avda. Gran Via nο. 199-203, 08907 L'Hospitalet de Llobregat, Barcelona; 8Andalusian School of Public Health, Campus Universitario de Cartuja, Cuesta del Observatorio 4, 18080 Granada; 9Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP); 10Public Health Department of Gipuzkoa, Basque Government, Avda de Navarra 4, 20013 San Sebastian; 11Department of Epidemiology, Murcia Regional Health Authority, Ronda de Levante 11, E30008 Murcia; 12Navarre Public Health Institute, C) Leyre 15, 31003 Pamplona, Navarra, Spain; 13University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ; 14MRC Epidemiology Unit, Box 285, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ; 15Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7LF, UK; 16Hellenic Health Foundation, 75 Mikras Asias Street, 115 27 Athens; 17WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, 75 Mikras Asias Street, 115 27 Athens, Greece; 18Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute - ISPO, Via Cosimo il Vecchio no. 2, I-50139 Florence; 19Nutritional Epidemiology Unit Fondazione IRCCS Istituto Nazionale Tumori, Via Venezian 1, I-20133 Milano; 20Cancer Registry and Histopathology Unit, ‘Civile - M.P. Arezzo’ Ηospital, ASP 7, Via Dante no. 109, I-97100 Ragusa; 21Human Genetic Foundation (HuGeF), Via Santena 7, I-10126 Turin, Italy; 22MRC/HPA Centre for Environment and Health, School of Public Health, Imperial College London St. Mary's Campus, Norfolk Place, London W21PG, UK; 23Centre for Nutrition and Health (CVG), National Institute for Public Health and the Environment, P.O. Box 1, 3720 BA Bilthoven, The Netherlands; 24Urology and Andrology, Department of Surgical and Perioperative Science, 25Nutritional Research, Department of Public Health and Clinical Medicine, Umeå University Hospital, S-90187 Umeå, Sweden; 26International Agency for Research on Cancer, 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France; 27Imperial College, St. Mary's Campus, Norfolk Place, London W21PG, UK Received March 14, 2011; Accepted May 2, 2011 DOI: 10.3892/or.2011.1359 Abstract. Forkhead box O3 (FOXO3) has a wide range of functions: it promotes tumor suppression, cell cycle arrest, repair Correspondence to: Dr Rudolf Kaaks, Department of Cancer of damaged DNA, detoxification of reactive oxygen species, Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany apoptosis and plays a pivotal role in promoting longevity. E-mail: [email protected] FOXO3 is a key downstream target of the PI3K-Akt pathway in response to cellular stimulation by growth factors or insulin Key words: genetic variability, forkhead box, prostate cancer and has been proposed as a bridge between ageing and tumor 980 CAMPA et al: FOXO3 POLYMORPHISMS AND PROSTATE CANCER RISK suppression. Three SNPs in the FOXO3 gene (rs3800231, Given the important role FOXO3 plays in PC, the strong rs9400239 and rs479744) that have been shown to be strongly effect that the three SNPs have on the longevity phenotype and consistently associated with longevity, were examined in and the overlap between ageing and cancer processes, we relation to PC risk in a case control study of 1571 incident PC hypothesized that they could confer altered PC susceptibility. cases and 1840 controls nested within the European Prospective We tested the association of rs3800231, rs9400239 and rs479744 Investigation into Cancer and Nutrition (EPIC). There was no with PC risk in a study of 1571 invasive PC cases and 1840 statistically significant association between the SNPs and PC controls nested within the European Prospective Investigation risk regardless of the model of inheritance (dominant, codomi- into Cancer and Nutrition (EPIC). This is the first report on nant and recessive). The associations were not modified by polymorphisms of FOXO3 and PC risk. disease aggressiveness, circulating levels of steroid sex hormones, or IGFs or BMI. We conclude that polymorphisms Materials and methods in the FOXO3 gene that are associated with longevity are not major risk factors for PC risk, in this population of Caucasian The EPIC cohort. A fully detailed description of the EPIC men. cohort has been published elsewhere (17). Briefly, EPIC consists of about 370,000 women and 150,000 men, aged 35-69, Introduction recruited between 1992 and 2005 in 10 Western European countries. FOXO transcription factors belong to the large forkhead family The vast majority (>97%) of subjects recruited in the EPIC of proteins, a group of transcriptional regulators characterized cohort are of European (‘Caucasian’) origin. All EPIC study by a conserved DNA-binding domain termed the ‘forkhead subjects provided anthropometric measurements (height, box’ (1). Emerging evidence suggests that FOXO factors play weight, and waist and hip circumferences) and extensive, a role as tumor suppressors in a variety of cancers, translating standardized questionnaire information about medical history, environmental stimuli into changes in gene expression programs diet, physical activity, smoking, and other lifestyle factors. that may coordinate organismal longevity and tumor suppression About 260,000 women and 140,000 men provided a blood (2-5). sample. Forkhead box O3 (FOXO3) has a wide range of functions: Cases of cancer occurring after recruitment into the cohort it promotes tumor suppression, cell cycle arrest, repair of and blood donation are identified through local and national damaged DNA, detoxification of reactive oxygen species, cancer registries in 7 of the 10 countries, and in France, apoptosis and autophagy, by upregulating specific gene- Germany, and Greece by a combination of contacts with expression programs. In addition, it can also regulate energy national health insurances and/or active follow-up through the metabolism and development of a number of tissues including study subjects or their next of kin. Follow-up on vital status is the prostate (3-5). Consistent with a key role of FOXO3 in achieved through record linkage with mortality registries. tumor suppression, this transcription factor is a key down- stream target of the PI3K-Akt pathway in response to cellular Selection of case and control subjects. Case subjects were stimulation by growth factors or insulin (6). Akt/PKB is often selected among men who developed PC after blood collection. constitutively activated in prostate cancer (PC) (7,8). This Control subjects were selected randomly matching the cases results in the deactivation of FOXO factors (9), which in turn for center of recruitment, age at blood donation, time between improves PC cells survival (10) and PC progression from consumption of food or drink and blood draw and time of day androgen-dependence to androgen-independence (11). In of blood draw and duration of follow-up. Each control should contrast, overexpression of FOXO3 in PC cells causes apoptosis have been free of cancer up to the duration of follow-up of the and induction of genes that inhibt cellular proliferation (6). index case. A total of 1571 incident PC cases and 1840 controls Moreover, FOXO factors have been found to physically interact were included in the present study. The study was approved with several tumor suppressors, including p53 (2,12) and by the Εthics Review Boards of the International Agency for SMAD transcription factors (13). Research on Cancer, and of the collaborating institutions The ability FOXO3 shows in controlling many critical responsible for subject recruitment in each of the EPIC cellular functions may be related to its demonstrated role in recruitment centers. promoting longevity. It is possible that FOXO3 could mediate the effect of ageing on tumor suppression. The hortologue of SNP selection. Three SNPs (rs3800231,
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