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J Natl Cancer Inst. 2015 Feb 23;107(4). pii: djv010. doi: 10.1093/jnci/djv010. Print 2015 Apr.

A prospective study of the immune system activation biomarker neopterin and colorectal cancer risk.

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Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrueke, Nuthetal, Germany (KA, HB); Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK (SCC, BBdM, MJG, YL, AJC, ER, PV); Division of Health Policy Translation, Institutes of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan (SCC); Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway (HZ, GST); Molecular Epidemiology Group, Max Delbrueck Center for Molecular Medicine, Berlin-Buch, Germany (TP); International Agency for Research on Cancer, Lyon, France (MJe, SYJK, HF, MJo); National Institute for Public Health and the Environment, Bilthoven, the Netherlands (BBdM); Department of Gastroenterology and Hepatology, University Medical Center, Utrecht, the Netherlands (BBdM); Department of Public Health and Primary Health Care, University of Bergen, Bergen, Norway (SEV); Division of Epidemiology, Norwegian Institute of Public Health, Bergen, Norway (SEV); Bevital AS, Bergen, Norway (ØM); Section for Pharmacology, Department of Clinical Science, University of Bergen, Bergen, Norway (HZ, PMU); Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen, Norway (PMU); Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (VF); Winship Cancer Institute, Emory University, Atlanta, GA (VF); Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway (EW); Department of Research, Cancer Registry of Norway, Oslo, Norway (EW); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (EW); Samfundet Folkhälsan, Helsinki, Finland (EW); Human Genetics Foundation (HuGeF), Torino, Italy (GS, PV); Inserm, Centre for research in Epidemiology and Population Health, U1018, Nutrition, Hormones and Women's Health team, F-94805, Villeju



Neopterin may be relevant for colorectal cancer (CRC) development, as a biomarker of cellular immune activity exerting pleiotropic effects on cellular ageing, oxidative stress, and inflammation. So far, the association between prediagnostic neopterin and colon and rectal cancer risk has not been evaluated in human populations.


A nested case-control study was conducted within the European Prospective Investigation into Cancer and Nutrition cohort using data on plasma concentrations of total neopterin (T-N, sum of neopterin and 7,8-dihydroneopterin) in 830 incident CRC case patients (561 colon and 269 rectal) matched within risk sets to 830 control participants. A subsequent replication study used data from the Hordaland Health Study, where 173 CRC case patients have been diagnosed among 6594 healthy participants over 12 years of follow-up.


After multivariable adjustment for a priori chosen CRC risk factors, a "U-shaped" association of T-N with CRC was revealed. Compared with the second quintile of the T-N distribution, the relative risks for the first, third, fourth, and fifth quintiles were 2.37 (95% CI = 1.66 to 3.39), 1.24 (95% CI = 0.87 to 1.77), 1.55 (95% CI = 1.08 to 2.22), and 2.31 (95% CI = 1.63 to 3.27), respectively. Replication of these associations within the Hordaland Health Study yielded similar results. No differences have been observed when the associations were explored by colon and rectal cancer site (two-sided P difference = .87) and after excluding case patients diagnosed within the first four follow-up years.


These novel findings provide evidence of the role of both suppressed and activated cell-mediated immunity as reflected by prediagnostic T-N concentrations in the development of CRC.

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