Open Access

Anne J. M. R. Geijsen, Eline H. van Roekel, Fränzel J. B. van Duijnhoven, David Achaintre, Thomas Bachleitner-Hofmann, Andreas Baierl, Michael M. Bergmann, Jürgen Böhm, Martijn J. L. Bours, Hermann Brenner, Stéphanie O. Breukink, Stefanie Brezina, Jenny Chang-Claude, Esther Herpel, Johannes H. W. de Wilt, Audrey Gicquiau, Biljana Gigic, Tanja Gumpenberger, Bibi M. E. Hansson, Michael Hoffmeister, Andreana N. Holowatyj, Judith Karner-Hanusch, Pekka Keski-Rahkonen, Eric T. P. Keulen, Janna L. Koole, Gernot Leeb, Jennifer Ose, Peter Schirmacher, Martin A. Schneider, Petra Schrotz-King, Anton Stift, Arve Ulvik, F. Jeroen Vogelaar, Evertine Wesselink, Moniek van Zutphen, Andrea Gsur, Nina Habermann, Ellen Kampman, Augustin Scalbert, Per Magne Ueland, Alexis B. Ulrich, Cornelia M. Ulrich, Matty P. Weijenberg, Dieuwertje E. Kok

• Colorectal cancer is the second most common cause of cancer-related death globally, with marked differences in prognosis by disease stage at diagnosis. We studied circulating metabolites in relation to disease stage to improve the understanding of metabolic pathways related to colorectal cancer progression. We investigated plasma concentrations of 130 metabolites among 744 Stages I–IV colorectal cancer patients from ongoing cohort studies. Plasma samples, collected at diagnosis, were analyzed with liquid chromatography-mass spectrometry using the Biocrates AbsoluteIDQ™ p180 kit. We assessed associations between metabolite concentrations and stage using multinomial and multivariable logistic regression models. Analyses were adjusted for potential confounders as well as multiple testing using false discovery rate (FDR) correction. Patients presented with 23, 28, 39 and 10% of Stages I–IV disease, respectively. Concentrations of sphingomyelin C26:0 were lower in Stage III patients compared to Stage I patients (pFDR < 0.05). Concentrations of sphingomyelin C18:0 and phosphatidylcholine (diacyl) C32:0 were statistically significantly higher, while citrulline, histidine, phosphatidylcholine (diacyl) C34:4, phosphatidylcholine (acyl-alkyl) C40:1 and lysophosphatidylcholines (acyl) C16:0 and C17:0 concentrations were lower in Stage IV compared to Stage I patients (pFDR < 0.05). Our results suggest that metabolic pathways involving among others citrulline and histidine, implicated previously in colorectal cancer development, may also be linked to colorectal cancer progression.