Biomarker patterns of inflammatory and metabolic pathways are associated with risk of colorectal cancer: results from the European Prospective Investigation into Cancer and Nutrition (EPIC)
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- 作者：Krasimira Aleksandrova (1)
Mazda Jenab (2)
H. Bas Bueno-de-Mesquita (3) (4)
Veronika Fedirko (2) (5) (6)
Rudolf Kaaks (7)
Annekatrin Lukanova (7) (8)
Fr?nzel J. B. van Duijnhoven (3) (9)
Eugene Jansen (3)
Sabina Rinaldi (2)
Isabelle Romieu (2)
Pietro Ferrari (2)
Neil Murphy (10)
Marc J. Gunter (10)
Elio Riboli (10)
Sabine Westhpal (11)
Kim Overvad (12)
Anne Tj?nneland (13)
Jytte Halkj?r (13)
Marie-Christine Boutron-Ruault (14) (15) (16)
Laure Dossus (14) (15) (16)
Antoine Racine (14) (15) (16)
Antonia Trichopoulou (17) (18)
Christina Bamia (18)
Philippos Orfanos (18)
Claudia Agnoli (19)
Domenico Palli (20)
Salvatore Panico (21)
Rosario Tumino (22)
Paolo Vineis (10) (23)
Petra H. Peeters (10) (24)
Eric J. Duell (25)
Esther Molina-Montes (26) (27) (28)
J. Ramón Quirós (29)
Miren Dorronsoro (30)
Maria-Dolores Chirlaque (27) (31)
Aurelio Barricarte (32)
Ingrid Ljuslinder (33)
Richard Palmqvist (34)
Ruth C. Travis (35)
Kay-Tee Khaw (36)
Nicholas Wareham (37)
Tobias Pischon (38)
Heiner Boeing (1) - 关键词：Colorectal cancer ; Biomarker patterns ; Inflammatory and metabolic pathways ; Principal component analysis ; European Prospective Investigation into Cancer and Nutrition (EPIC)
- 刊名：European Journal of Epidemiology
- 出版年：2014
- 出版时间：April 2014
- 年：2014
- 卷：29
- 期：4
- 页码：261-275
- 全文大小：
- 参考文献：1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893-17. doi:10.1002/ijc.25516 . CrossRef
2. Aleksandrova K, Nimptsch K, Pischon T. Influence of obesity and related metabolic alterations on colorectal cancer risk. Curr Nutr Rep. 2013;2(1):1-. doi:10.1007/s13668-012-0036-9 . CrossRef
3. Louie SM, Roberts LS, Nomura DK. Mechanisms linking obesity and cancer. Biochim Biophys Acta. 2013;1831(10):1499-08. doi:10.1016/j.bbalip.2013.02.008 . CrossRef
4. Bardou M, Barkun AN, Martel M. Obesity and colorectal cancer. Gut. 2013;62(6):933-7. doi:10.1136/gutjnl-2013-304701 . CrossRef
5. Hull M, Lagergren J. Obesity and colorectal cancer. Gut. 2013;. doi:10.1136/gutjnl-2013-304988 .
6. Jenab M, Riboli E, Cleveland RJ, et al. Serum C-peptide, IGFBP-1 and IGFBP-2 and risk of colon and rectal cancers in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer. 2007;121(2):368-6. doi:10.1002/ijc.22697 . CrossRef
7. Otani T, Iwasaki M, Sasazuki S, Inoue M, Tsugane S, Japan Public Health Center-based Prospective Study Group. Plasma C-peptide, insulin-like growth factor-I, insulin-like growth factor binding proteins and risk of colorectal cancer in a nested case–control study: the Japan public health center-based prospective study. Int J Cancer. 2007;120(9):2007-2. doi:10.1002/ijc.22556 . CrossRef
8. Ma J, Giovannucci E, Pollak M, et al. A prospective study of plasma C-peptide and colorectal cancer risk in men. J Natl Cancer Inst. 2004;96(7):546-3. CrossRef
9. Rinaldi S, Rohrmann S, Jenab M, et al. Glycosylated hemoglobin and risk of colorectal cancer in men and women, the European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomarkers Prev. 2008;17(11):3108-5. doi:10.1158/1055-9965.EPI-08-0495 . CrossRef
10. Saydah SH, Platz EA, Rifai N, Pollak MN, Brancati FL, Helzlsouer KJ. Association of markers of insulin and glucose control with subsequent colorectal cancer risk. Cancer Epidemiol Biomarkers Prev. 2003;12(5):412-.
11. Aleksandrova K, Jenab M, Boeing H, et al. Circulating C-reactive protein concentrations and risks of colon and rectal cancer: a nested case–control study within the European Prospective Investigation into Cancer and Nutrition. Am J Epidemiol. 2010;172(4):407-8. doi:10.1093/aje/kwq135 . CrossRef
12. Tsilidis KK, Branchini C, Guallar E, Helzlsouer KJ, Erlinger TP, Platz EA. C-reactive protein and colorectal cancer risk: a systematic review of prospective studies. Int J Cancer. 2008;123(5):1133-0. doi:10.1002/ijc.23606 . CrossRef
13. Leufkens AM, van Duijnhoven FJ, Woudt SH, et al. Biomarkers of oxidative stress and risk of developing colorectal cancer: a cohort-nested case–control study in the European Prospective Investigation into Cancer and Nutrition. Am J Epidemiol. 2012;175(7):653-3. doi:10.1093/aje/kwr418 . CrossRef
14. van Duijnhoven FJ, Bueno-De-Mesquita HB, Calligaro M, et al. Blood lipid and lipoprotein concentrations and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition. Gut. 2011;60(8):1094-02. doi:10.1136/gut.2010.225011 . CrossRef
15. Jafri H, Alsheikh-Ali AA, Karas RH. Baseline and on-treatment high-density lipoprotein cholesterol and the risk of cancer in randomized controlled trials of lipid-altering therapy. J Am Coll Cardiol. 2010;55(25):2846-4. doi:10.1016/j.jacc.2009.12.069 . CrossRef
16. Lavigne PM, Jafri H, Karas R. High-density lipoprotein cholesterol and cancer incidence: data from the Framingham Heart Study. J Am Coll Cardiol. 2012;59(13s1):E1764. doi:10.1016/S0735-1097(12)61765-3 . CrossRef
17. Trayhurn P, Wood IS. Signalling role of adipose tissue: adipokines and inflammation in obesity. Biochem Soc Trans. 2005;33(Pt 5):1078-1. doi:10.1042/BST20051078 .
18. Hauner H. Secretory factors from human adipose tissue and their functional role. Proc Nutr Soc. 2005;64(2):163-. CrossRef
19. Dalamaga M, Diakopoulos KN, Mantzoros CS. The role of adiponectin in cancer: a review of current evidence. Endocr Rev. 2012;33(4):547-4. doi:10.1210/er.2011-1015 . CrossRef
20. Piya MK, McTernan PG, Kumar S. Adipokine inflammation and insulin resistance: the role of glucose, lipids and endotoxin. J Endocrinol. 2013;216(1):T1-5. doi:10.1530/JOE-12-0498 . CrossRef
21. Aleksandrova K, Boeing H, Jenab M, et al. Leptin and soluble leptin receptor in risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition cohort. Cancer Res. 2012;72(20):5328-7. doi:10.1158/0008-5472.CAN-12-0465 . CrossRef
22. Xu XT, Xu Q, Tong JL, et al. Meta-analysis: circulating adiponectin levels and risk of colorectal cancer and adenoma. J Dig Dis. 2011;12(4):234-4. doi:10.1111/j.1751-2980.2011.00504.x . CrossRef
23. Perrier S, Jarde T. Adiponectin, an anti-carcinogenic hormone? A systematic review on breast, colorectal, liver and prostate cancer. Curr Med Chem. 2012;19(32):5501-2. CrossRef
24. Aleksandrova K, Boeing H, Jenab M, et al. Total and high-molecular weight adiponectin and risk of colorectal cancer: the European Prospective Investigation into Cancer and Nutrition Study. Carcinogenesis. 2012;33(6):1211-. doi:10.1093/carcin/bgs133 . CrossRef
25. Song M, Zhang X, Wu K, et al. Plasma adiponectin and soluble leptin receptor and risk of colorectal cancer: a prospective study. Cancer Prev Res. 2013;6(9):875-5. doi:10.1158/1940-6207.CAPR-13-0169 . CrossRef
26. Neumeier M, Weigert J, Schaffler A, et al. Different effects of adiponectin isoforms in human monocytic cells. J Leukoc Biol. 2006;79(4):803-. doi:10.1189/jlb.0905521 . CrossRef
27. Rinaldi S, Cleveland R, Norat T, et al. Serum levels of IGF-I, IGFBP-3 and colorectal cancer risk: results from the EPIC cohort, plus a meta-analysis of prospective studies. Int J Cancer. 2010;126(7):1702-5. doi:10.1002/ijc.24927 .
28. Chi F, Wu R, Zeng YC, Xing R, Liu Y. Circulation insulin-like growth factor peptides and colorectal cancer risk: an updated systematic review and meta-analysis. Mol Biol Rep. 2013;40(5):3583-0. doi:10.1007/s11033-012-2432-z . CrossRef
29. Kaaks R, Toniolo P, Akhmedkhanov A, et al. Serum C-peptide, insulin-like growth factor (IGF)-I, IGF-binding proteins, and colorectal cancer risk in women. J Natl Cancer Inst. 2000;92(19):1592-00. CrossRef
30. Mathews JD, Buckley JD, Gledhill VX. Pattern recognition in medicine—a place for the use of principal component analysis and factor analysis. Aust N Z J Med. 1974;4(5):509-5. CrossRef
31. Hu FB. Dietary pattern analysis: a new direction in nutritional epidemiology. Curr Opin Lipidol. 2002;13(1):3-. CrossRef
32. Jolliffe I. Principal component analysis. New York: Springer; 1986. CrossRef
33. Edwards KL, Austin MA, Newman B, Mayer E, Krauss RM, Selby JV. Multivariate analysis of the insulin resistance syndrome in women. Arterioscler Thromb. 1994;14(12):1940-. CrossRef
34. Dossus L, Lukanova A, Rinaldi S, et al. Hormonal, metabolic, and inflammatory profiles and endometrial cancer risk within the EPIC cohort—a factor analysis. Am J Epidemiol. 2013;177(8):787-9. doi:10.1093/aje/kws309 . CrossRef
35. Bingham S, Riboli E. Diet and cancer—the European Prospective Investigation into Cancer and Nutrition. Nat Rev Cancer. 2004;4(3):206-5. doi:10.1038/nrc1298nrc1298 . CrossRef
36. Slimani N, Deharveng G, Unwin I, et al. The EPIC nutrient database project (ENDB): a first attempt to standardize nutrient databases across the 10 European countries participating in the EPIC study. Eur J Clin Nutr. 2007;61(9):1037-6. doi:10.1038/sj.ejcn.1602679 . CrossRef
37. Kaaks R, Riboli E. Validation and calibration of dietary intake measurements in the EPIC project: methodological considerations. European Prospective Investigation into Cancer and Nutrition. Int J Epidemiol. 1997;26(Suppl 1):S15-5. CrossRef
38. Haftenberger M, Lahmann PH, Panico S, et al. Overweight, obesity and fat distribution in 50- to 64-year-old participants in the European Prospective Investigation into Cancer and Nutrition (EPIC). Public Health Nutr. 2002;5(6B):1147-2. CrossRef
39. Sterne JA, White IR, Carlin JB, et al. Multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls. BMJ. 2009;338:b2393. doi:10.1136/bmj.b2393bmj.b2393 . CrossRef
40. Yuan Y. Multiple imputation using SAS software. J Stat Softw. 2011;45(6):1-5.
41. Riboli E, Hunt KJ, Slimani N, et al. European Prospective Investigation into Cancer and Nutrition (EPIC): study populations and data collection. Public Health Nutr. 2002;5(6B):1113-4. doi:10.1079/PHN2002394S1368980002001350 . CrossRef
42. World Cancer Research Fund/American Institute for Cancer Research. Food nutrition, physical activity, and the prevention of cancer: a global perspective. Washington, DC: AICR; 2007.
43. Rohrmann S, Linseisen J, Becker S, et al. Concentrations of IGF-I and IGFBP-3 and brain tumor risk in the European Prospective Investigation into Cancer and Nutrition. Cancer Epidemiol Biomarkers Prev. 2011;20(10):2174-2. doi:10.1158/1055-9965.EPI-11-0179 . CrossRef
44. Aleksandrova K, Boeing H, Jenab M, et al. Metabolic syndrome and risks of colon and rectal cancer: the European prospective investigation into cancer and nutrition study. Cancer Prev Res. 2011;4(11):1873-3. doi:10.1158/1940-6207.CAPR-11-0218 . CrossRef
45. Rodrigues L, Kirkwood BR. Case–control designs in the study of common diseases: updates on the demise of the rare disease assumption and the choice of sampling scheme for controls. Int J Epidemiol. 1990;19(1):205-3. CrossRef
46. Zietz B, Herfarth H, Paul G, et al. Adiponectin represents an independent cardiovascular risk factor predicting serum HDL-cholesterol levels in type 2 diabetes. FEBS Lett. 2003;545(2-):103-. CrossRef
47. Altinova AE, Toruner F, Bukan N, et al. Decreased plasma adiponectin is associated with insulin resistance and HDL cholesterol in overweight subjects. Endocr J. 2007;54(2):221-. CrossRef
48. Van Linthout S, Foryst-Ludwig A, Spillmann F, et al. Impact of HDL on adipose tissue metabolism and adiponectin expression. Atherosclerosis. 2010;210(2):438-4. doi:10.1016/j.atherosclerosis.2010.01.001 . CrossRef
49. Kangas-Kontio T, Huotari A, Ruotsalainen H, et al. Genetic and environmental determinants of total and high-molecular weight adiponectin in families with low HDL-cholesterol and early onset coronary heart disease. Atherosclerosis. 2010;210(2):479-5. doi:10.1016/j.atherosclerosis.2009.12.022 . CrossRef
50. Belalcazar LM, Lang W, Haffner SM, et al. Adiponectin and the mediation of HDL-cholesterol change with improved lifestyle: the Look AHEAD Study. J Lipid Res. 2012;53(12):2726-3. doi:10.1194/jlr.M030213 . CrossRef
51. An W, Bai Y, Deng SX, et al. Adiponectin levels in patients with colorectal cancer and adenoma: a meta-analysis. Eur J Cancer Prev. 2012;21(2):126-3. doi:10.1097/CEJ.0b013e32834c9b55 . CrossRef
52. Moon HS, Liu X, Nagel JM, et al. Salutary effects of adiponectin on colon cancer: in vivo and in vitro studies in mice. Gut. 2013;62(4):561-0. doi:10.1136/gutjnl-2012-302092 . CrossRef
53. Per M. Oxidative stress in the pathogenesis of colorectal cancer: cause or consequence? Biomed Res Int. 2013;2013:9. doi:10.1155/2013/725710 .
54. Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: how are they linked? Free Radical Biol Med. 2010;49(11):1603-6. doi:10.1016/j.freeradbiomed.2010.09.006 . CrossRef
55. Perse M. Oxidative stress in the pathogenesis of colorectal cancer: cause or consequence? Biomed Res Int. 2013;2013:725710. doi:10.1155/2013/725710 . CrossRef
56. Inokuma T, Haraguchi M, Fujita F, Tajima Y, Kanematsu T. Oxidative stress and tumor progression in colorectal cancer. Hepatogastroenterology. 2009;56(90):343-.
57. Chan JL, Bluher S, Yiannakouris N, Suchard MA, Kratzsch J, Mantzoros CS. Regulation of circulating soluble leptin receptor levels by gender, adiposity, sex steroids, and leptin: observational and interventional studies in humans. Diabetes. 2002;51(7):2105-2. CrossRef
58. Sandhofer A, Laimer M, Ebenbichler CF, Kaser S, Paulweber B, Patsch JR. Soluble leptin receptor and soluble receptor-bound fraction of leptin in the metabolic syndrome. Obes Res. 2003;11(6):760-. doi:10.1038/oby.2003.106 . CrossRef
59. Banu S, Jabir NR, Manjunath CN, Shakil S, Kamal MA. C-peptide and its correlation to parameters of insulin resistance in the metabolic syndrome. CNS Neurol Disord: Drug Targets. 2011;10(8):921-. CrossRef
60. Kraegen EW, Cooney GJ, Ye J, Thompson AL. Triglycerides, fatty acids and insulin resistance–hyperinsulinemia. Exp Clin Endocrinol Diabetes. 2001;109(4):S516-6. CrossRef
61. Ginsberg HN, Zhang YL, Hernandez-Ono A. Regulation of plasma triglycerides in insulin resistance and diabetes. Arch Med Res. 2005;36(3):232-0. doi:10.1016/j.arcmed.2005.01.005 . CrossRef
62. Kalofoutis C, Piperi C, Kalofoutis A, Harris F, Phoenix D, Singh J. Type II diabetes mellitus and cardiovascular risk factors: current therapeutic approaches. Exp Clin Cardiol. 2007;12(1):17-8.
63. Tsushima M, Nomura AM, Lee J, Stemmermann GN. Prospective study of the association of serum triglyceride and glucose with colorectal cancer. Dig Dis Sci. 2005;50(3):499-05. CrossRef
64. Lee SA, Kallianpur A, Xiang YB, et al. Intra-individual variation of plasma adipokine levels and utility of single measurement of these biomarkers in population-based studies. Cancer Epidemiol Biomarkers Prev. 2007;16(11):2464-0. doi:10.1158/1055-9965.EPI-07-0374 . CrossRef - 作者单位：Krasimira Aleksandrova (1)
Mazda Jenab (2)
H. Bas Bueno-de-Mesquita (3) (4)
Veronika Fedirko (2) (5) (6)
Rudolf Kaaks (7)
Annekatrin Lukanova (7) (8)
Fr?nzel J. B. van Duijnhoven (3) (9)
Eugene Jansen (3)
Sabina Rinaldi (2)
Isabelle Romieu (2)
Pietro Ferrari (2)
Neil Murphy (10)
Marc J. Gunter (10)
Elio Riboli (10)
Sabine Westhpal (11)
Kim Overvad (12)
Anne Tj?nneland (13)
Jytte Halkj?r (13)
Marie-Christine Boutron-Ruault (14) (15) (16)
Laure Dossus (14) (15) (16)
Antoine Racine (14) (15) (16)
Antonia Trichopoulou (17) (18)
Christina Bamia (18)
Philippos Orfanos (18)
Claudia Agnoli (19)
Domenico Palli (20)
Salvatore Panico (21)
Rosario Tumino (22)
Paolo Vineis (10) (23)
Petra H. Peeters (10) (24)
Eric J. Duell (25)
Esther Molina-Montes (26) (27) (28)
J. Ramón Quirós (29)
Miren Dorronsoro (30)
Maria-Dolores Chirlaque (27) (31)
Aurelio Barricarte (32)
Ingrid Ljuslinder (33)
Richard Palmqvist (34)
Ruth C. Travis (35)
Kay-Tee Khaw (36)
Nicholas Wareham (37)
Tobias Pischon (38)
Heiner Boeing (1)
1. Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert Allee 114-116, 14558, Nuthetal, Germany
2. International Agency for Research on Cancer (IARC-WHO), Lyon, France
3. National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
4. Department of Gastroenterology and Hepatology, University Medical Center, Utrecht, The Netherlands
5. Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA
6. Winship Cancer Institute, Emory University, Atlanta, GA, USA
7. Division of Cancer Epidemiology, German Cancer Research Centre, Heidelberg, Germany
8. Department of Medical Biosciences/Pathology, University of Ume?, Ume?, Sweden
9. Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands
10. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
11. Institute of Clinical Chemistry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
12. Department of Epidemiology, School of Public Health, Aarhus University, Aarhus, Denmark
13. Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark
14. Inserm, Centre for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women’s Health Team, 94805, Villejuif, France
15. UMRS 1018, Univ Paris Sud, 94805, Villejuif, France
16. IGR, 94805, Villejuif, France
17. Hellenic Health Foundation, Athens, Greece
18. WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece
19. Nutritional Epidemiology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
20. Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Florence, Italy
21. Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy
22. Cancer Registry and Histopathology Unit, “M.P.Arezzo-Hospital, Ragusa, Italy
23. HuGeF Foundation, Turin, Italy
24. Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, The Netherlands
25. Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), Barcelona, Spain
26. Escuela Andaluza de Salud Pública, Granada, Spain
27. CIBER Epidemiology and Public Health CIBERESP, Spain http://www.ciberesp.es/
28. Instituto de Investigación Biosanitaria de Granada (Granada.bs), Granada, Spain
29. Public Health Directorate, Asturias, Spain
30. Epidemiology and Health Information, Public Health Division of Gipuzkoa, Basque Regional Health Department, San Sebastian, Spain
31. Department of Epidemiology, Murcia Regional Health Authority, Murcia, Spain
32. Navarre Public Health Institute, Pamplona, Spain
33. Department of Radiation Sciences, Ume? University Hospital, Ume?, Sweden
34. Department of Medical Biosciences, Pathology, Ume? University, Ume?, Sweden
35. Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
36. Clinical Gerontology Unit, Addenbrooke’s Hospital, University of Cambridge School of Clinical Medicine, Cambridge, UK
37. MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK
38. Molecular Epidemiology Group, Max Delbrueck Center for Molecular Medicine (MDC), Berlin-Buch, Germany - ISSN：1573-7284
文摘
A number of biomarkers of inflammatory and metabolic pathways are individually related to higher risk of colorectal cancer (CRC); however, the association between biomarker patterns and CRC incidence has not been previously evaluated. Our study investigates the association of biomarker patterns with CRC in a prospective nested case–control study within the European Prospective Investigation into Cancer and Nutrition?(EPIC). During median follow-up time of 7.0 (3.7-.4) years, 1,260 incident CRC cases occurred and were matched to 1,260 controls using risk-set sampling. Pre-diagnostic measurements of C-peptide, glycated hemoglobin, triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), C-reactive protein (CRP), reactive oxygen metabolites (ROM), insulin-like growth factor 1, adiponectin, leptin and soluble leptin receptor (sOB-R) were used to derive biomarker patterns from principal component analysis (PCA). The relation with CRC incidence was assessed using conditional logistic regression models. We identified four biomarker patterns ‘HDL-C/Adiponectin fractions- ‘ROM/CRP- ‘TG/C-peptide-and ‘leptin/sOB-R-to explain 60?% of the overall biomarker variance. In multivariable-adjusted logistic regression, the ‘HDL-C/Adiponectin fractions- ‘ROM/CRP-and ‘leptin/sOB-R-patterns were associated with CRC risk [for the highest quartile vs the lowest, incidence rate ratio (IRR)?=?0.69, 95?% CI 0.51-.93, P-trend?=?0.01; IRR?=?1.70, 95?% CI 1.30-.23, P-trend?=?0.002; and IRR?=?0.79, 95?% CI 0.58-.07; P-trend?=?0.05, respectively]. In contrast, the ‘TG/C-peptide-pattern was not associated with CRC risk (IRR?=?0.75, 95?% CI 0.56-.00, P-trend?=?0.24). After cases within the first 2 follow-up years were excluded, the ‘ROM/CRP-pattern was no longer associated with CRC risk, suggesting potential influence of preclinical disease on these associations. By application of PCA, the study identified ‘HDL-C/Adiponectin fractions- ‘ROM/CRP-and ‘leptin/sOB-R-as biomarker patterns representing potentially important pathways for CRC development.