Multicenter Study

. 2017 Dec 1;46(6):1823-1835.

doi: 10.1093/ije/dyx174.

Physical activity, mediating factors and risk of colon cancer: insights into adiposity and circulating biomarkers from the EPIC cohort

Krasimira Aleksandrova¹, Mazda Jenab², Michael Leitzmann³, Bas Bueno-de-Mesquita^{4

5

6

7}, Rudolf Kaaks⁸, Antonia Trichopoulou^{9

10}, Christina Bamia^{9

10}, Pagona Lagiou^{9

11}, Sabina Rinaldi², Heinz Freisling², Marion Carayol², Tobias Pischon¹², Dagmar Drogan¹³, Elisabete Weiderpass^{14

15

16

17}, Paula Jakszyn¹⁸, Kim Overvad¹⁹, Christina C Dahm¹⁹, Anne Tjønneland²⁰, Marie-Christine Bouton-Ruault^{21

22

23}, Tilman Kühn²⁴, Eleni Peppa⁹, Elissavet Valanou⁹, Carlo La Vecchia^{9

25}, Domenico Palli²⁶, Salvatore Panico²⁷, Carlotta Sacerdote²⁸, Claudia Agnoli²⁹, Rosario Tumino³⁰, Anne May³¹, Jonna van Vulpen³¹, Kristin Benjaminsen Borch¹⁴, Sunday Oluwafemi Oyeyemi¹⁴, J Ramón Quirós³², Catalina Bonet¹⁸, María-José Sánchez^{33

34}, Miren Dorronsoro³⁵, Carmen Navarro^{34

36

37}, Aurelio Barricarte^{34

38

39}, Bethany van Guelpen⁴⁰, Patrik Wennberg⁴¹, Timothy J Key⁴², Kay-Tee Khaw⁴³, Nicholas Wareham⁴⁴, Nada Assi², Heather A Ward⁶, Dagfinn Aune⁶, Elio Riboli⁶, Heiner Boeing⁴⁵

Affiliations

¹ Nutrition, Immunity and Metabolism Start-up Lab, Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany.
² International Agency for Research on Cancer (IARC-WHO), Lyon, France.
³ Department of Epidemiology and Preventive Medicine, Regensburg University Medical Center, Regensburg, Germany.
⁴ National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
⁵ Department of Gastroenterology and Hepatology, University Medical Center, Utrecht, The Netherlands.
⁶ Division of Epidemiology, Public Health and Primary Care, Imperial College, London, UK.
⁷ Department of Social and Preventive Medicine, University of Malaya, Kuala Lumpur, Malaysia.
⁸ Division of Cancer Epidemiology, German Cancer Research Centre, Heidelberg, Germany.
⁹ Hellenic Health Foundation, Athens, Greece.
¹⁰ WHO Collaborating Center for Nutrition and Health, Department of Hygiene, Epidemiology and Medical Statistics, National and Kapodistrian University of Athens (NKUA), Athens, Greece.
¹¹ Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
¹² Molecular Epidemiology Group, Max Delbrueck Center for Molecular Medicine (MDC), Berlin-Buch, Germany.
¹³ Quality and Health Services Research Unit, AOK Research Institute, Berlin, Germany.
¹⁴ Department of Community Medicine, University of Tromsø, Tromsø, Norway.
¹⁵ Department of Research, Cancer Registry of Norway, Oslo, Norway.
¹⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
¹⁷ Genetic Epidemiology Group, Folkhalsan Research Center, Helsinki, Finland.
¹⁸ Cancer Epidemiology Research Program, Catalan Institute of Oncology and Bellvitge Biomedical Research Institute, Barcelona, Spain.
¹⁹ Department of Public Health, Aarhus University, Aarhus, Denmark.
²⁰ Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark.
²¹ Centre for Research in Epidemiology and Population Health, Villejuif, France.
²² Universite Paris Sud, UMRS 1018, F-94805, Villejuif, France.
²³ IGR, F-94805, Villejuif, France.
²⁴ German Cancer Research Center, Division of Cancer Epidemiology, Heidelberg, Germany.
²⁵ Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy.
²⁶ Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute, Florence, Italy.
²⁷ Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy.
²⁸ Unit of Cancer Epidemiology, Città della Salute e della Scienza University-Hospital and Center for Cancer Prevention (CPO), Turin, Italy.
²⁹ Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
³⁰ Cancer Registry and Histopathology Unit, 'M.P. Arezzo' Hospital, Ragusa, Italy.
³¹ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
³² Public Health Directorate, Asturias, Oviedo, Spain.
³³ Escuela Andaluza de Salud Pública. Instituto de Investigación Biosanitaria de Granada, Granada, Spain.
³⁴ Consortium for Biomedical Research in Epidemiology and Public Health, Madrid, Spain.
³⁵ Public Health Division of Gipuzkoa, Basque Regional Health Department, San Sebastian, Spain.
³⁶ Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain.
³⁷ Department of Health and Social Sciences, Universidad de Murcia, Murcia, Spain.
³⁸ Navarre Public Health Institute, Pamplona, Navarra, Spain.
³⁹ Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.
⁴⁰ Department of Radiation Sciences Oncology, Umeå University, Umeå, Sweden.
⁴¹ Department of Public Health and Clinical Medicine, Family Medicine, Umeå University, Umeå, Sweden.
⁴² Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁴³ Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁴⁴ MRC Epidemiology Unit, Addenbrooke's Hospital, Cambridge, UK.
⁴⁵ Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany.

PMID: 29025032
PMCID: PMC6241846
DOI: 10.1093/ije/dyx174

Multicenter Study

Physical activity, mediating factors and risk of colon cancer: insights into adiposity and circulating biomarkers from the EPIC cohort

Krasimira Aleksandrova et al. Int J Epidemiol. 2017.

. 2017 Dec 1;46(6):1823-1835.

doi: 10.1093/ije/dyx174.

Authors

Affiliations

¹ Nutrition, Immunity and Metabolism Start-up Lab, Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany.
² International Agency for Research on Cancer (IARC-WHO), Lyon, France.
³ Department of Epidemiology and Preventive Medicine, Regensburg University Medical Center, Regensburg, Germany.
⁴ National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
⁵ Department of Gastroenterology and Hepatology, University Medical Center, Utrecht, The Netherlands.
⁶ Division of Epidemiology, Public Health and Primary Care, Imperial College, London, UK.
⁷ Department of Social and Preventive Medicine, University of Malaya, Kuala Lumpur, Malaysia.
⁸ Division of Cancer Epidemiology, German Cancer Research Centre, Heidelberg, Germany.
⁹ Hellenic Health Foundation, Athens, Greece.
¹⁰ WHO Collaborating Center for Nutrition and Health, Department of Hygiene, Epidemiology and Medical Statistics, National and Kapodistrian University of Athens (NKUA), Athens, Greece.
¹¹ Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
¹² Molecular Epidemiology Group, Max Delbrueck Center for Molecular Medicine (MDC), Berlin-Buch, Germany.
¹³ Quality and Health Services Research Unit, AOK Research Institute, Berlin, Germany.
¹⁴ Department of Community Medicine, University of Tromsø, Tromsø, Norway.
¹⁵ Department of Research, Cancer Registry of Norway, Oslo, Norway.
¹⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
¹⁷ Genetic Epidemiology Group, Folkhalsan Research Center, Helsinki, Finland.
¹⁸ Cancer Epidemiology Research Program, Catalan Institute of Oncology and Bellvitge Biomedical Research Institute, Barcelona, Spain.
¹⁹ Department of Public Health, Aarhus University, Aarhus, Denmark.
²⁰ Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark.
²¹ Centre for Research in Epidemiology and Population Health, Villejuif, France.
²² Universite Paris Sud, UMRS 1018, F-94805, Villejuif, France.
²³ IGR, F-94805, Villejuif, France.
²⁴ German Cancer Research Center, Division of Cancer Epidemiology, Heidelberg, Germany.
²⁵ Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy.
²⁶ Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute, Florence, Italy.
²⁷ Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy.
²⁸ Unit of Cancer Epidemiology, Città della Salute e della Scienza University-Hospital and Center for Cancer Prevention (CPO), Turin, Italy.
²⁹ Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
³⁰ Cancer Registry and Histopathology Unit, 'M.P. Arezzo' Hospital, Ragusa, Italy.
³¹ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
³² Public Health Directorate, Asturias, Oviedo, Spain.
³³ Escuela Andaluza de Salud Pública. Instituto de Investigación Biosanitaria de Granada, Granada, Spain.
³⁴ Consortium for Biomedical Research in Epidemiology and Public Health, Madrid, Spain.
³⁵ Public Health Division of Gipuzkoa, Basque Regional Health Department, San Sebastian, Spain.
³⁶ Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain.
³⁷ Department of Health and Social Sciences, Universidad de Murcia, Murcia, Spain.
³⁸ Navarre Public Health Institute, Pamplona, Navarra, Spain.
³⁹ Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.
⁴⁰ Department of Radiation Sciences Oncology, Umeå University, Umeå, Sweden.
⁴¹ Department of Public Health and Clinical Medicine, Family Medicine, Umeå University, Umeå, Sweden.
⁴² Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁴³ Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁴⁴ MRC Epidemiology Unit, Addenbrooke's Hospital, Cambridge, UK.
⁴⁵ Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany.

PMID: 29025032
PMCID: PMC6241846
DOI: 10.1093/ije/dyx174

Abstract

Background: There is convincing evidence that high physical activity lowers the risk of colon cancer; however, the underlying biological mechanisms remain largely unknown. We aimed to determine the extent to which body fatness and biomarkers of various biologically plausible pathways account for the association between physical activity and colon cancer.

Methods: We conducted a nested case-control study in a cohort of 519 978 men and women aged 25 to 70 years followed from 1992 to 2003. A total of 713 incident colon cancer cases were matched, using risk-set sampling, to 713 controls on age, sex, study centre, fasting status and hormonal therapy use. The amount of total physical activity during the past year was expressed in metabolic equivalent of task [MET]-h/week. Anthropometric measurements and blood samples were collected at study baseline.

Results: High physical activity was associated with a lower risk of colon cancer: relative risk ≥91 MET-h/week vs <91 MET-h/week = 0.75 [95% confidence interval (CI): 0.57 to 0.96]. In mediation analyses, this association was accounted for by waist circumference: proportion explained effect (PEE) = 17%; CI: 4% to 52%; and the biomarkers soluble leptin receptor (sOB-R): PEE = 15%; 95% CI: 1% to 50% and 5-hydroxyvitamin D (25[OH]D): PEE = 30%; 95% CI: 12% to 88%. In combination, these factors explained 45% (95% CI: 20% to 125%) of the association. Beyond waist circumference, sOB-R and 25[OH]D additionally explained 10% (95% CI: 1%; 56%) and 23% (95% CI: 6%; 111%) of the association, respectively.

Conclusions: Promoting physical activity, particularly outdoors, and maintaining metabolic health and adequate vitamin D levels could represent a promising strategy for colon cancer prevention.

Keywords: Physical activity; adiposity; biomarkers; colon cancer; mediating factors.

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Conflict of interest statement

None of the funders/sponsors had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The authors disclose no potential conflicts of interest related to this study.

We would like to express special thanks to Ellen Kohlsdorf (EPIC-Potsdam, Germany) and Bertrand Hemon (IARC-France) for their work on data management and technical assistance. We thank all participants in the EPIC study for their outstanding cooperation. Persons named in the acknowledgement have confirmed their agreement.

Data sharing: For information on how to submit an application for gaining access to EPIC data and/or biospecimens, please follow the instructions at http://epic.iarc.fr/access/index.php

Figures

**Figure 1**
Schematic presentation of suggested mediating role of body fatness and biomarkers of various biological pathways as explanatory mechanisms of the association between high physical activity and colon cancer risk Causal path diagram for the potential indirect effects (c') of the independent variable (IV) - physical activity - on the dependent variable (DV) - colon cancer - through the hypothesized mediator variables (MV) - body fatness and biomarkers of various biological pathways The mediation effect of biomarkers beyond body fatness (d') was evaluated by calculating proportion of effect explained by each of the biomarkers in a model that included both physical activity and adiposity measures (body mass index and waist circumference).

See this image and copyright information in PMC

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Physical activity, mediating factors and risk of colon cancer: insights into adiposity and circulating biomarkers from the EPIC cohort

Affiliations

Physical activity, mediating factors and risk of colon cancer: insights into adiposity and circulating biomarkers from the EPIC cohort

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Miscellaneous