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Using gene-environment interactions to explore pathways for colorectal cancer risk.

Authors

Bouras E, Yu R, Kim AE, Markozannes G, Murphy N, Albanes D, Anderson LN, Barry EL, Berndt SI, Bishop DT, Brenner H, Burnett-Hartman A, Campbell PT, Carreras-Torres R, Chan AT, Cheng I, Devall MA, Diez-Obrero V, Dimou N, Drew DA, ...show more Gruber SB, Gsur A, Hoffmeister M, Hsu L, Huyghe JR, Kawaguchi E, Keku TO, Kundaje A, Küry S, Le Marchand L, Lewinger JP, Li L, Lynch BM, Moreno V, Morrison JL, Newton CC, Obón-Santacana M, Palmer JR, Papadimitriou N, Pellatt AJ, Peoples AR, Pharoah PDP, Platz EA, Qu C, Ruiz-Narvaez E, Mendez JS, Schoen RE, Stern MC, Thomas CE, Tian Y, Um CY, Visvanathan K, Vodicka P, Vymetalkova V, White E, Wolk A, Woods MO, Wu AH, Gunter MJ, Gauderman WJ, Peters U, Evangelou M, Tsilidis KK

Affiliations

  • Department of Epidemiology and Biostatistics, School of Public Health-Faculty of Medicine, Imperial College London, London, UK; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece. Electronic address: ebouras@imperial.ac.uk.
  • Department of Mathematics, Faculty of Natural Sciences, Imperial College London, London, UK.
  • Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Department of Epidemiology and Biostatistics, School of Public Health-Faculty of Medicine, Imperial College London, London, UK; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
  • Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.
  • Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
  • Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
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  • Institute for Health Research, Kaiser Permanente Colorado, Denver, CO, USA.
  • Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908, Barcelona, Spain; Digestive Diseases and Microbiota Group, Girona Biomedical Research Institute (IDIBGI), Salt, 17190, Girona, Spain.
  • Broad Institute of Harvard and MIT, Cambridge, MA, USA; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Department of Epidemiology and Biostatistics, University of California-San Francisco, San Francisco, CA, USA.
  • Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA; Department of Public Health Sciences, Center for Public Health Genomics, Charlottesville, VA, USA.
  • Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908, Barcelona, Spain; Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), Barcelona, 08908, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029, Madrid, Spain; Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, 08908, Spain.
  • Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Department of Medical Oncology & Therapeutics Research and Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, USA.
  • Center for Cancer Research, Medical University of Vienna, Vienna, Austria.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Biostatistics, University of Washington, Seattle, WA, USA.
  • Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
  • Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA.
  • Department of Computer Science, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA.
  • Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France.
  • Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
  • Department of Family Medicine, University of Virginia, Charlottesville, VA, USA.
  • Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
  • Department of Population Science, American Cancer Society, Atlanta, GA, USA.
  • Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908, Barcelona, Spain; Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), Barcelona, 08908, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029, Madrid, Spain.
  • Slone Epidemiology Center, at Boston University, Boston, MA, USA.
  • Intermountain Health, Salt Lake City, UT, USA.
  • Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
  • Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA.
  • Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Departments of Medicine and Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; School of Public Health, Capital Medical University, Beijing, China.
  • Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic; Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic.
  • Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA.
  • Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
  • Memorial University of Newfoundland, Discipline of Genetics, St. John's, Canada.
  • Department of Epidemiology and Biostatistics, School of Public Health-Faculty of Medicine, Imperial College London, London, UK; Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France.
  • Department of Epidemiology and Biostatistics, School of Public Health-Faculty of Medicine, Imperial College London, London, UK; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece. Electronic address: k.tsilidis@imperial.ac.uk.

Abstract

BACKGROUND: Colorectal cancer (CRC) is a significant public health concern, highlighting the critical need for identifying novel intervention targets for its prevention.

METHODS: We conducted genome-wide interaction analyses for 15 exposures with established or putative CRC risk [body mass index (BMI), height, physical activity, smoking, type 2 diabetes, use of menopausal hormone therapy, non-steroidal anti-inflammatory drugs, and intake of alcohol, calcium, fibre, folate, fruits, processed meat, red meat, and vegetables], and used interaction estimates to explore pathways and genes underlying CRC risk. The adaptive combination of Bayes Factors (ADABF), and over-representation analysis (ORA) were used for pathway analyses, and findings were further investigated using publicly available resources [hallmarks of cancer, Open Targets Platform (OTP)].

FINDINGS: A total of 1973 pathways using ADABF, and 840 pathways using ORA, out of the 2950 analysed, were enriched (P < 0.05) for at least one exposure, as well as 1227 genes within the enriched pathways. Data were available for 811/1227 coding genes in the OTP, 241 of which were supported by strong relative abundance of prior evidence (overall OTP score > 0.05). Fifty percent of the genes (617/1227) mapped to at least one hallmark of cancer, most of which (388/617) pertained to the Sustaining Proliferative Signalling hallmark. Our findings reflect previously established pathways for CRC risk and highlight the emerging importance of several less studied genes. Common pathways were found for several combinations of exposures, potentially suggesting common underlying mechanisms.

INTERPRETATION: The results of the present analysis provide a basis for further functional research. If confirmed, they may help elucidate the etiological associations between risk factors and CRC risk and ultimately inform personalized prevention strategies.

FUNDING: This study was funded by Cancer Research UK (CRUK; grant number:PPRCPJT∖100005) and World Cancer Research Fund International (WCRF; IIG_FULL_2020_022). Funding for grant IIG_FULL_2020_022 was obtained from Wereld Kanker Onderzoek Fonds (WKOF) as part of the World Cancer Research Fund International grant programme. Full funding details for the individual consortia are provided in the acknowledgements.

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Publication Details

PubMed ID
41076992

Digital Object Identifier
10.1016/j.ebiom.2025.105964

Publication
EBioMedicine. 2025 Nov; Volume 121: Pages 105964

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