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  • Laskar, R.S.Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France; Early Cancer Institute, Department of Oncology, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom (author)

Genome-wide association studies and Mendelian randomization analyses provide insights into the causes of early-onset colorectal cancer

  • Article/chapterEnglish2024

Publisher, publication year, extent ...

  • Elsevier,2024
  • electronicrdacarrier

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  • LIBRIS-ID:oai:DiVA.org:umu-224251
  • https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-224251URI
  • https://doi.org/10.1016/j.annonc.2024.02.008DOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • Background: The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC.Patients and methods: We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR.Results: We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) β, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors—such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin—higher alcohol drinking, and lower education attainment with increased EOCRC risk.Conclusions: Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions.

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  • Qu, C.Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States (author)
  • Huyghe, J.R.Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States (author)
  • Harrison, T.Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States (author)
  • Hayes, R.B.Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, United States (author)
  • Cao, Y.Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, United States; Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St Louis, United States; Alvin J. Siteman Cancer Center, St Louis, United States (author)
  • Campbell, P.T.Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, United States (author)
  • Steinfelder, R.Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States (author)
  • Talukdar, F.R.Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom (author)
  • Brenner, H.Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany (author)
  • Ogino, S.Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, United States; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States; Program in Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, United States; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, United States (author)
  • Brendt, S.Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, United States (author)
  • Bishop, D.T.Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom (author)
  • Buchanan, D.D.Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, United States; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Melbourne, Australia; Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Australia (author)
  • Chan, A.T.Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, United States; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States (author)
  • Cotterchio, M.Ontario Health (Cancer Care Ontario), Toronto, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, Canada (author)
  • Gruber, S.B.Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, United States (author)
  • Gsur, A.Center for Cancer Research, Medical University of Vienna, Vienna, Austria (author)
  • van Guelpen, BethanyUmeå universitet,Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM),Onkologi(Swepub:umu)beyvan99 (author)
  • Jenkins, M.A.Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia (author)
  • Keku, T.O.Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, United States (author)
  • Lynch, B.M.Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia; Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Australia; Physical Activity Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia (author)
  • Le Marchand, L.University of Hawaii Cancer Center, Honolulu, United States (author)
  • Martin, R.M.Medical Research Council (MRC) Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom; National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, United Kingdom (author)
  • McCarthy, K.Department of Colorectal Surgery, North Bristol NHS Trust, Bristol, United Kingdom (author)
  • Moreno, V.Cancer Prevention and Control Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain; CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain (author)
  • Pearlman, R.Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, United States (author)
  • Song, M.Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, United States; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, United States; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, United States (author)
  • Tsilidis, K.K.Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece (author)
  • Vodička, P.Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic; Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Czech Republic, Pilsen, Czech Republic (author)
  • Woods, M.O.Memorial University of Newfoundland, Discipline of Genetics, St. John's, Canada (author)
  • Wu, K.Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, United States (author)
  • Hsu, L.Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States (author)
  • Gunter, M.J.Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom (author)
  • Peters, U.Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States; Department of Epidemiology, University of Washington, Seattle, United States (author)
  • Murphy, N.Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France (author)
  • Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France; Early Cancer Institute, Department of Oncology, School of Clinical Medicine, University of Cambridge, Cambridge, United KingdomPublic Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States (creator_code:org_t)

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  • In:Annals of Oncology: Elsevier35:6, s. 523-5360923-75341569-8041

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