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Genome-wide association studies and Mendelian randomization analyses provide insights into the causes of early-onset colorectal cancer
RS. Laskar, C. Qu, JR. Huyghe, T. Harrison, RB. Hayes, Y. Cao, PT. Campbell, R. Steinfelder, FR. Talukdar, H. Brenner, S. Ogino, S. Brendt, DT. Bishop, DD. Buchanan, AT. Chan, M. Cotterchio, SB. Gruber, A. Gsur, B. van Guelpen, MA. Jenkins, TO....
Language English Country England, Great Britain
Document type Journal Article, Meta-Analysis
Grant support
001
World Health Organization - International
- MeSH
- Genome-Wide Association Study * MeSH
- Adult MeSH
- Genetic Predisposition to Disease * MeSH
- Polymorphism, Single Nucleotide MeSH
- Colorectal Neoplasms * genetics epidemiology MeSH
- Humans MeSH
- Mendelian Randomization Analysis * MeSH
- Risk Factors MeSH
- Case-Control Studies MeSH
- Age of Onset MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Meta-Analysis MeSH
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.
Alvin J Siteman Cancer Center St Louis
Cancer Epidemiology Division Cancer Council Victoria Melbourne
Cancer Research UK Cambridge Institute University of Cambridge Cambridge UK
Center for Cancer Research Medical University of Vienna Vienna Austria
Center for Gastrointestinal Biology and Disease University of North Carolina Chapel Hill USA
CIBER de Epidemiología y Salud Pública Madrid
Colorectal Oncogenomics Group Department of Clinical Pathology The University of Melbourne Parkville
Dalla Lana School of Public Health University of Toronto Toronto Canada
Department of Clinical Sciences Faculty of Medicine University of Barcelona Barcelona Spain
Department of Colorectal Surgery North Bristol NHS Trust Bristol UK
Department of Epidemiology and Population Health Albert Einstein College of Medicine Bronx USA
Department of Epidemiology Harvard T H Chan School of Public Health Harvard University Boston
Department of Epidemiology University of Washington Seattle USA
Department of Hygiene and Epidemiology University of Ioannina School of Medicine Ioannina Greece
Department of Medical Oncology Dana Farber Cancer Institute Boston
Department of Nutrition Harvard T H Chan School of Public Health Boston USA
Department of Oncologic Pathology Dana Farber Cancer Institute Boston
Department of Radiation Sciences Oncology Unit Umeå University Umeå
Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston
Faculty of Medicine and Biomedical Center in Pilsen Charles University Pilsen Czech Republic
Genomic Medicine and Family Cancer Clinic Royal Melbourne Hospital Parkville Australia
Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University Prague
Leeds Institute of Cancer and Pathology University of Leeds Leeds UK
Memorial University of Newfoundland Discipline of Genetics St John's Canada
Physical Activity Laboratory Baker Heart and Diabetes Institute Melbourne Australia
Population Health Sciences Bristol Medical School University of Bristol Bristol
Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle
University of Hawaii Cancer Center Honolulu USA
University of Melbourne Centre for Cancer Research Victorian Comprehensive Cancer Centre Melbourne
Wallenberg Centre for Molecular Medicine Umeå University Umeå Sweden
References provided by Crossref.org
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- $a Laskar, R S $u 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, UK. Electronic address: laskarr@iarc.who.int
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