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

R S Laskar; C Qu; J R Huyghe; T Harrison; R B Hayes; Y Cao; P T Campbell; R Steinfelder; F R Talukdar; H Brenner; S Ogino; S Brendt; D T Bishop; D D Buchanan; A T Chan; M Cotterchio; S B Gruber; A Gsur; B van Guelpen; M A Jenkins; T O Keku; B M Lynch; L Le Marchand; R M Martin; K McCarthy; V Moreno; R Pearlman; M Song; K K Tsilidis; P Vodička; M O Woods; K Wu; L Hsu; M J Gunter; U Peters; N Murphy; Colorectal Transdisciplinary (CORECT) Study, the Colon Cancer Family Registry (CCFR), Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO)

doi:10.1016/j.annonc.2024.02.008

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

Ann Oncol. 2024 Feb 24:S0923-7534(24)00058-9. doi: 10.1016/j.annonc.2024.02.008. Online ahead of print.

Authors

R S Laskar¹, C Qu², J R Huyghe², T Harrison², R B Hayes³, Y Cao⁴, P T Campbell⁵, R Steinfelder², F R Talukdar⁶, H Brenner⁷, S Ogino⁸, S Brendt⁹, D T Bishop¹⁰, D D Buchanan¹¹, A T Chan¹², M Cotterchio¹³, S B Gruber¹⁴, A Gsur¹⁵, B van Guelpen¹⁶, M A Jenkins¹⁷, T O Keku¹⁸, B M Lynch¹⁹, L Le Marchand²⁰, R M Martin²¹, K McCarthy²², V Moreno²³, R Pearlman²⁴, M Song²⁵, K K Tsilidis²⁶, P Vodička²⁷, M O Woods²⁸, K Wu²⁹, L Hsu², M J Gunter³⁰, U Peters³¹, N Murphy³²; Colorectal Transdisciplinary (CORECT) Study, the Colon Cancer Family Registry (CCFR), Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO)

Affiliations

¹ 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.
² Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle.
³ Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York.
⁴ Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis; Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St Louis; Alvin J. Siteman Cancer Center, St Louis.
⁵ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, USA.
⁶ Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
⁷ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁸ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston; Program in Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston.
⁹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, USA.
¹⁰ Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
¹¹ Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Melbourne; Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Australia.
¹² Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, USA.
¹³ Ontario Health (Cancer Care Ontario), Toronto; Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
¹⁴ Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, USA.
¹⁵ Center for Cancer Research, Medical University of Vienna, Vienna, Austria.
¹⁶ Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå; Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
¹⁷ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia.
¹⁸ Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, USA.
¹⁹ 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; Physical Activity Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia.
²⁰ University of Hawaii Cancer Center, Honolulu, USA.
²¹ Medical Research Council (MRC) Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol; National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol.
²² Department of Colorectal Surgery, North Bristol NHS Trust, Bristol, UK.
²³ Cancer Prevention and Control Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona; CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid; Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
²⁴ Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus.
²⁵ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, USA.
²⁶ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
²⁷ Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague; Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic.
²⁸ Memorial University of Newfoundland, Discipline of Genetics, St. John's, Canada.
²⁹ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, USA.
³⁰ 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, UK.
³¹ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle; Department of Epidemiology, University of Washington, Seattle, USA.
³² Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France. Electronic address: murphyn@iarc.who.int.

PMID: 38408508
DOI: 10.1016/j.annonc.2024.02.008

Abstract

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.

Keywords: GWAS; Mendelian randomization; early-onset colorectal cancer; genetics; risk factors.

Grants and funding

001/WHO_/World Health Organization/International