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

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 modi fi able risk factors underlying EOCRC are unknown. We conducted the fi rst EOCRC-speci fi c genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modi fi able 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 modi fi able 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 identi fi ed a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% con fi dence 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 identi fi ed new EOCRCsusceptibility genes, and in addition to pathways such as transforming growth factor (TGF) b , 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 d such as body fat percentage, waist circumference, waist -to -hip ratio, basal metabolic rate, and fasting insulin d higher alcohol drinking, and lower education attainment with increased EOCRC risk. Conclusions: Our novel fi ndings indicate inherited susceptibility to EOCRC and suggest modi fi able lifestyle and metabolic targets that could also be used to risk -stratify individuals for personalized screening strategies or other interventions.