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

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. Colorectal cancer (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 analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC.

PATIENTS AND METHODS: We conducted a genome-wide association study meta-analysis of 6,176 EOCRC cases and 65,829 controls from Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), Colorectal Transdisciplinary study (CORECT), Colon Cancer Family Registry (CCFR), and UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample Mendelian randomization (MR).

RESULTS: We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (OR=1.80 [95%CI=1.47-2.22]) but show that most of the common genetic susceptibility was from non-coding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC susceptibility genes, and in addition to pathways such as TGFβ, SMAD, BMP, and 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.

CONCLUSION: 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.