• Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France. papadimitrioun@iarc.who.int.
• MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK.
• Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France.
• Cancer Biology and Therapeutics Group, UCD Conway Institute, School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland.
• Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health, Bethesda, MD, USA.
• Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
• Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France.
• University of Hawaii Cancer Center, Honolulu, HI, USA.
• Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA.
• Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

BACKGROUND: Observational studies have linked childhood obesity with elevated risk of colorectal cancer; however, it is unclear if this association is causal or independent from the effects of obesity in adulthood on colorectal cancer risk.

METHODS: We conducted Mendelian randomization (MR) analyses to investigate potential causal relationships between self-perceived body size (thinner, plumper, or about average) in early life (age 10) and measured body mass index in adulthood (mean age 56.5) with risk of colorectal cancer. The total and independent effects of body size exposures were estimated using univariable and multivariable MR, respectively. Summary data were obtained from a genome-wide association study of 453,169 participants in UK Biobank for body size and from a genome-wide association study meta-analysis of three colorectal cancer consortia of 125,478 participants.

RESULTS: Genetically predicted early life body size was estimated to increase odds of colorectal cancer (odds ratio [OR] per category change: 1.12, 95% confidence interval [CI]: 0.98-1.27), with stronger results for colon cancer (OR: 1.16, 95% CI: 1.00-1.35), and distal colon cancer (OR: 1.25, 95% CI: 1.04-1.51). After accounting for adult body size using multivariable MR, effect estimates for early life body size were attenuated towards the null for colorectal cancer (OR: 0.97, 95% CI: 0.77-1.22) and colon cancer (OR: 0.97, 95% CI: 0.76-1.25), while the estimate for distal colon cancer was of similar magnitude but more imprecise (OR: 1.27, 95% CI: 0.90-1.77). Genetically predicted adult life body size was estimated to increase odds of colorectal (OR: 1.27, 95% CI: 1.03, 1.57), colon (OR: 1.32, 95% CI: 1.05, 1.67), and proximal colon (OR: 1.57, 95% CI: 1.21, 2.05).

CONCLUSIONS: Our findings suggest that the positive association between early life body size and colorectal cancer risk is likely due to large body size retainment into adulthood.