Early-onset colorectal cancer: initial clues and current views

Abstract

Over the past several decades, the incidence of early-onset colorectal cancer (EOCRC; in patients <50 years old) has increased at an alarming rate. Although robust and scientifically rigorous epidemiological studies have sifted out environmental elements linked to EOCRC, our knowledge of the causes and mechanisms of this disease is far from complete. Here, we highlight potential risk factors and putative mechanisms that drive EOCRC and suggest likely areas for fruitful research. In addition, we identify inconsistencies in the evidence implicating a strong effect of increased adiposity and suggest that certain behaviours (such as diet and stress) might place nonobese and otherwise healthy people at risk of this disease. Key risk factors are reviewed, including the global westernization of diets (usually involving a high intake of red and processed meats, high-fructose corn syrup and unhealthy cooking methods), stress, antibiotics, synthetic food dyes, monosodium glutamate, titanium dioxide, and physical inactivity and/or sedentary behaviour. The gut microbiota is probably at the crossroads of these risk factors and EOCRC. The time course of the disease and the fact that relevant exposures probably occur in childhood raise important methodological issues that are also discussed. The incidence of early-onset colorectal cancer (in patients <50 years old) is increasing at an alarming rate. This Review highlights potential risk factors and putative mechanisms that drive this disease, and suggests likely areas for fruitful research, including diet, stress and antibiotics. The alarming rise in early-onset colorectal cancer (EOCRC) over the past four decades described by epidemiological studies and cancer registry data requires coordination and follow-up with mechanistic in vitro testing, animal experimentation and human intervention studies. EOCRC occurs in both people who are obese and those who are nonobese, and the rising incidence is global. Some solutions to EOCRC can be deployed now (for example, awareness campaigns); some can be deployed with additional work to overcome barriers (such as identifying surrogate end points); and some can deployed with money, time, ingenuity and scientific rigour (for example, uncovering mechanisms and gene–environment interactions). Key elements driving EOCRC are exposed when four metrics are fulfilled: one, a temporal relationship exists that follows that of EOCRC; two, exposure is global, as with EOCRC; three, evidence exists of inflammatory or microbiome-modifying properties or evidence of an effect on the distal colon or rectum; and four, exposure occurs during development from conception to adulthood. The following elements reach all four of the above metrics: a westernized diet including red and processed meats; consumption of monosodium glutamate, titanium dioxide, high-fructose corn syrup and synthetic dyes; obesity; stress; and widespread use of antibiotics. Delineation of exposomal elements attacking the rectum versus colon and their interactions with genetics is a critical step to understanding this disease for purposes of chemoprevention and treatment.