Risk Factors in Sporadic Early-Onset Colorectal Cancer, Current Evidence and Emerging Insights: A Systematic Review

Background: The incidence of early-onset colorectal cancer (EOCRC) is rising globally, yet its underlying risk factors remain incompletely understood, particularly in cases without recognised hereditary syndromes. Objectives: To update and synthesise the current body of evidence on modifiable and non-modifiable risk factors for sporadic early-onset colorectal cancer. Methods: A systematic review of peer-reviewed articles published in English reporting original observational research examining risk factors for sporadic early-onset colorectal cancer (<50 years old) was conducted. PubMed and EMBASE databases were searched from inception to March 2025. Across studies, effect measures varied; therefore, the synthesis focused on the consistency of associations rather than the direct comparison of effect sizes. Results: The initial search identified 2575 papers; 34 studies were included after screening. Several consistent associations were identified, with dietary and lifestyle factors along with metabolic conditions emerging as key risk factors. EOCRC risk was higher in males (adjusted odds ratio (aOR) 1.36-2.21 across studies), individuals of Caucasian ethnicity (aORs 1.48-2.56), and in individuals whose age was approaching 50 years (per year, aORs 1.05-1.11). Putatively sporadic EOCRC was associated with a family history of CRC or other cancers (aORs up to 8.61). Other key factors linked to higher risk included obesity (aORs 1.92-2.88; adjusted Hazard Ratios (aHRs) 1.04-1.82), metabolic syndrome (aORs 1.25-2.48; aHRs 1.2-1.26), diabetes (aORs 1.24-3.42), Western dietary patterns (aORs 1.84-2.99), and sedentary behaviours (adjusted relative risks (aRR) 1.69-2.44). Moderate-to-vigorous exercise appeared protective (aORs 0.34-0.58), as did higher vitamin D levels (aHRs 0.41-0.61). Evidence for smoking, alcohol, medications and early/in utero environmental exposures was inconsistent. Conclusions: Lifestyle and metabolic factors, including Western dietary patterns, obesity and sedentary behaviours, were associated with sporadic EOCRC. Family history also emerged as a significant contributor to putatively sporadic disease, suggesting heritable influences beyond recognised syndromes and interplay between environmental factors and genetic predisposition. Future research should focus on integrated tumour and germline profiling, including broader genomic analyses in well-characterised cohorts, to better understand potential pathogenic mechanisms and support the development of risk stratification approaches.