• Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
• Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
• Epidemiology, University of Michigan, Ann Arbor, Michigan, USA.
• Channing Division of Network Medicine, Harvard Medical School, Boston, Massachusetts, USA.
• Epidemiology, Harvard University T H Chan School of Public Health, Boston, Massachusetts, USA.
• Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.
• Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
• Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
• Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
• Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.

OBJECTIVE: 'Environmental' factors associated with colorectal cancer (CRC) risk include modifiable and non-modifiable variables. Whether those with different non-modifiable baseline risks will benefit similarly from reducing their modifiable CRC risks remains unclear.

DESIGN: Using 7945 cases and 8893 controls from 11 population-based studies, we combined 17 risk factors to characterise the overall environmental predisposition to CRC (environmental risk score (E-score)). We estimated the absolute risks (ARs) of CRC of 10 and 30 years across E-score using incidence-rate data from the Surveillance, Epidemiology, and End Results programme. We then combined the modifiable risk factors and estimated ARs across the modifiable risk score, stratified by non-modifiable risk profile based on genetic predisposition, family history and height.

RESULTS: Higher E-score was associated with increased CRC risk (OR_quartile, 1.33; 95% CI 1.30 to 1.37). Across E-scores, 30-year ARs of CRC increased from 2.5% in the lowest quartile (Q1) to 5.9% in the highest (Q4) quartile for men, and from 2.1% to 4.5% for women. The modifiable risk score had a stronger association in those with high non-modifiable risk (relative excess risk due to interaction=1.2, 95% CI 0.5 to 1.9). For those in Q4 of non-modifiable risk, a decrease in modifiable risk reduced 30-year ARs from 8.9% to 3.4% for men and from 6.0% to 3.2% for women, a level lower or comparable to the average population risk.

CONCLUSIONS: Changes in modifiable risk factors may result in a substantial decline in CRC risk in both sexes. Those with high inherited risk may reap greater benefit from lifestyle modifications. Our results suggested comprehensive evaluation of environmental factors may facilitate CRC risk stratification.