Heterogeneity of Colorectal Cancer Risk Factors by Anatomical Subsite in 10 European Countries: A Multinational Cohort Study

Abstract

Background & aims: Colorectal cancer located at different anatomical subsites may have distinct etiologies and risk factors. Previous studies that have examined this hypothesis have yielded inconsistent results, possibly because most studies have been of insufficient size to identify heterogeneous associations with precision.

Methods: In the European Prospective Investigation into Cancer and Nutrition study, we used multivariable joint Cox proportional hazards models, which accounted for tumors at different anatomical sites (proximal colon, distal colon, and rectum) as competing risks, to examine the relationships between 14 established/suspected lifestyle, anthropometric, and reproductive/menstrual risk factors with colorectal cancer risk. Heterogeneity across sites was tested using Wald tests.

Results: After a median of 14.9 years of follow-up of 521,330 men and women, 6291 colorectal cancer cases occurred. Physical activity was related inversely to proximal colon and distal colon cancer, but not to rectal cancer (P heterogeneity = .03). Height was associated positively with proximal and distal colon cancer only, but not rectal cancer (P heterogeneity = .0001). For men, but not women, heterogeneous relationships were observed for body mass index (P heterogeneity = .008) and waist circumference (P heterogeneity = .03), with weaker positive associations found for rectal cancer, compared with proximal and distal colon cancer. Current smoking was associated with a greater risk of rectal and proximal colon cancer, but not distal colon cancer (P heterogeneity = .05). No heterogeneity by anatomical site was found for alcohol consumption, diabetes, nonsteroidal anti-inflammatory drug use, and reproductive/menstrual factors.

Conclusions: The relationships between physical activity, anthropometry, and smoking with colorectal cancer risk differed by subsite, supporting the hypothesis that tumors in different anatomical regions may have distinct etiologies.

Keywords: Anatomic Subsite; Colorectal Cancer; Distal Colon; Heterogeneity; Proximal Colon; Rectum; Risk Factors.

Figure 1

Multivariable-adjusted HRs and 95% CIs for colorectal cancer incidence for both sexes combined in relation to lifestyle factors, by anatomic site. For alcohol consumption, physical activity, and smoking status: multivariable models–Cox regression using age as the underlying time variable and stratified by sex, center, and age at recruitment. Models mutually adjusted, and additionally adjusted for body mass index, height, education level, ever use of menopausal hormone therapy, and intakes of alcohol, red and processed meats, calcium, and fiber. For ever NSAID use and prevalent diabetes: multivariable models–Cox regression using age as the underlying time variable and stratified by sex, center, and age at recruitment adjusted for body mass index, height, physical activity; smoking status and intensity; education level; ever use of menopausal hormone therapy; and intakes of alcohol, red and processed meats, calcium, and fiber. Information on NSAID use was available from only 6 centers: Cambridge, Utrecht, Heidelberg, Potsdam, Aarhus, and Copenhagen. Prox-dist-rect, proximal, distal, rectal.

Figure 2

Multivariable-adjusted HRs and 95% CIs for colorectal cancer incidence for both sexes combined in relation to anthropometric measures, by anatomic site. Multivariable models only–Cox regression using age as the underlying time variable and stratified by center and age at recruitment, and adjusted for physical activity, smoking status and intensity, education level, ever use of menopausal hormone therapy, and intakes of alcohol, red and processed meats, calcium, and fiber. Multivariable model for height was adjusted further for body mass index. Multivariable models for body mass index, waist circumference, and waist-to-hip ratio were adjusted further for height. Prox-dist-rect, proximal, distal, rectal.

Figure 3

Multivariable-adjusted HRs and 95% CIs for colorectal cancer incidence in relation to reproductive and menstrual factors among women, by anatomic site. Multivariable models only–Cox regression using age as the underlying time variable and stratified by center and age at recruitment, and adjusted for body mass index, height, physical activity, smoking status and intensity, education level, ever use of menopausal hormone therapy, and intakes of alcohol, red and processed meats, calcium, and fiber. Prox-dist-rect, proximal, distal, rectal.