Risk Factor Profiles Differ for Cancers of Different Regions of the Colorectum

Abstract

Background & aims: The molecular features of colorectal tumors differ with their anatomic location. Colorectal tumors are usually classified as proximal or distal. We collected data from 3 cohorts to identify demographic, clinical, anthropometric, lifestyle, and dietary risk factors for colorectal cancer (CRC) at 7 anatomic subsites. We examined whether the associations differ among refined subsites and whether there are trends in associations from cecum to rectum.

Methods: We collected data from the Nurses' Health Study, Nurses' Health Study 2, and Health Professionals Follow-up Study (45,351 men and 178,016 women, followed for a median 23 years) on 24 risk factors in relation to risk of cancer in cecum, ascending colon, transverse colon, descending colon, sigmoid colon, rectosigmoid junction, and rectum. Hazard ratios were estimated using Cox proportional hazards regression. We tested for linear and nonlinear trends in associations with CRC among subsites and within proximal colon, distal colon, and rectum.

Results: We documented 3058 cases of CRC (474 in cecum, 633 in ascending colon, 250 in transverse colon, 221 in descending colon, 750 in sigmoid colon, 202 in rectosigmoid junction, and 528 in rectum). The positive associations with cancer risk decreased, from cecum to rectum, for age and family history of CRC. In contrast, the inverse associations with cancer risk increased, from cecum to rectum, for endoscopic screening and intake of whole grains, cereal fiber, and processed red meat. There was a significant nonlinear trend in the association between CRC and female sex, with hazard ratios ranging from 1.73 for ascending colon cancer to 0.54 for sigmoid colon cancer. For proximal colon cancers, the association with alcohol consumption and smoking before age 30 years increased from the cecum to transverse colon. For distal colon cancers, the positive association with waist circumference in men was greater for descending vs sigmoid colon cancer.

Conclusions: In an analysis of 3058 cases of CRC, we found that risk factor profiles differed for cancers along the colorectum. Proximal vs distal classifications are not sufficient to encompass the regional variations in colorectal tumor features and risk factors.

Keywords: Epidemiology; Microbiome; Precision Prevention; Spatial Variation.

Figure 1

Multivariable associations of demographic, clinical and lifestyle factors with subsite-specific risk of colorectal cancer according to age at diagnosis (Younger-onset CRC: diagnosed at age of <60 years; older-onset CRC: diagnosed at age of ≥60 years) in the NHS, NHS2, and HPFS. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using age- and cohort-stratified Cox proportional hazards model with further adjustment for race, height (continuous), family history of colorectal cancer (yes or no), history of lower gastrointestinal endoscopic screening (yes or no), body mass index (continuous), pack-years of smoking (continuous), physical activity (continuous), alcohol intake (continuous), and regular aspirin use (yes or no). When age and sex are the main exposures, the model was only adjusted for each other of the two variables. P for heterogeneity was calculated between younger-onset CRC and older-onset CRC using the contrast test method. Abbreviations: BMI, body mass index; CRC, colorectal cancer; HPFS, the Health Professionals Follow-up Study; NHS, the Nurses’ Health Study.

Figure 2

Multivariable associations of dietary factors with subsite-specific risk of colorectal cancer according to age at diagnosis (Younger-onset CRC: diagnosed at age of <60 years; older-onset CRC: diagnosed at age of ≥60 years) in the NHS, NHS2, and HPFS. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using age- and cohort-stratified Cox proportional hazards model with further adjustment for race, height (continuous), family history of colorectal cancer (yes or no), history of lower gastrointestinal endoscopic screening (yes or no), body mass index (continuous), pack-years of smoking (continuous), physical activity (continuous), alcohol intake (continuous), and regular aspirin use (yes or no). P for heterogeneity was calculated between younger-onset CRC and older-onset CRC using the contrast test method. Abbreviations: CRC, colorectal cancer; EDIP, empirical dietary inflammatory pattern; EDIH, empirical dietary index for hyperinsulinemia; HPFS, the Health Professionals Follow-up Study; NHS, the Nurses’ Health Study.