Anatomic Classification of Colorectal Cancer Is Too Broad for Accurate Risk Prediction
Key findings
- Using data from three large U.S. prospective cohorts, researchers at Massachusetts General Hospital evaluated risk factors for colorectal cancer (CRC) across seven anatomic subsites of the proximal and distal colon and rectum
- The associations of certain risk factors with CRC varied substantially across the subsites and even within the proximal colon, distal colon and rectum
- These findings challenge the oversimplified classification of CRC and have implications for improving prevention strategies
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It's long been held that the risk factors for colorectal cancer (CRC) differ in three anatomic locations: proximal colon, distal colon or rectum. Increasing evidence points to differences within these subsites in terms of molecular features, gene mutations and the composition and abundance of the gut microbiota.
Mingyang Song, MD, ScD, assistant professor in the Department of Medicine at Massachusetts General Hospital, and colleagues subdivided the conventional three anatomic locations into seven sites. Using data on more than 223,000 U.S. residents, they determined that the risk factor profile of CRC differs across these subsites, as they report in Gastroenterology.
Study Details
The researchers used data from three large epidemiologic studies:
- The Nurses' Health Study, which enrolled 121,700 female registered nurses ages 30 to 55 in 1976
- The Health Professionals Follow-up Study, which enrolled 51,529 male health professionals ages 40 to 75 years in 1986
- The Nurses' Health Study 2, which enrolled 116,430 female registered nurses ages 25 to 42 in 1989
Every two years, participants were mailed a questionnaire inquiring about their medical history and lifestyle factors. Food frequency questionnaires were mailed every four years starting in 1980, 1986 and 1991, respectively, and those years were used as the study baselines for the current analysis.
On each biennial questionnaire, participants were asked whether they had been diagnosed with CRC during the previous two years. When a participant reported such a diagnosis, study physicians blinded to exposure data reviewed their medical records to determine the tumor subsite: cecum, ascending colon, transverse colon, descending colon, sigmoid colon, rectosigmoid junction or rectum.
178,016 women and 45,351 men were followed for a median of 23 years, and 3,058 with CRC had anatomic data available.
Risk Factors
Risk factors were found to differ for cancers along the colorectum. These factors included demographics, lifestyle and dietary factors.
Demographic Risk Factors
- Older age: Association with CRC decreased from the cecum (HR per 5 years, 1.62) to the rectum (1.32)
- Family history of CRC: Association with CRC decreased from the cecum (HR, 1.86–1.10)
- Female sex: The highest HR was observed for ascending colon cancer (1.73) and the lowest for sigmoid colon cancer (0.54)
Lifestyle Factors
- Alcohol intake: Association with CRC increased from the cecum to transverse colon (HR per 14 g/day, 0.99–1.25)
- Smoking before age 30: As above (HR per 20 pack-years, 1.08–1.43)
Dietary Intake
- Whole grains: Association with CRC increased from the cecum to the rectum (HR per 20 g/day, 1.08–0.75)
- Cereal fiber: Association with CRC increased from the cecum to the rectum (HR per 5 g/day, 1.13–0.60)
- Processed red meat: Association with CRC increased from the cecum to the rectum (HR per 3 servings/week, 0.96–1.23)
- Folate: Significant difference in risk between cancers in the descending colon and sigmoid colon (HR per 400 mg/day, 1.10 vs. 0.76)
- Empirical Dietary Inflammatory Pattern: Most strongly associated with cancers in the cecum and sigmoid colon (HR per 1 unit, 1.54 and 1.52)
- Empirical Dietary Index for Hyperinsulinemia: Significant difference in risk between cancers in the transverse colon and descending colon (HR per 1 unit, 2.19 vs. 2.02) and between cancers in the rectosigmoid junction and rectum (0.71 vs. 1.54)
The Hope for Precision Prevention
A better understanding of CRC risk factors according to tumor subsites might allow the development of location-specific prediction tools that would be more accurate than current models. In turn, more accurate risk assessments might enable better screening and prevention strategies. For example, dietary modifications that improve metabolic health might prove to reduce the risk of distal colon cancer. Although there is a long road ahead before science can actualize the promises of precision prevention, this study provides the proof of principle.
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