In a combined cohort made up 134,365 women and men, we found that relative risks for family history of colon or rectal cancer and physical activity were significantly different between colon cancer and rectal cancer.
Our finding, that physical activity is more strongly associated with colon cancer rather than rectal cancer, is consistent with the previous literature. One possible biological mechanism to explain this difference is that the colon is more susceptible to the effects of insulin. With increased physical activity, insulin sensitivity improves. 37
If insulin and insulin-like growth factors are responsible for promoting adenoma development or growth, it is possible that the receptors responsible for this effect are less common in the rectum compared to the colon. Furthermore, we found some disparity between the effect of BMI in men and women. These results are consistent with the hypothesis that the mechanism by which BMI influences risk of colon and rectal cancer are more complex and less consistent in women than in men, possibly influenced by the effects of estrogen.38
Similarly, our findings of an increased risk for colon cancer with increased adult height are consistent with previous literature.13
Previously, it has been proposed that adult height may be a proxy for energy balance during childhood, which would also be related to insulin resistance and levels of growth factors.11
As proposed above, one explanation for the differential association we found for height and physical activity between the colon and rectum is the possibility that the colon has a different pattern of receptors for these growth factors and/or a different sensitivity to insulin effects compared to the rectum. The potential for a gradient of hormone receptors between the colon and rectum is supported by the fact that the colon and rectal mucosa arise from different embryonic tissue, the colon arising from the midgut and the rectum arising from the hindgut.6
More generally, the colon and rectum serve different functions and are exposed to fecal matter for different durations. The rectum is exposed to the fecal in a more concentrated and direct way compared to the colon. Also, as undigested matter travels through the colon, it is coated with alkaline mucus. The different levels of pH in proximal and distal locations within the colon may influence susceptibility to environmental factors.6
In their histologic study of large bowel carcinogenesis, Konishi et al
suggest that cancers that arise in the distal colon and rectum begin as adenomatous polyps whereas a de novo
pathway is more important in lesions that arise in the proximal colon. Also, the prevalence of K-ras mutations and mutation patterns in the p53
gene in rectal cancers differ from those seen in colon cancers.40
In a recent review, Iocapetta highlights the clinical and molecular differences between tumors of the proximal and distal colon. One compelling difference is that the familial forms of colorectal cancer, familial polyposis syndrome (FAP) and hereditary nonpolyposis coli (HNPCC), arise first in different sections of the colon (FAP: rectum and distal colon, HNPCC: proximal colon).6
These findings are compatible with different etiologic factors for colon cancer and rectal cancers.
Previously, risk estimates for rectal cancer have been reported in the NHS and the HPFS cohorts for several variables. These secondary analyses have suggested that there are etiologic differences between the 2 outcomes. For example, in an analysis of family history and colorectal cancer in these 2 cohorts, Fuchs et al.31
reported relative risk (RR) of 1.99 (95% confidence interval (CI): 1.50 –2.63) for colon cancer and a relative risk of 0.86 (95% CI: 0.43–1.70) for rectal cancer among those who reported a family history of colon or rectal cancer. They report a p
-value for the difference between colon and rectal cancer that is based on a simple 1 degree of freedom chi-square test. Our methods offer a more rigorous comparison of these the risk estimates for the 2 outcomes and provide flexibility in allowing some risk estimates to be the same and other to be different based on likelihood ratio methods.35
Our results confirm the hypothesis that a family history of colon or rectal cancer appears to affect risk for colon cancer more strongly than risk for rectal cancer; however, because the questionnaire only queried a history of colon or
rectal cancer, we cannot rule out the possibility that colon cancer cases arose in those with a family history of colon cancer and rectal cancer arose in those with a family history of rectal cancer.
For several variables such as smoking, calcium and beef as a main dish, our results appear slightly weaker than what was previously reported in these cohorts. Generally, these differences can be explained by comparing model specification and follow-up time from each of those results. Previous analyses within these cohorts often used covariates in their models that were at the time known or suspected to be confounders. With time, our understanding of possible confounding factors has improved and therefore we are now able to control for confounding more precisely. Thus, in comparison to prior analyses we have increased the number of covariates in our models and hopefully better captured the underlying associations. Furthermore, with longer follow-up time and therefore more cases, we have improved power to report accurate and precise risk estimates, particularly with respect to rectal cancer. Because we combined the results from the men and women and did not evaluate finer definitions of subsite (e.g., proximal colon vs. distal colon), we may have, for example, also underestimated associations that exist most strongly in the proximal colon.
One example of differences between our results and previous analyses in these cohorts is for pack-years before age 30. Giovannucci et al
has previously reported results for smoking before age 30 in these cohorts by subsite. In the HPFS, they reported a significant association with colon cancer for ≥16 pack-years before age 30 vs
. 0 pack-years before age 30 (RR = 1.96, 95% CI: 1.16 –3.29) and found suggestive but not statistically significant results for rectal cancer (RR = 1.62, 95% CI: 0.60–4.37). These results however were based on total colorectal cases up to 1992, including only 44 rectal cancer cases. In the NHS, they reported elevated risks for both colon and rectal cancer among women 55 and older. However, the RR and CI were slightly stronger for rectal cancer (greater than 10 pack-years vs
. zero pack-years: RR colon = 1.59, 95% CI: 1.14 –2.23; RR rectal = 2.36, 95% CI: 1.22– 4.55).9
Although our results showed weaker associations for colon cancer and rectal cancer than what was found previously, our relative risks are within the confidence intervals they reported. Furthermore, their multivariate models were specified with different covariates than in our study. Giovannucci et al
controlled for age, family history, BMI, and intake of saturated fat, dietary fiber, folate and alcohol, whereas our multivariate models also include height, beef, pork or lamb as a main dish, processed meat, calcium and history of endoscopy. Our results that show a slightly stronger association between cigarette smoking and rectal cancer than for colon cancer are also consistent with a recent prospective cohort study by Terry et al
In their cohort of 89,835 women, they found statistically significant associations between 40 or more years since smoking commenced vs
. never smokers and rectal cancer (hazard ratio = 2.27, 95% CI: 1.06–4.87) but weaker results and nonstatistically significant associations for colon cancer (hazard ratio = 1.12, 95% CI: 0.62–2.04). Further investigations of smoking and rectal cancer should be undertaken to clarify and confirm this association.
Another variable for which our results differ slightly from the previously published findings is calcium. In their analysis, Wu et al
found the strongest association of calcium with disease arising in the distal colon (multivariate pooled RR for >1,250 mg/day versus = 500 mg/day = 0.65, 95% CI = 0.43– 0.98). However, their results were stronger in men than women (men: multivariate RR = 0.58, 95% CI = 0.32–1.05; women: multivariate RR = 0.73, 95% CI = 0.41–1.27). Furthermore, there appeared to be a threshold effect with intakes above 700 mg/day. Since we are combining the proximal and distal colon and, in the PLR model, looking at calcium as a continuous variable, our effect estimates appear weaker. Since previously there was a suggestion of a threshold effect, the interpretation of the relative risk in the polytomous model for calcium in particular, but also to some degree the other variables, must be interpreted with caution, since for the PLR analysis we specified the exposures as continuous variables.
A visual comparison of relative risks can suggest a difference in their contribution to disease in each subsite. However, visually comparing the relative risks from separate logistic models, particularly from different cohorts can be problematic due to the dependence of standardized regression coefficients on study-specific variability in risk factors. Also, a comparison of statistical significance between outcomes is limited by the dependence of levels of statistical significance on numbers of events for each component of the outcome. One major strength of our study is that the Marshall and Chisholm method we used for the polytomous logistic regression models allows for some exposure variables to vary by outcome while others remain the same.
One limitation of our study is that with 339 rectal cancer cases, we may not have enough power to detect small differences in risk estimates between colon and rectal cancer. Therefore, we cannot rule out etiologic differences between the colon and rectum that were suggested by nonsignificant p-values. Given our sample size, for example, it would be premature to conclude a lack of differential risk for colon and rectal cancer with increased height (p = 0.07).
Another limitation of our study is that we considered the colon in its entirety when in fact, etiologic distinctions between the proximal and distal colon may exist. Possibly more significant differences may lie between the proximal (or distal) colon and the rectum, but these differences are not detectable when combining estimates between the proximal and distal colon. In fact, heterogeneity in tumor formation and growth are likely more precisely defined by molecular characteristic rather than anatomic location. However, differentiating risk factors using anatomic definitions may undercover patterns for future analyses using molecular markers.
Some degree of measurement error in our dietary and lifestyle variables is inevitable but any random misclassification of the exposure variables would only attenuate the associations we observed and would not differentially influence one outcome and not the other. However, because in this analysis we are focused on differences between the colon and rectum, any measurement error would reduce our power to compare estimates. The questions used to obtain dietary and lifestyle data from these 2 cohorts are very similar for all variables with the exception of physical activity (and aspirin, which we did not include for this reason). The slight differences in the way we used the physical activity information may have caused some error associated with combining the cohort information for this variable. However, because we used the information from 1986 for both cohorts (directly comparable derivations of MET-hours) for the polytomous logistic regression analysis, these results should still be valid.
In summary, our findings support the hypothesis that some risk factors, including family history, physical activity and possibly height, differ in their association with colon and rectal cancer. We cannot exclude the possibility that the remaining variables we examined actually have different associations with colon and rectal cancer that were not appreciated due to lack of statistical power. Because risk factors for colorectal cancer do not appear to contribute equally to colon and rectal cancers, future investigations into risk for colorectal cancer should ideally be done differentially by subsite.