Diabetes mellitus was associated significantly with colorectal cancer on univariate analysis (OR: 3.5; 95% CI: 1.2–10.3; P=0.025) and after multivariate analysis (OR: 5.4; 95% CI: 1.4–19.9; P=0.012). A history of schistosomiasis was also associated with colorectal cancer on univariate analysis (OR: 2.4; 95% CI: 1.4–4.2; P=0.001) and multivariate analyses (OR: 2.4; 95% CI: 1.3–4.3; P=0.006). The use of NSAIDs, alcohol or smoking was not associated with colorectal cancer in this study.
A history of any cancer among first-degree relatives was associated with colorectal cancer on univariate analysis (OR: 2.4; 95% CI: 1.2–4.8; P=0.018). This remained significant after multivariate analysis (OR: 3.2; 95% CI 1.4–7.6; P=0.007). However, there was no association with colorectal cancer among first-degree relatives (OR: 1.5; 95% CI: 0.1–25.5; P=0.090).
This is the first study to investigate the factors associated with colorectal cancer in an African population using confirmed neoplasia as the endpoint. The results show that diabetes mellitus, urban domicile, schistosomiasis and a family history of cancer are associated with colorectal cancer in this population. Our findings imply that the increasing incidence of colorectal cancer in Zimbabwe is partly related to the emerging epidemic of diabetes mellitus against a background of increasing urbanization. The association of schistosomiasis with colorectal cancer is surprising, but this could contribute towards the frequent early-onset colorectal cancers, together with hereditary factors.
Diabetes mellitus is a recognized risk factor for colorectal cancer, independent of diet, physical exercise, smoking, obesity or the metabolic syndrome (Yuhara et al., 2011; Jarvandi et al., 2013). This effect is probably mediated by the high levels of insulin and insulin-like growth factors. Hyperinsulinaemia potentiates the activation of the ras pathway, whereas insulin-like growth factors inhibit apoptosis of the colonic epithelial cells (Guo et al., 1992; Leitner et al., 1997). In animal studies, it has been found that insulin stimulates aberrant crypt foci and promotes the development of colonic tumours (Tran et al., 1996; Corpet et al., 1997). There is a growing diabetes epidemic in sub-Saharan Africa, which is driven by increasing levels of obesity, particularly among the affluent (Bailey et al., 2016). Obesity is also an independent risk factor of colorectal cancer (Renehan et al., 2008). We did not assess the effect of obesity on colorectal cancer in our study because of difficulties in estimating the premorbid BMI in the cases. Our findings imply that the increasing incidence of diabetes mellitus is contributing toward the increasing incidence of colorectal cancer.
There was an association between having lived in an urban area at any point in life and colorectal cancer in our study. Urbanization in Africa is associated with dietary changes, particularly an increased intake of meat, meat products and energy- dense foods, with a reduction in the consumption of staple starches and plant-based foods (Vorster et al., 2011). A high intake of meat and processed meat products is an established risk factor for colorectal cancer (Bouvard et al., 2015). Urbanization is also associated with a sedentary lifestyle, which is associated independently with colorectal cancer (Wolin et al., 2009).
The high frequency of relatively early-onset colorectal cancer in sub-Saharan African has consistently raised questions about the role of hereditary factors in this population (Cronje et al., 2009). Specifically, it has been suggested that there is a higher than expected frequency of Lynch-type syndromes. This is consistent with the high frequency of mismatch repair protein deficiency in colorectal cancers in the region, albeit in a limited number of studies (Cronje et al., 2009). In our study, any cancer in first-degree relatives was associated with a threefold increase in the risk of colorectal cancer. However, there was no association with colorectal cancer in first-degree relatives, which could be because of the relatively small sample size. Molecular genetic studies are underway in our cohort to determine the frequency of common familial syndromes and their relationship with phenotype.
A surprise finding was the association of previous schistosomiasis with colorectal cancer. It is likely that the participants recalled S. haematobium infection rather than S. mansoni. However, it is reasonable to assume that they were exposed to both parasites as coinfection is common in the endemic areas in Zimbabwe (Midzi et al., 2014). Mechanistically, S. mansoni, which causes chronic colonic inflammation, is a more plausible cause of colorectal cancer than S. haematobium, which infests the bladder. Although S. haematobium is an established cause of bladder cancer, the role of S. mansoni as a carcinogen is uncertain, because of the lack of well-designed studies (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 1994). The frequency of schistosomiasis in patients with colorectal cancer in Egypt was comparable to that in the general population (Soliman et al., 2001). Cases of concomitant colorectal cancer and schistosomiasis have been reported to be younger and more likely to have mucinous morphology than those with colorectal cancer alone (Madbouly et al., 2007). These studies were small, and not designed to substantiate an association between colorectal cancer and schistosomiasis. Although our study has a well-selected control group, this does not conclusively prove a causal relationship. Moreover, we could not confirm the previous schistosomiasis diagnosis in both cases and controls. Thus, further studies, with more objective measures of exposure to schistosomiasis, are needed to corroborate our findings.
Our study has some limitations, which must be taken into account when interpreting the results. As stated earlier, the effect of obesity was not accounted for and this could have magnified the impact of diabetes mellitus and urbanization. It is also possible that the role of hereditary factors could simply reflect a clustering of cancers in families because of shared environmental factors. This was minimized by including most of the putative risk factors of colorectal cancer in the regression models. Case–control studies have an inherent susceptibility to recall bias. This can be minimized by ensuring that data are obtained in the same way in both cases and controls. In our study, there was no reason to believe that cases had a heightened awareness of the potential risk factors of colorectal cancer. In addition, the questionnaire was structured in a way that made the recall as objective as possible. Although the interviewer was not blinded to the status of each participant, there is little reason to suspect that this influenced data collection.
We have established the factors associated with colorectal cancer in an African population. Key among this is diabetes mellitus, which is a major contributor towards the growing burden of noncommunicable diseases in sub-Saharan Africa (Dalal et al., 2011). Thus, primary prevention programmes against diabetes mellitus, principally targeting obesity, can have far-reaching benefits. Our findings on the role of schistosomiasis require confirmation, but lend support for the intensification of existing eradication programmes. The role of genetic susceptibility requires further characterization using molecular genetic techniques. Although population-based colorectal cancer screening programmes are not feasible in low-income countries, our findings identify opportunities for targeted screening. These could potentially be offered to patients with type 2 diabetes mellitus, first-degree relatives of patients with colorectal cancer and individuals with previous schistosomiasis.
This work was supported by the Wellcome Trust through the Southern African Consortium for Research Excellence (SACORE).
There are no conflicts of interest.
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