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A case–control study of risk factors for colorectal cancer in an African population

Katsidzira, Leolina,e; Gangaidzo, Innocent Ta; Makunike-Mutasa, Rudob; Manyanga, Tadiosa; Matsena-Zingoni, Zvifadzod; Thomson, Sandiee; Matenga, Jonathan Aa; Rusakaniko, Simbarashec; Ramesar, Rajf

European Journal of Cancer Prevention: May 2019 - Volume 28 - Issue 3 - p 145–150
doi: 10.1097/CEJ.0000000000000439
Research Papers: Gastrointestinal Cancer
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SDC

The interplay between hereditary and environmental factors in the causation of colorectal cancer in sub-Saharan Africa is poorly understood. We carried out a community based case–control study to identify the risk factors associated with colorectal cancer in Zimbabwe. We recruited 101 cases of colorectal cancer and 202 controls, matched for age, sex and domicile. Potential risk factors including family history, socioeconomic status, urbanization, diabetes mellitus and previous schistosomiasis were evaluated. Conditional logistic regression was used to estimate the odds ratios associated with the different factors. Cases were more likely to have a tertiary education (32.7 vs. 13.4%, P<0.001) and a higher income (18.8 vs. 6.9%, P=0.002). After multivariate analysis, diabetes mellitus [odds ratio (OR): 5.3; 95% confidence interval (CI): 1.4–19.9; P=0.012], previous urban domicile (OR: 2.8; 95% CI: 1.0–7.8; P=0.042), previous schistosomiasis (OR: 2.4; 95% CI: 1.4–4.2; P=0.001) and cancer in a first-degree relative (OR: 2.4; 95% CI: 1.2–4.8; P=0.018) were associated independently with colorectal cancer. Our findings suggest that family history, diabetes mellitus, previous schistosomiasis and approximation to a western lifestyle are the predominant associations with colorectal cancer in Africans. This offers opportunities for targeted prevention and hypothesis-driven research into the aetiology of colorectal cancer in this population.

Departments of aMedicine

bHistopathology

cCommunity Medicine, College of Health Sciences, University of Zimbabwe

dNational Institute of Health Research, Harare, Zimbabwe

eDepartment of Medicine, Division of Gastroenterology, University of Cape Town and Groote Schuur Hospital

fMRC/UCT Human Genetics Research Unit, Division of Human Genetics, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa

Correspondence to Leolin Katsidzira, MMed(Med), Department of Medicine, College of Health Sciences, University of Zimbabwe, PO Box A178, Avondale, Harare, Zimbabwe Tel: +263 4 731000; fax: +263 4 251017; e-mail: lkatsidzira@hotmail.com

Received July 10, 2017

Accepted January 1, 2018

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Introduction

Colorectal cancer in sub-Saharan Africa often presents with advanced disease, with a high mortality among affected individuals (Chalya et al., 2013). It is increasingly being recognized as a significant contributor to cancer burden in the region, and is the sixth most common cancer (Parkin et al., 2014; Katsidzira et al., 2017). In Zimbabwe, the incidence of colorectal cancer has been increasing steadily over the past two decades (Chokunonga et al., 2013; Katsidzira et al., 2016). The age-standardized incidence rate per 100 000 (ASR) in Zimbabwe increased from 8.1 in men and 8.2 in women in 1991–1995 to 14.9 in men and 14.2 women in 2010 (Chokunonga et al., 2013).

Although improved diagnosis undoubtedly contributes towards the increase in the incidence of colorectal cancer in sub-Saharan Africa, other possible reasons have also been advanced (Katsidzira et al., 2017). It has been postulated that the increasing incidence reflects the extent to which associated risk factors are becoming prevalent. However, the burden of colorectal cancer in sub-Saharan African remains significantly below what is reported in high-income countries. The ASR of colorectal cancer in men and women in different countries in Europe in 2012 was as follows: Denmark (69.4; 53.4), UK (55.6; 36.7), France (53.8; 36.9) and Germany (59.7; 34.8) (Ferlay et al., 2013).

Estimates from these high-incidence countries suggest that 65% of colorectal cancers are sporadic, driven by dietary and lifestyle factors, and 5% are caused by specific germline disorders such as Lynch syndrome and familial adenomatous polyposis (Lichtenstein et al., 2000). The extent to which these environmental and genetic elements contribute towards colorectal cancer in Africa is unclear. It has been suggested that hereditary factors are predominant in Africa as 25% of affected individuals are younger than 40 years of age (Cronje et al., 2009; Katsidzira et al., 2017). The tumours in these young individuals often show signet ring cell or mucinous histology. These features are associated with Lynch syndrome, and young age of onset is generally associated with familial cancers (Umar et al., 2004). The presence of an inherent susceptibility among Africans is further supported by a high frequency of early-onset colorectal cancer among African–Americans (Agrawal et al., 2005).

However, the much higher frequency of colorectal cancer among African–Americans also emphasizes the impact of environmental factors. The ASR in African–Americans was estimated to be 58.3 and 42.7 in men and women between 2009 and 2013 (Siegel et al., 2017). In Zimbabwe, the recent increase in the incidence of colorectal cancer is more apparent among older adults, which is consistent with environmental causes (Katsidzira et al., 2016). To clarify these uncertainties in the African context, we carried out a case–control study to determine the risk factors associated with colorectal cancer among black Zimbabweans.

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Materials and methods

Study population

In Zimbabwe, tertiary healthcare services, including pathology laboratories, are centralized in the two largest cities: Harare and Bulawayo. Harare referrals come from the northern two-thirds of the country, where roughly 70% of the population lives. This health services structure enables the identification of most confirmed cases of colorectal cancer from this region at the various clinical and laboratory facilities in Harare. Therefore, a network of clinicians, hospitals and laboratories involved in the diagnosis and management of colorectal cancer was set up in Harare to identify incident cases for a case–control study. Participants were recruited using these colorectal cancer referral pathways. Age-matched and sex-matched control participants were identified from the communities where the cases resided.

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Case and control selection

All black Zimbabwean patients older than 18 years of age with an index diagnosis of confirmed colorectal cancer were considered for recruitment. The principal investigator (LK) was informed whenever a new case of colorectal cancer was identified. All patients were contacted as soon as possible after being identified and no later than 6 months after diagnosis. Patients with cognitive impairment or recurrent colorectal cancer were excluded. The permanent home address of each patient was identified with reference to the Zimbabwean 2012 national census enumeration maps. Two controls were selected randomly from households in the corresponding enumeration area for each case. These were matched for sex and age to within 5 years. Individuals with a history of gastrointestinal cancer or unexplained gastrointestinal symptoms were excluded as controls. Informed written consent was obtained from all participants.

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Data collection

All participants were interviewed for specific risk factors related to colorectal cancer. Cases were interviewed either in hospital or at home after discharge, and all controls were interviewed at home. The questionnaire covered demographic and socioeconomic characteristics including level of education, employment status, income and domicile at different stages of life. Any place where a participant lived continuously for at least 12 months was recorded. A comprehensive medical history was obtained including the use of NSAIDs, the presence of diabetes mellitus, schistosomiasis or inflammatory bowel disease, smoking and alcohol use. An affirmative answer to previous schistosomiasis was assumed to indicate previous exposure to Schistosoma haematobium and Schistosoma mansoni. Participants who had stopped drinking alcohol or smoking within 12 months of the interview were considered to be current users. A family history of cancer and colorectal cancer in first-degree and second-degree relatives was also obtained.

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Statistical analysis

A sample size of 100 cases and 200 controls was calculated to have at least 80% power to detect an absolute difference of 20% in exposure rates between the two groups using a two-sided α of 0.05. Baseline characteristics were compared using the χ2-test or the Student t-test for categorical or continuous variables, respectively. Conditional logistic regression was used to determine the independent associations of colorectal cancer. Odds ratios (OR) and their 95% confidence intervals (CI) were calculated. Initially, univariate analysis was used for all potential factors. Statistically significant factors on univariate analysis (P<0.05) or biologically plausible factors were further analysed using multivariate conditional logistic regression. A P-value of less than 0.05 was considered significant. All statistical analyses were carried out using Stata/MP version 12.0 (StataCorp LLC, College Station, Texas, USA).

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Ethical approval

The study was approved by the Medical Research Council of Zimbabwe (MRCZ/B/357).

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Results

A total of 101 cases of colorectal cancer and 202 controls were recruited between November 2012 and December 2015. Figure 1 outlines the participant recruitment process. The response rate for eligible individuals who were approached to participate was 91% for cases and 90% for controls. There were 75 left-sided and 22 right-sided cases. The location could not be verified in three cases, and one case had synchronous tumours in the rectum and at the hepatic flexure. Table 1 shows the baseline characteristics of the cases and controls. As expected, the mean age, sex distribution and domicile were similar between cases and controls. There was a high proportion of early-onset colorectal cancers, with 20% of cases younger than 40 years of age. Cases were more likely to have a tertiary education (college, polytechnics, university) compared with controls (32.7 vs. 13.4%, P<0.001), and to be in the highest income bracket (earning>USD $1000/month) (18.8 vs. 6.9%, P=0.002). The average monthly income in Zimbabwe is USD $298 per month (Zimbabwe National Statistical Agency, 2013).

Fig. 1

Fig. 1

Table 1

Table 1

Tables 2 and 3 show the univariate and multivariate analyses, respectively. As expected, there were no differences in the domicile of the cases and controls at the time of recruitment. However, having lived in an urban area for at least 1 year was associated with colorectal cancer on univariate analysis (OR: 2.84; 95% CI: 1.04–7.78; P=0.042). This remained significant on multivariate analysis (OR: 3.65; 95% CI: 1.09–12.24; P=0.036). Although a higher level of education and income were associated with colorectal cancer on univariate analysis, this effect was not evident after multivariate analysis.

Table 2

Table 2

Table 3

Table 3

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).

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Discussion

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.

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Conclusion

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.

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Acknowledgements

This work was supported by the Wellcome Trust through the Southern African Consortium for Research Excellence (SACORE).

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Conflicts of interest

There are no conflicts of interest.

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Keywords:

Africa South of the Sahara; colorectal neoplasms; incidence; risk factors

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