| dc.description.abstract | Introduction: In Uganda, there has been a gradual increase in the burden of colorectal cancer (CRC) in the last decades. CRC is presenting at a young age, late stage, and runs an aggressive course. Understanding the reasons for this scenario is important. Hence, the purpose of this study was to determine the distribution of molecular subtypes, molecular markers, risk factors and determinants of survival of CRC. Methods: Five studies were conducted with cross-sectional, case-control, and cohort study designs involving the Kampala Cancer Registry and four hospitals in Uganda. For the period 2008-2019, patients’ data and CRC tumour samples were examined using Haematoxylin & eosin (H&E), immunohistochemistry (IHC) and molecular genetic laboratory methods. The analyses were carried out using descriptive, logistical regressions and survival analyses. Results: A total of 404 patient samples were evaluated in study 1. The median(IQR) age was 54(43-67) years. Moderate and poor-grade tumours constituted 77.8% and late -disease constituted 60.8% of presentations. The histopathologic subtypes were 4.1% signet ring colorectal carcinoma (SRCC), 10% mucinous adenocarcinoma (MAC), and 86% classical adenocarcinoma (AC). There were 40.9% microsatellite instable (MSI)-positive CRC tumours and the molecular subtypes included 0% type 1, 2.3% type 2, 3.3% type 3, 45.7% type 4 and 38.0% type 5. In study 2 there were 74.1% left-sided p53 positive tumours compared to 25.9% right-sided colon tumours (p=0.0004). All CDX2 negative participants were associated with LVI (p=0.005). There were 43.7% VEGF-1 tumours with stage IV CRC compared to 12.5% VEGF-1 tumours with stage I disease (p=0.0479). A positive correlation was found between the grade and tissue CRC carcinoembryonic antigen (CEA) intensity (p=0.0232). Among CEA positive tumours, there were 31.4% stage IV and 15.1% stage I (p=0.0101). There was no relation beween preoperative plasma CEA and CEA CRC tissue intensity (p=0.725). In study 3 there were 387 participants of which 129 were cases. Urban residence (aOR: 82.79; p<0.001), family history of GI cancer (aOR:61.09; p<0.001) and past smoking (aOR:4.73; p=0.036) were associated with a high risk for CRC. Consumption of beef 2-3x/week (aOR:3.24; p<0.035) was a risk factor. Protective factors included consumption of millet for ≥4x/week (aOR:0.23; p=0.003), spinach for ≥4x/week (aOR:0.32; p=0.043) and potatoes 2-3x/week (aOR: 0.30; p=0.044). In study 4, 306 patient data were analyzed. There was no association between PAH-DNA adducts and CRC (aOR: 0.69; p=0.09). In study 5, data for 247 participants were analyzed. The 3-year survival was 33.3%. Factors associated with increased mortality were stage II (aHR:2.38; p=0.032), stage III(aHR:2.62; p=0.007) and stage IV(aHR:5.10; p<0.001). Curative surgery alone (aHR:0.64; p=0.028) and curative surgery with chemotherapy (aHR:0.54; p=0.009) were associated with better survival. MAC and SRCC showed a tendency towards poorer survival than AC. Conclusions and recommendations: A higher proportion of MAC and SRCC has been found in Uganda compared to Western populations. Many young CRC participants presented with poorly differentiated and advanced-stage tumours, with MSI-positive tumours mainly due to Lynch syndrome. MSI testing, immunohistochemistry and colonoscopic surveillance is cheaper than germline testing, and in Uganda may be carried out on CRC partients with MSI positive histology. P53 expression is more commonly present in left-sided colon tumours. VEGF-1 was expressed at with advanced-stage CRC; loss of CDX2 expression was associated with the presence of LVI and a positive correlation was found between a higher CEA tissue expression and grade of CRC. A family history of CRC, urbanization and smoking were found to increase the likelihood of CRC. The levels of leukocyte PAH-DNA adducts were low and not found to be associated with CRC in Ugandan patients. The survival rate of CRC in Uganda is low with MAC and SRCC having a tendency towards a poorer survival compared to AC. In Uganda, more public health education is needed to increase awareness among the population to present early to hospital and implementation of a national screening programme is necessary to improve the national survival rate. | en_US |
