Colorectal cancer (CRC) is one of the most common forms of neoplasia in Western populations but is uncommon in sub-Saharan Africa. In developing countries such as South Africa, differences in lifestyles and environment exist between the various population groups. These differences and the diverse patterns of cancer that exist, provide an ideal opportunity to study the pathogenesis of colorectal cancer. In South Africa, the incidence of CRC in black patients is approximately ten fold lower than that of white South African patients. The majority of black South African CRC patients presents with tumours without macroscopic polyps. Recently five genes involved in DNA mismatch repair (MMR) have been implicated in hereditary nonpolyposis colorectal cancer (HNPCC). In this retrospective study, paraffin-embedded normal and tumour tissues from 109 black, and 110 Caucasian CRC patients were studied. To screen for the possible involvement of DNA mismatch repair genes, the presence of microsatellite instability (MSI) was investigated. In total 40 patients presented with MSI-H tumours, 27/109 (24,8%) tumours from black patients and 13/110 (11,8%) tumours from Caucasian patients. The proportion of MSI-H tumours from black patients attending Chris Hani Baragwanath Hospital (CHB) (12,2%; 5/41) and that of Caucasian patients is in accordance to published results on sporadic tumours. However the finding that 32,4% of black patients attending Kalafong and Pretoria Academic Hospitals, have tumours with MSI-H is much higher than is commonly reported in Western populations and is significantly higher than that of the Caucasian patients (p = 0.002; χ2-test). It has been observed that patients who present at CHB live mainly in urban Johannesburg/Soweto, in comparison to those seen at KPH who are mostly from peri-urban and rural areas. Failure of PCR amplification, owing to the absence of high quality tissue, allowed 32 of the 40 MSI-H tumours to be fully screened for mutations in hMLH1 and hMSH2 using exon-by-exon PCR single strand conformation polymorphism (SSCP) analysis. Sixteen pathogenic mutations were found in 14 tumours, 10/22 (45%) from black patients and 4/10 (40%) from caucasian patients. Five tumours presented with two mutations each, one is a compound heterozygote and the other four tumours are double heterozygotes. Ten of the sixteen mutations identified, are novel. Five (5/32; 16%) of the pathogenic mutations are germline in origin, four (4/22; 18%) of which were detected in tumours from black patients. Thus HNPCC was diagnosed in ~0,93% (1/107) of Caucasian and 3,85% (4/104) of black patients via germline mutations. The frequency of recognised DNA repair gene mutations in black patients with HNPCC is four times higher than that in Caucasian patients with HNPCC. This is consistent with the notion that penetrance of HNPCC cancer is independent of environmental factors which is true as the frequency of HNPCC in a low incidence population (black South Africans) is much higher than that of a high incidence population (Caucasian South Africans). A missense mutation in hMSH2 (codon 127) was identified in three black patients. It is listed in the ICG-HNPCC database as a pathogenic mutation (in a Nigerian family). However, further investigation demonstrated that this is a polymorphic change exclusive to black Africans. Somatic mutations were detected in 6 (27%) tumours from black and 3 (30%) tumours from Caucasian patients. In conclusion, the observed microsatellite instability and mutations in hMLH1 and hMSH2 thus clearly implicate the involvement of DNA mismatch repair genes in the pathogenesis of colorectal cancers of black and Caucasian South African patients. This study represents the first investigation of DNA mismatch repair genes in tumours from both population groups. It is also the first report of black South Africans with HNPCC. / Dissertation (MSc (Human Genetics))--University of Pretoria, 2005. / Genetics / unrestricted

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