Please read the abstract in the section 00front of this document / Dissertation (MSc (Chemical Pathology))--University of Pretoria, 2005. / Chemical Pathology / unrestricted

Endometrial carcinoma, which is preceded by non-malignant hyperplasia, is the fifth most common cancer in women worldwide. Various genetic alterations appear to be early events in the pathogenesis of endometrial cancer. The PTEN/MMAC1/TEP1 gene is most commonly mutated in endometrioid adenocarcinoma. This gene, on chromosome 10q23, codes for a tumour suppressor protein which displays lipid and dual-specific protein phosphatase activity. It has been implicated in several signal transduction pathways and seems to be involved in the negative regulation of the PI3K-, the MAPK- and the FAK pathways. Studies have shown that caucasian Americans have a 4-fold higher frequency of PTEN mutations than African Americans. An association of PTEN mutation status with clinical outcome has been found, where patients with PTEN mutation-positive endometrial carcinoma had a better prognosis than those without PTEN mutations. It has been hypothesized that the molecular pathogenesis of endometrial carcinoma within Caucasians and Black African groups may be different. The present study aimed to investigate the PTEN gene in caucasians and Black South African women with endometrial hyperplasia and carcinoma. The correlation between the frequency and type of mutations and the pathological features of the cancers (stage and grade) were also assessed. Paraffin¬embedded tissue samples from patients with endometrial hyperplasia [n=10] and cancer [n=47] were analysed for PTEN mutations using exon-by-exon PCR-SSCP. Thirty-two mutations were detected of which 24 were pathogenic (23 in the adenocarcinomas, one in the hyperplasias). These included 10 frameshift, 7 nonsense, 4 missense and 3 splice site mutations. Pathogenic mutations were located throughout the gene with the highest frequency observed in exon 5 (39.1%; 9/23), followed by exons 1 and 8 (both 17.4%; 4/23). This data does not differ significantly from published findings (P>0.05; x2-test). Pathogenic mutations were present in 54% (20/37) of the endometrioid adenocarcinomas and 10% (1/10) of the hyperplasias. No mutations were detected in the serous papillary cancers and poorly differentiated carcinomas. Fifty-five % (6/11) of tumours from Caucasians and 52% (13/25) of the tumours from Black South Africans had genetic alterations. When comparing the African and caucasian groups there were no significant differences with regards to PTEN mutation frequency (P>0.05; x2-test). Mutations occurred in early and advanced stage endometrial carcinomas, although the majority of the samples were stage 1 endometrioid adenocarcinomas. In the present study no association between the frequency of PTEN mutations and the grade and stage of the endometrial cancer were found (P>0.05; x2-test). To validate these observations, however, a larger sample size representative of all the grades and stages of endometrial carcinoma needs to be analyzed. / Dissertation (MSc (Human Genetics))--University of Pretoria, 2006. / Genetics / unrestricted

Colorectal cancer (CRC) is one of the most common forms of cancer in Western nations, it is however uncommon in sub-Saharan Africa. In South Africa there is an approximate ten-fold lower incidence of CRC in black patients compared to Caucasian patients. This could be due to differences in lifestyles and environment that exist between the various population groups. Underlying molecular events could also account for the difference in susceptibility to colorectal cancer. Mutations in the Peutz-Jeghers syndrome (PJS) gene, STK11, predispose to amongst others colorectal cancer. To examine the role of this gene in South African patients with CRC, DNA from 208 tumours (104 black patients, 104 Caucasian patients) was screened for STK11 mutations via PCR-SSCP analysis. In total 8 novel missense mutations, one of which was germline, were identified in seven tumours (~3.4% 7/208) from 5 black and two Caucasian patients. One tumour from a Caucasian patient was found to be a compound heterozygote. Peutz-Jeghers syndrome was thus diagnosed in 0.96% (1/104) of black patients via a germ line mutation. Thus 4.8% (5/104) of tumours from black patients and 1.9% (2/104) of tumours from Caucasian patients harbour STK11 missense mutations. In addition, 3 synonymous and 5 intronic mutations were detected in a further 73 tumours from black patients, whereas only 3 synonymous and 5 intronic mutations were detected in 25 tumours from Caucasian patients. The present study is the sixth to suggest that somatic mutation of the STK11 gene in sporadic colorectal cancer of Caucasians is an infrequent event. However, this is only the second study of a non-Western population to show somatic mutations in sporadic cases of CRC. Furthermore with regard to the anatomic site of tumours with somatic missense mutations, the present study found that for black patients 7.69% (2/26) of the left-sided tumours, 2% (1/50) of rectal tumours and 4.54% (1/22) of right-sided tumours harboured mutations. Thus the frequency of missense mutations of left-sided CRC tumours compared to right-sided tumours was not significantly elevated (÷2-test, 1df, p = 0.881) in the black population. This study represents the first investigation into the role of the STK11 gene in putative sporadic cases of CRC from both black and Caucasian South African patients. The observed mutations clearly show that mutations of the STK11 gene are infrequent in the CRCs of the South African Caucasian population, and more frequent in the South African black population. This may be a reflection of the differences in lifestyle and incidence of CRC in the different populations. / Dissertation (MSc (Human Genetics))--University of Pretoria, 2006. / Genetics / unrestricted