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.