Molecular profiling of oesophageal squamous cell carcinomas in the South African population
Oesophageal squamous cell carcinoma (OSCC) has a high prevalence in the Asiatic belt and areas of Africa. In South Africa (SA), the incidence of this cancer in the Eastern Cape is one of the highest in the world. The molecular carcinogenesis of this disease remains unresolved. Single nucleotide polymorphism (SNP) array technology provides a high resolution technique to determine DNA copy number imbalances across the whole genome. DNA copy number changes can affect oncogenes and tumour suppressor genes, contributing to carcinogenesis. The aim of this study was to map common chromosomal break points previously identified in five SA OSCC cell lines by multi colour fluorescence in situ hybridisation (FISH) and to characterise copy number changes in these cell lines and OSCC patient’s specimens using SNP array technology. Genome wide copy number analysis was performed on the cell lines and 51 OSCC retrospective samples from the Eastern Cape region using Affymetrix® 500K SNP arrays. A number of genes were significantly affected by copy number changes across specimens. The copy number status of some of these candidate genes identified by arrays, were verified by (FISH) in a subset of the samples. Expression of the EPHA3, FGF3, FGF4, FGF19 and C-MYC candidate genes was assessed in the cell lines and four fresh samples. The common translocation break point previously detected in 5 cell lines involving chromosome 3p11.2 correlated with deletions affecting the EPHA3 gene in 4 of the 5 cell lines and was deleted in 74% of the OSCC cohort. EPHA3 is an ephrin A3 receptor tyrosine kinase that has been shown to have both oncogenic and tumour suppressor functionality. In addition, significant regions of amplification and deletion identified genes (CCND1, C-MYC, FHIT, SFRP1, SFRP2, FGF3, FGF4, FGF19, SMAD4, SMAD6 and FBXW7) involved in the Wnt, TGF-β and FGF. Deletion of the genes, WRN, ATM, RAD18 and XRCC4 involved in DNA repair pathways, may contribute to genetic instability that is characteristic of OSCC. This study has highlighted some molecular pathways that may contribute to better understanding carcinogenesis of OSCC in South Africa.
Ph.D., Faculty of Health Sciences, University of the Witwatersrand, 2011