The genetics of oesophageal cancer in South African populations

Student thesis: Doctoral ThesisDoctor of Philosophy


Oesophageal cancer is a common form of cancer in South Africa. The predominant subtype is oesophageal squamous cell carcinoma (OSCC) and the disease has a very poor prognosis. The aim of this thesis was to investigate the genetics of OSCC in the South African Black and Mixed Ancestry populations. Genetic susceptibility to OSCC was explored initially through case-control association studies of 18 variants with strong evidence of association with the disease in other populations. Most loci did not show association in the South African populations. However, in the Mixed Ancestry population, ALDH2 +82 A>G (rs886205) and RUNX1 rs2014300 were associated with OSCC (odds ratio (OR) = 0.70, 95% confidence interval (CI) = 0.55-0.89, P=0.0038; and OR = 1.33, 95% CI = 1.09-1.63, P=0.0055, respectively). Further investigation of PLCE1 in the Black population found Arg548Leu (rs17417407) to be associated with disease (OR = 0.74, 95% CI = 0.60-0.93; P=0.008). These findings suggest that there may be substantial differences in the genetic architecture of OSCC in African populations. Additionally, genetic susceptibility was explored in the Black population using the Immunochip, a genotyping array containing ~200,000 variants. Although no polymorphisms were significantly associated with OSCC, several variants in TGFBR3 showed suggestive evidence of association, which was promising as the TGF-β pathway has been shown to have an important role in the development of the disease. In a pilot study to investigate somatic mutations in OSCC, the whole-exomes of 8 blood-tumour pairs were sequenced, with mutations identified in several tumour suppressor genes, including TP53, KL and APC. Sanger sequencing of two candidate genes, TP53 and PPM1D, in all available samples, showed that 60% of tumours contained TP53 mutations, and that 36% of tumours showed evidence of loss of heterozygosity at the PPM1D locus, suggesting that it may be an important alteration for OSCC development.
Date of AwardNov 2013
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorChristopher Mathew (Supervisor) & Cathryn Lewis (Supervisor)

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