The Clinical Genomics of African Oesophageal Cancer

Abstract

In South Africa, oesophageal cancer is responsible for the 6th highest cancer-related deaths, with oesophageal squamous cell carcinoma (OSCC) being the most prevalent type at an incidence rate of 8.6/cases/100,000 for males and 4.7/cases/100,000 for females. It is often diagnosed at a late stage due to its asymptomatic nature, making it too late for any form of therapeutic interventions to be introduced. Information regarding the genetics of this disease on the African continent is limited, even more so in South Africa. This makes the task of identifying molecular markers, development of diagnostic and monitoring tools quite difficult. Therefore, the aim of this study was to identify the somatic mutation profiles of African patients with OSCC, thereby assisting in the expansion of knowledge regarding the genomic landscape as well fostering the development of molecular markers that could be useful in the diagnosis and treatment of this cancer. This was done by isolating DNA from blood, saliva and tumour samples and conducting whole exome sequencing (WES) on 21 matched blood/OSCC tumour samples. Data analysis was performed using R. The WES from 21 matched blood/tumour pairs revealed that somatic single nucleotide variants (SNV) were much more prevalent in comparison to somatic insertions or deletions (indels). The tumour mutation burden (TMB) was ~2 mutations per Mb. Tumour Protein 53 (TP53) was the most commonly mutated gene with 11 of the 12 mutations occurring in the DNA binding domain of the protein. Mutations in TP53, Titin (TTN) and Mucin 19 (MUC19) suggested that these genes were involved in relatively early events in the development of the tumours. Analysis of copy number alterations revealed a high degree of complexity in the tumour genome, with frequent amplification detected on chromosomes 1p33, 11q23.3 and 21q22.2, and common regions of deletion on chromosomes 5q31.2 and 7q32.3. Three mutational signatures were identified and the molecular pathway analysis showed that the NOTCH, RTK-KAS, and TP53 pathways were the most significantly altered pathways. The alterations discovered in this study have contributed to the greater scheme of the molecular landscape of OSCC.