GENOMIC ANALYSIS OF AFRICAN OESOPHAGEAL SQUAMOUS CELL CARCINOMA

Oesophageal squamous cell carcinoma (OSCC) is a form of cancer of the oesophagus that is very common in many developing countries, with about 85% of cases occurring in these countries. There are no early symptoms and the patients report to hospital when the cancer is already at an advanced stage.

Despite the high incidence in many parts of Africa, very little is known about the causes of the disease and the genetic risk if individuals. In this study we will do whole genome sequence analysis on patient DNA in order to identify the genetic changes and potential environmental carcinogens and mutagens that could play a role in the development of the disease. We will also explore the use of this information for personalised anticancer drug therapy based on patient specific gene defects

Oesophageal Cancer (OC) is the eighth most common cancer in the world and is classified as either adenocarcinoma (OADC) or squamous cell carcinoma (OSCC). The aetiology of OSCC is not clear, with the developing world accounting for 85% of its global incidence.

Clinically, OSCC is largely asymptomatic, resulting in late presentation with advanced dysphagia and a very poor prognosis with a 5-year survival rate of less than 10%. In Africa, treatment is largely palliative, involving surgery or insertion of a stent to enable swallowing. The high incidence and poor prognosis for OSCC constitute an important public health problem. Despite the high prevalence and mortality of OSCC in Africa, no systematic or genome-wide sequencing studies have been done on this cancer in any African country and very little is known about the molecular and genetic aberrations in OSCC in Africa.

This study will subject matched normal and tumour DNA samples to whole genome sequencing (WGS) that would allow us to identify key driver and somatic gene mutations to generate mutation signatures that may provide clues as to environmental mutagens and non-human pathogenic (viral) DNA sequences. RNA sequencing of tumour tissue will be performed in parallel to match somatic mutation data with transcription profiles. An extensive panel of genes selected from the initial data generated by WGS will be sequenced in a large set of tumours from South and East Africa to establish and compare the frequency of driver gene mutations in these regions. Together with the demographic data on each patient, we hope to identify somatic mutation signatures that may reveal genetic pathways and environmental exposures driving tumourigenesis. The final objective is to identify potential therapeutic targets that can be used for drug repurposing and new drug development.

In this project we will also establish a multidisciplinary research consortium with strong international links and establish a bio-resource of patient samples linked to clinical and epidemiological data. Research projects will be set up at collaborating partner institutions in Africa to fuel postgraduate research and expansion of research infrastructure. The expertise of collaborators at the Sanger Institute will be invaluable in training students in cancer genomics and bioinformatics. The collaborating Kenyan and South African institutions will participate actively in conducting molecular biology experiments and all subsequent data analyses. Special attention will be given to capacity building in bioinformatics and statistical analysis at the African Centres using the data generated in this project.