GENOMIC ANALYSIS OF AFRICAN OESOPHAGEAL SQUAMOUS CELL CARCINOMA
Lead Research Organisation:
University of Cape Town
Department Name: UNLISTED
Abstract
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
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
Technical Summary
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.
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.
Publications
Senthebane D
(2017)
The Role of Tumor Microenvironment in Chemoresistance: To Survive, Keep Your Enemies Closer
in International Journal of Molecular Sciences
Mwapagha LM
(2017)
Delineation of the HPV11E6 and HPV18E6 Pathways in Initiating Cellular Transformation.
in Frontiers in oncology
Senthebane DA
(2018)
The Role of Tumor Microenvironment in Chemoresistance: 3D Extracellular Matrices as Accomplices.
in International journal of molecular sciences
Van Loon K
(2018)
The African Esophageal Cancer Consortium: A Call to Action.
in Journal of global oncology
Dzobo K
(2018)
Three-Dimensional Organoids in Cancer Research: The Search for the Holy Grail of Preclinical Cancer Modeling
in OMICS: A Journal of Integrative Biology
Talukdar FR
(2018)
Molecular landscape of esophageal cancer: implications for early detection and personalized therapy.
in Annals of the New York Academy of Sciences
Matejcic M
(2019)
The Relationship Between Environmental Exposure and Genetic Architecture of the 2q33 Locus With Esophageal Cancer in South Africa.
in Frontiers in genetics
Chen WC
(2019)
Association of genetic variants in CHEK2 with oesophageal squamous cell carcinoma in the South African Black population.
in Carcinogenesis
Van Der Watt P
(2020)
Circadian clock genes are rhythmically expressed but downregulated in cervical cancer and oesophageal cancer cells and act to repress cancer cell proliferation
in Molecular Cancer Research
Title | Processing and analysis of blood and tissue samples from oesophageal cancer patients in a resource poor setting |
Description | We developed a cost effective workflow for the processing and analysis of blood and tissue samples from oesophageal cancer patients in resource-constrained settings. The procedure is also applicable to other types of tissues and tumours, subject to he outcome of the kind of quality control assessmentsoutlined in this study. |
Type Of Material | Technology assay or reagent |
Year Produced | 2021 |
Provided To Others? | Yes |
Impact | Oesophageal squamous cell carcinoma (OSCC) has a high incidence in Eastern and Southern Africa, with late clinical presentation and a very poor prognosis. There is limited research on the molecular pathology of this cancer in Africa, partly as a result of a lack of infrastructure for biobanking and sample processing in many African countries. The aim of this study was to establish a practical and robust workflow to collect, store, and process esophageal cancer samples such that both the tissue architecture and quality of the samples would be preserved and suitable for future genomic research. We developed a workflow that allows storage of fresh biopsy tissue in sterile Eppendorf tubes containing RNAlater, an efficient RNAse inhibitor. OSCC biopsy samples stored in RNAlater for up to 18 months showed not altered tissue morphology, thus allowing histological assessment by experienced pathologists and determination of tumor content in each biopsied sample. DNA and RNA extracted from tissue samples were assessed for purity, size, and yield. The quantity and quality of nucleic acids obtained were suitable for genomic applications, and whole-exome sequencing of DNA from tumor tissues produced sequence data with a high proportion of both usable reads and correct base calling. We conclude that this workflow may be applicable to a wide range of malignancies for future genomic research in low-resource settings. |
Description | DNA Sequence Analysis of African Oesophageal Squamous cell carcinoma |
Organisation | The Wellcome Trust Sanger Institute |
Country | United Kingdom |
Sector | Charity/Non Profit |
PI Contribution | Collect tissue samples, prepare DNA, Genetic analysis of sequence data |
Collaborator Contribution | DNA sequencing and bioinformatics analyses |
Impact | Too Early |
Start Year | 2017 |