There’s still about 10 per cent of the human genome (our complete set of DNA) that we know little about, and parts of that may affect the development of childhood cancer. In this pilot project, Professor Harrison and Dr Sarra Ryan are developing revolutionary, state-of-the-art technologies to explore this region for the first time, to improve our understanding of how childhood cancer develops and how we might stop it.
Whole Genome Sequencing (WGS) lets us look for abnormalities within a person’s DNA, helping us target treatments for cancer. But so far we’ve been unable to chart 5-10 per cent of the human genome. This project is developing new technology to help us map the complete DNA sequence.
Sequencing the unsequenceable: development of ground-breaking technologies to investigate the role of complex genomic sequences in childhood cancer
Professor Christine Harrison
Newcastle NE1 4LP
The human genome – our complete set of DNA – was famously sequenced (decoded) under the Human Genome Project, a massive international collaboration costing around $3 billion, which was declared complete in 2003. Today we have the technology to sequence a person’s genome for around £1,000. We call this Whole Genome Sequencing, or WGS, and it enables us to look for abnormalities (including mutations) within the DNA of an individual.
WGS has identified key genes important in the development of childhood cancer. However, although the term ‘whole genome’ is used, 5-10 per cent of the genome remains uncharted. We need to find out how important this part is in disease development.
The research team believes that variants or mutations must exist within the DNA sequence that affect the normal function of the centromere. To understand more about leukaemia, we need to find out about the genetic risk factors that contribute to the disease.
This 12-month pilot project will help us better understand the role of the centromere in childhood cancer. This will allow doctors to help children with cancer and children at risk of developing cancer.
By developing ways to decode the centromere DNA sequence, we will begin to why children born with the chromosomal abnormality are more likely to develop leukaemia; but also why some with the same abnormality don’t develop it.
So the research team will focus on children who have a germline (inherited) chromosomal abnormality with an enormous risk of developing leukaemia.
DNA is packaged into chromosomes. Most human cells have 46 chromosomes, arranged into 23 pairs. Each chromosome contains a ‘centromere’ – important in cell division. Centromeres are part of the ‘uncharted’ 5-10 per cent of the genome, which is very difficult to sequence. Research has shown that some people have abnormal centromeres, which increase their susceptibility to cancer.
Christine and colleagues recently made a breakthrough discovery that carriers of a rare inherited chromosomal abnormality known as rob(15;21)c, are much more likely to develop leukaemia. They believe that the ‘trigger’ for leukaemia in these children is something in the unique structure of the centromere.
Building on this discovery, the research team is developing revolutionary new technologies that will help us decode the complete DNA sequence of the centromere for the first time. Their study will focus on the centromere of the specific rob(15;21)c chromosomal abnormality so we can learn what cause some children to develop leukaemia.
This will help us identify children who may be at risk of cancer sooner – and increase their chances of being treated successfully.
It will also help us work out how the disease forms, and potentially find ways to stop it.
Christine Harrison is Professor of Childhood Cancer Cytogenetics at the Northern Institute for Cancer Research, Newcastle University, and a world-leader in childhood leukaemia research. On her team is Dr Sarra Ryan, a Research Associate with expertise in molecular biology and next generation sequencing
They’re collaborating with Mark Akeson, Professor of Biomolecular Engineering at the University of California, Santa Cruz. Professor Akeson is a prominent figure in the development of cutting-edge technologies, which he’s already used to explore an uncharted region of chromosome X.
With the support of other key collaborators (Dr Daniel Turner, Oxford Nanopore Technologies; Dr Chris Tyler-Smith, The Wellcome Trust Sanger Institute), this is a unique team of researchers, capable of developing novel approaches to answering increasingly important biological questions about childhood cancer and leukaemia.