Investigating uncharted genomic sequences in childhood leukaemia

10 October 2016

Professor Christine Harrison, Newcastle University

Sequencing the unsequenceable: investigating uncharted genomic sequences in childhood leukaemia:
around 10 per cent of the human genome remains unexplored, with some of the uncharted regions believed to play a role in 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 it may be prevented.

Amount of grant: £55,022 | Date of award: July 2016

Background

Professor Christine HarrisonThe human genome – our complete set of DNA – was famously sequenced (decoded) under the Human Genome Project, which was declared complete in 2003. This was the result of a massive international collaboration, costing around $3 billion.

Today, advances in technology mean that it is possible to sequence the genome of an individual for around £1,000. The process is known as Whole Genome Sequencing, or WGS, and it enables us to look for abnormalities (including mutations) within the DNA of an individual. Such discoveries are driving the application of precision medicine in the treatment of cancer, and other diseases, by the design of treatments that target specific mutations.
[photo: Professor Christine Harrison]

WGS has identified key genes important in the development of childhood cancer. However, although the term ‘whole genome’ is used, 5 to 10 per cent of the genome remains uncharted. The role of these uncharted regions in disease development remain unknown – and their investigation has been hindered by the limitations of current sequencing technologies.

DNA is packaged into chromosomes. Most human cells have 46 chromosomes, arranged into 23 pairs. Each chromosome contains a ‘centromere’- a body that is important in cell division. Centromeres are part of the ‘uncharted’ regions of the genome, which have proved particularly challenging to sequence. It is becoming increasingly evident that some individuals have abnormal centromeres, which increase their susceptibility to cancer.

They have a solid study design, a very focused scientific question and the right expertise to overcome potential problems.
External reviewer
Professor Harrison and colleagues recently made a breakthrough discovery that carriers of a rare inherited chromosomal abnormality known as rob(15;21)c, have an enormous risk of developing leukaemia. They believe that the ‘trigger’ for leukaemia in these individuals resides in the unique structure of the centromere.

Following on from this discovery, Professor Harrison and her colleague Dr Sarra Ryan are developing revolutionary new technologies that will provide the opportunity to elucidate the complete DNA sequence of the centromere for the first time and identify any mutations or variants that may have a biological function in cancer development. Their study will focus on the development of new, cutting-edge technologies to sequence the centromere of the specific rob(15;21)c chromosomal abnormality that predisposes carriers to leukaemia.

About the research team

Dr Sarra RyanChristine Harrison is Professor of Childhood Cancer Cytogenetics at the Northern Institute for Cancer Research, Newcastle University. She is a world-leader in childhood leukaemia research, having played an important role in improving our understanding of childhood leukaemia genetics over the last 30 years.

Sarra Ryan is a Research Associate within Professor Harrison’s team with expertise in molecular biology and next generation sequencing

Professor Harrison and Dr Ryan in Newcastle are 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 novel, cutting-edge technologies, which he has 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), they represent a unique team of researchers, capable of developing these novel approaches to answer difficult, yet increasingly important, biological question in childhood cancer and leukaemia.
[photo: Dr Sarra Ryan]

"The authors are top experts in their field and the collaboration they propose is likely to be successful. Importantly, they propose to tackle the problem with a multi-disciplinary approach of clinical oncology and next-generation sequencing." External reviewer

What difference will this project make?

The proposed project will lead both to fundamental understanding of initiating genomic events in childhood ALL, as well as to potentially new prognostic biomarkers.
External reviewer
Improving our understanding of the role of the centromere in childhood cancer will have significant benefits for children with cancer and children at risk of developing cancer.

In this 12-month pilot project, the research team will focus on patients that have a germline (inherited) chromosomal abnormality with an enormous risk of developing leukaemia.

Through the development of methods capable of elucidating the centromere DNA sequence, we will begin to understand i) why people born with the chromosomal abnormality are predisposed to leukaemia; and ii) why some carriers do not develop leukaemia.

Professor Harrison and Dr Ryan believe that variants or mutations must exist within the DNA sequence that affect the normal function of the centromere. Detection of such genetic risk factors that contribute to leukaemia will facilitate our understanding of the disease and help us to identify individuals that may be at risk of cancer, improving the prognosis of these patients through early detection.

Furthermore, a greater understanding of cancer development will be beneficial towards treatment of these patients, as it provides the opportunity to unravel how the disease forms and mechanisms that we can put in place to prevent disease initiation.

Read more: About acute lymphoblastic leukaemia | Other leukaemia projects

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