Nature Genetics Paper published by Professor Kristijan Ramadan Group

Recent work by Professor Kristijan Ramadan, Associate Professor and MRC Senior Group Leader in the University of Oxford's Department of Oncology, his team Dr. Bruno Vaz, Swagata Halder and Judith Oehler, and colleagues from across the world has discovered a gene which is directly related to both ageing and cancer.

Professor Kristijan Ramadan

The scientists investigated three boys from Morocco and Australia.  All three boys developed very early liver cancer and two died while still teenagers.  This is remarkable because this type of liver cancer is usually associated with either hepatitis infection or from alcohol abuse, but in both cases is rarely seen before late middle age.  All three boys also showed significant signs of early ageing; e.g. chromosomal instability, low body weight, lipodystrophy and muscular degeneration.

Carefully looking at the boys' genetic code, the scientists discovered one gene which was damaged in all three cases.  The gene is called SPRTN.  This gene is really important for preventing mutations which arise when our cells try to repair DNA that has been damaged during the process of copying; something that happens all our lives, whenever new cells are needed.  So having a damaged version of the SPRTN gene leaves people very vulnerable to picking up mutations whenever their cells copy their DNA.

Figure: Panel a: Genomic localisation and protein structure of SPRTN. The position of the identified mutations is shown both at the gene (top) and protein level (bottom). The protein diagram depicts the predicted functional domains of SPRTN. Panel b: Axial view of magnetic resonance imaging (MRI) of the liver of SPRT-mutated patient. Blue arrow indicates a tumour, shown to be a hepatocellular carcinoma. Panel c: Representation of how SPRTN-mutations cause DNA replication fork stress (green and red tracts in the background) that leads to hepatocellular carcinoma (left circle) or to arrest of cell proliferation with 53BP1 DNA damage foci (ageing; right circle).



Having damaged DNA and repairing DNA is a normal daily routine for your body, and one it handles very well, but nothing is perfect and over time, small mistakes build up and this in part explains why we age the way we do.  It also explains how cancer can get started.  Normally this happens late in life, but if someone has damaged SPRTN, mutations build-up very quickly - the result is that the signs of ageing and development of cancer happen maybe five decades before they would normally. In summary, the group has discovered the first monogenic cause of hepatocellular carcinoma, which suggests SPRTN as a subject for further study of hepatocarcinogenesis.

Understanding how we age and how we get cancer is vital if we are to develop new ways of early detection and better treatments.  The importance of this discovery is underlined by the interest shown by the top scientific journal for human genetics (Nature Genetics).

This work in Professor Ramadan's laboratory in Oxford was supported by funding from the Medical Research Council, the Department of Oncology at the University of Oxford and the Swiss National Science Foundation. The full paper is available from Nature Genetics.

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