Li Fraumeni Syndrome (LFS), a rare genetic condition that predisposes sufferers to cancer development, is associated with mutations in the TP53 tumour suppressor gene.
Although rare, LFS sufferers have a highly elevated risk of developing one or more cancers, with some estimates putting the life-time risk at 70% for males and 100% for females.
However, new research published today in leading online oncology journal ecancermedicalscience, suggests that cancer development may be due to more than a mutated tumour suppressor function.
In a new paper by Pan Pantziarka PhD, a scientist working for the Anticancer Fund and co-ordinator of the Repurposing Drugs in Oncology (ReDO) project, it is suggested that there are other important functions of the TP53 gene that contribute to this elevated cancer risk.
"Our knowledge of the multi-faceted functions of TP53 has grown enormously in the last few years," Pantziarka says, "yet much of this new information has yet to be integrated into our understanding of the disease process in people with LFS."
Sue Armstrong, author of ‘p53: The Gene that Cracked the Cancer Code’, points out that: ‘TP53 is the most commonly mutated gene in human cancer. Indeed it’s probably fair to say that if this key tumour suppressor is functioning properly, it’s almost impossible for cancer to develop.
"It follows that to be born with mutant - and therefore malfunctioning - TP53 in every cell in the body is to be extremely vulnerable to cancer.
'This is the tragic fate of people with Li Fraumeni Syndrome, for whom conventional therapies rarely offer more than temporary respite. So, new ways of looking at, and treating, cancer are sorely needed."
Known as the 'guardian of the genome', the p53 protein is at the heart of an array of signalling networks involved in responding to DNA damage, metabolic stress, immunity, senescence and ageing.
In people with normal p53 function, the kinds of damage that cause cells to become cancerous trigger a damage response that normally leads to the cell self-destructing before it can proliferate, a process called apoptosis. But in people born with a mutated TP53 gene this process does not take place.
However, there is more to cancer than delinquent cells, increasingly we understand that cancer also involves a supporting micro-environment to provide a blood supply, nutrients, protection from an immune response and so on. These factors may also involve p53, and Pantziarka's hypothesis suggests that people with LFS are born 'primed for cancer' because many of these cancer-support systems are already in place thanks to the mutation.
Pantziarka has first-hand knowledge of this disease process himself, having lost his first wife and his teenage son, George, to cancers due to LFS. George, for example, developed his first cancer at the age of two and subsequently developed two further primary cancers before succumbing to metastatic sarcoma in 2011.
The story is told in a recent book, 'For The Love of George' by Irene Kappes, available from Amazon and other booksellers. The family have also established the George Pantziarka TP53 Trust to provide support for other families and to promote research into the condition.
This new hypothesis does more than provide a more nuanced view of cancer development in people with LFS, it also suggests that many of these additional factors may be amenable to drug treatment.
"By expanding our view of carcinogenesis in LFS we may also be broadening the range of interventions available to us to change things.
'The key thing,' Pantziarka underlines, "is to start looking at active measures we can take to reduce this risk. Drugs such as metformin may hold the promise of reducing that life-time risk by some significant margin."
In perhaps the most radical section of the paper, it is suggested that some other cancer predisposition syndromes, caused by mutations in other genes, may share some of the same features of LFS despite the different genetic drivers.
If this is the case, as the paper suggests, then perhaps some of the active measures which warrant investigation in LFS may also apply to a range of different genetic cancer predisposition syndromes.
In such a case the prospect of a clinical trial that targets multiple high-risk patient populations is an alluring prospect.
"With limited population sizes it is difficult to design cancer-prevention trials because the sample sizes are too low,"Pantziarka explains, "but if my theory is correct then we can pool different populations into the same trial and look for reduced cancer incidence across the board."
Pantziarka Pan (2015) Primed for cancer: Li Fraumeni Syndrome and the pre-cancerous niche ecancer 9 541 DOI: 10.3332/ecancer.2015.541
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