Primed for cancer: Li Fraumeni Syndrome and the pre-cancerous niche

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Published: 26 Oct 2015
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Dr Pan Pantziarka - Anticancer Fund, Brussels, Belgium

Dr Pantziarka discusses the risks associated with Li Fraumeni Syndrome, the complex issues which surround the diagnosis and management of the disease and the pharmacological interventions which have the potential to reduce the cancer risk in individuals with Li Fraumeni Syndrome.

Dear Dr Pantziarka’s paper on Li Fraumeni Syndrome here.


Primed for cancer: Li Fraumeni Syndrome and the pre-cancerous niche

Dr Pan Pantziarka - Anticancer Fund, Brussels, Belgium

What is Li Fraumeni Syndrome?

Li Fraumeni Syndrome is a rare cancer predisposition syndrome. It’s normally associated with a mutation in the p53 tumour suppressor gene and it’s a germline mutation so it’s autosomal dominant.

What cancers are most associated with this syndrome?

People with LFS have a very highly elevated risk of developing cancers. For males the lifetime risk is around 70% and for females, because of an elevated risk of breast cancer, it’s around 100%. Around 50% of people with LFS will develop their first cancer before the age of 30 and the most common cancers are breast cancer in women, especially early onset breast cancers, and bone and soft tissue sarcomas. It’s also not uncommon for people with LFS to get through a first primary cancer and then develop second, third or more primary cancers in their lifetimes.

How are Li Fraumeni Syndrome patients diagnosed and managed?

Diagnosis of LFS is not routine, even in paediatric cancer patients germline testing of TP53 does not take place. There’s a highly complex algorithm to decide whether a test is warranted. Once a person is diagnosed with LFS there is normally a surveillance programme in place so that they will be routinely scanned and checked for developing malignancies. There are no active measures to prevent cancer or reduce the risk of cancer except for risk-reducing mastectomy in women.

Can you talk about the role of the host microenvironment in cancer initiation?

Our view of cancer is changing, we no longer think of cancer as a disease of a delinquent cell. We increasingly understand that cancers can’t exist without a supporting microenvironment. The other thing that we are also discovering is that TP53 is an incredibly diverse transcription factor. It’s involved not just as a tumour suppressor but it’s there with functions in the immune system, in handling metabolic stress, in senescence, in aging, so a whole range of functions over and above its role in the apoptotic process. Now, these two things, a new view of cancer that incorporates the microenvironment and the new understanding of the roles of p53 signalling, have not quite made it into our view of LFS which is primarily viewed in relation to the role of TP53 as a tumour suppressor. We know that in patients with LFS there is elevated oxidative stress, this is in non-cancer patients, that there are a host of factors which are related to chronic inflammation which are assumed to be pro-tumorigenic; we know that chronic inflammation is a driver of tumorigenesis.

One of the things I’m interested in is the idea of a pre-cancerous niche. This is a tissue environment that is primed for cancer initiation and development. It’s a host environment characterised by chronic inflammation, high levels of oxidative stress, the release of pro-angiogenic factors, immune dysfunction and so on. Now, these are all things which are associated with mutated TP53, therefore, one of the ideas that I am developing is that cancer initiation in Li Fraumeni Syndrome is related to the host environment being there, ready for cancer, before there is a cancer present and that cancer initiation in Li Fraumeni Syndrome may be associated with this chronic inflammation, with this highly oxidative stressful environment, causing additional mutations over and above the TP53 which then drives the cancer initiation and progression. This gives us a more nuanced view of cancer initiation in Li Fraumeni Syndrome; it means that the host environment is already primed for cancer and that the high levels of oxidative stress, together with other factors, mean that additional mutational events take place which, on top of the mutated TP53, drive cancer.

Are there any drugs that can prevent cancer formation in these individuals?


Currently there are no prophylactic measures taken to reduce the risk of cancer in patients with LFS. Now, it’s very difficult to drug transcription factors and especially something as complex as TP53. But what we can do is look at pharmacological interventions that address some of the elements of that pre-cancerous niche. If we can reduce the chronic inflammation, reduce the oxidative stress, reform that damaged immune system then we are in a position where fewer cancers may be initiated and therefore we can reduce the risk of cancer in these patients that have a very high risk of cancer.

There are a number of possible drugs which are attractive in this respect, chief among them metformin, which is already being looked at in terms of cancer prevention in high risk breast cancer, and also aspirin, which is being investigated in Lynch Syndrome as a way of reducing the risk of cancer in people who are predisposed to it. Currently there are no research programmes in LFS on this but the rationale for undertaking this work certainly exists.