Gene Focus: TP53 Variants

Saturday 29 February 2020 is Rare Disease Day. Our blog focuses on TP53 genetic variants, Li-Fraumeni syndrome and the ongoing research into screening methods for families affected.


Overall, it is estimated that 1 in 2 people born after 1960 will be diagnosed with a cancer[1]. A rare disease affects less than 1 in 2,000 people within the general population (European Union definition)[2]. Therefore, we would certainly say on the whole that cancer is not a rare disease. However, there are over 50 different types of cancer and, by this definition, about a third of these cancer types are considered to be rare[3].


Historically we defined cancers by the organ/tissue in which they arise (breast cancer, lung cancer). With increasing knowledge around cancer genetics and genomics, we can define cancers more precisely, defining them on a ‘molecular’ level by the genetic variants driving tumours. Meaning populations of patients are becomingly increasingly smaller. If we consider populations of patients with hereditary genetic variants and variants in individual genes, then the affected populations become much smaller.


One gene that is well understood to have an impact in cancer is TP53. TP53 is a tumour suppressor gene that codes for the P53 protein, known as the ‘guardian of the genome’. P53 is a key protein in recognising damaged DNA and instructing either repair of the DNA or cell death. This is a key feature that prevents cells with damaged DNA from further dividing and forming tumours.


Genetic variants in TP53 that interrupt the protein function therefore have a significant impact on the body’s natural mechanism for preventing cancer and it has been identified that individuals with germline TP53 variants have a significantly increased lifetime risk of cancer.


There have been a multitude of studies to identify the types of cancers that TP53 variant carriers are at an increased risk of developing. It is understood that TP53 variants have a tissue-specific affect, as opposed to generally increasing risk across all cancer types. TP53 variants are strongly correlated to increased risk of breast carcinoma, soft tissue sarcomas, osteosarcoma, brain tumours, phyllodes tumour of the breast, and childhood tumours such as adrenocortical carcinoma [4].


Li-Fraumeni Syndrome (LFS) is the name given to inherited risk of this spectrum of cancer types. In around 75% of individuals/families with LFS, the germline TP53 variant has been identified. In a sizeable minority, no clearly causative TP53 variant has been identified. Thought to affect somewhere between 1 in 5,000 and 1 in 20,000 people worldwide, LFS is an archetypal cancer susceptibility syndrome and rare disease[5].


Early laboratory studies suggested that cells with deficient P53 had increased sensitivity to damage by ionising radiation, such as x-rays. Accordingly, it has become widespread in clinical practice to exercise caution regarding radiation exposure in individuals with LFS.


Management of individuals with a TP53 variant or LFS recommended by NICE[6] comprises increased breast cancer screening via MRI surveillance for women aged between 20-49 years. NICE also advises enhanced screening for women aged 50-69 years old, albeit that the risk of developing a cancer would appear to be significantly lower for women over the age of 50 years old with a TP53 variant that have not previously developed cancer.


There have also been a number of studies evaluating use of whole body MRI (WB-MRI) for screening individuals with TP53 variants. This enables detection of multiple cancer types using an imaging technique that doesn’t involve ionising radiation.


The UK SIGNIFY study was delivered at The Royal Marsden NHS Foundation Trust and Central Manchester University Hospitals NHS Foundation Trust and involved one-off WB-MRI screening of 44 individuals with TP53 variants and a group of 44 population-matched individuals with no known hereditary risk of cancer. Researchers were looking at both the benefit of regular screening in terms of identification of cancer[7]and the psychosocial impact that WB-MRI screening had on individuals[8].


Baseline results from the study were supportive of WB-MRI screening for patients with TP53 variants. No cancers were identified in the control group, but through WB-MRI screening, cancers were diagnosed in four of the TP53 variant carriers. In two of the individuals, two separate primary tumours were identified simultaneously.


Results of the psychosocial questionnaires also concluded that there was no significant adverse impact of WB-MRI screening on the general psychological wellbeing of TP53 variant carriers. However, it was identified that in general TP53 variant carriers are likely to incorrectly understate their risk of cancer compared to the general population and had significantly increased levels of clinically significant depression/anxiety. This suggest a better need for ongoing information and support for variant carriers.


CanGene-CanVar investigators Evans, Lalloo and Hanson, working within Work-Package 3, have been closely involved in studies of WB-MRI and activity to explore its implementation into routine NHS clinical care.



[1] https://www.cancerresearchuk.org/health-professional/cancer-statistics/risk [2] https://ec.europa.eu/health/non_communicable_diseases/rare_diseases_en [3] https://www.cancerresearchuk.org/health-professional/cancer-statistics/incidence [4] https://www.nature.com/articles/1204621 [5] https://ghr.nlm.nih.gov/condition/li-fraumeni-syndrome#genes [6] https://www.nice.org.uk/guidance/cg164/chapter/Recommendations [7] https://link.springer.com/article/10.1007/s10689-017-9965-1 [8] https://jmg.bmj.com/content/jmedgenet/early/2019/11/07/jmedgenet-2019-106407.full.pdf

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This work was supported by Cancer Research UK [C61296/A27223]