TP53 gene determines severe blood cancer development

Myelodysplastic syndromes (MDS) are a group of common blood cancers in which blood cell production in the bone marrow is impaired, and patients show an increase in immature blast cells as the disease progresses. Whilst some types of MDS can remain mild for years, some can be far more serious. For example, patients with MDS are 30% more likely to go on and develop more high-risk forms of blood cancer such as acute myeloid leukaemia (AML).

AML and MDS patients are commonly found with mutations in the TP53 protein (also known as Tumour Protein p53), which is the most frequently mutated gene found in cancers. MDS patients with TP53 mutations not only have a high risk of developing diseases such as AML, but are also associated with developing cancers that are resistant to conventional therapies and poorer prognoses.

TP53’s normal function is to detect DNA damage and prevent cells from passing this damage on to daughter cells. When TP53 is mutated, the protein made from this gene (called p53) can no longer perform this protective function, and this can result in cancer. There is a need to better understand mutated versions of TP53 and if specific genetic appearances have worse patient outcomes than others.

A new international study published in Nature lead by Memorial Sloan Kettering, with involvement from Oxford’s Prof Jacqueline Boultwood and Dr Andrea Pellagatti, Radcliffe Department of Medicine has revealed that the allelic state of TP53 has important implications on the appearance and outcome of MDS.

The study analyzed genetic and clinical data from 4,444 patients with MDS who were being treated at hospitals all over the world. Researchers from 25 centers in 12 countries were involved in the study.

What they uncovered was that having two mutated copies of the TP53 gene — as opposed to a single mutated copy — is associated with much worse outcomes for MDS patients.

This has large implications in the clinical understanding of MDS and in the risk assessment of patients that have it. Researchers believe that, going forward, all MDS patients should have their TP53 genetic status assessed at diagnosis, in order to categorize patients into ‘high risk’ groups and ensure they are monitored for the appearance of cancers such as AML. Future clinical trials should also be designed with these molecular differences in mind to ensure patients are provided with the most appropriate treatment.

The next step in this research is to assess why having two copies of TP53 has such a large impact on the development of severe blood cancers. One current theory is that having one un-mutated copy is enough to ensure that TP53 performs its normal function and that that cells are protected against DNA damage.

About the researchers

This international study was supported in part by the Celgene Corporation, the MDS Foundation, Inc. & Blood Cancer UK. Researchers from across the world, including UK, Sweden, Japan, US, Brazil, Thailand & Italy, were involved.

Andrea Pellagatti, Radcliffe Department of Medicine, investigates the molecular pathogenesis of MDS. Thus far his work has performed the largest study to date of gene expression profiling in MDS and this work has resulted in the identification of key genes and pathways deregulated in this disorder.

Jacqueline Boultwood is a Professor of Molecular Haematology at the Radcliffe Department of Medicine. Her work on the molecular pathogenesis of MDS includes the determination of several subtypes and understanding of the molecular landscape of MDS and the genetic basis of disease progression to AML.

For more information about this particular study, please see the Memorial Sloan Kettering Cancer Centre website.