Mutations of gene TP53 and myelodysplastic syndrome

Mutations of gene TP53 represent a factor in determining the seriousness of myelodysplastic syndrome

Mutations in one or both copies of TP53 gene represent the most important variable in predicting the disease outcome, according to a study published in Nature Medicine. The results of this study have immediate implications for risk evaluation and treatment of patients suffering from this type of blood cancer.

Nature Medicine published a comprehensive study showing that patients suffering from myelodysplastic syndrome (MDS, a type of blood cancer) present poor disease outcomes if they have two mutated copies of gene TP53 (a gene that usually mutates in cancer patients) instead of just one mutated copy.

The Memorial Sloan Kettering Cancer Center (USA) led this study, which could count on wide international cooperation. Thanks to MIUR-PRIN state funds, Professor Matilde Y. Follo from the Department of Biomedical and Neuromotor Sciences at the University of Bologna participated in this research. Professor Follo carries out her research at the Direct Signal Transduction Lab led by Professor Lucio Cocco, who has a decade-long research record into myelodysplastic syndromes and signalling.

Follo says that "these results bear immediate clinical relevance to risk evaluation and treatment of patients suffering from MDS, which is a precursor of Acute myeloid leukaemia".

Gene TP53 is also known as the "genome guardian". Indeed, its role is to identify DNA damage and prevent the transmission of toxic genome mutations during the copying process, by producing the p53 protein. In case of mutations of gene TP53, protein p53 is unable to perform its protective function. And this may lead to cancer.

Similarly, to every gene in the human genome, each cell has two copies of TP53 one inherited from the mother, the other from the father. Until recently, it was not clear if the outcome of the disease would have been any different in case the mutations happened in one or both TP53 gene copies. This study shed some light on this issue.

This research was carried out within the framework of action of the Working Group for the Prognosis of MDS, which aims at developing and promoting new international guidelines for MDS treatment. This study draws from the genetic and clinic analysis of 4,444 patients being treated in in hospitals all over the world.

Using innovative computational methods, researchers found out that one-third of MDS patients presented one mutated copy of gene TP53, while the remaining two-thirds showed mutations in both copies. Depending on the group of patients, the observed disease outcomes were significantly different.

"Patients with one mutated copy of gene TP53 showed outcomes that are very similar to those of patients without any mutation. Indeed, their response to treatments was good and the disease progression rates were lower, resulting in better survival", explains professor Follo. "The group of patients with two mutated copies of gene TP53 experienced worse disease outcomes, including higher resistance to treatments, faster progression rates of the disease and lower chances of survival".

Indeed, the results of this study show that the most important variable in predicting the disease outcomes is the presence or one or two mutated copies of TP53 gene. According to researchers, these results should encourage to dig deeper into the role of this variable within other tumoral forms.

"These results prompt us to analyse the role of this variable in other tumoral forms, as gene TP53 undergoes frequent mutations in cancer patients", confirms professor Follo. "Moreover, they also show the need for clinical trials that are designed by taking into account such molecular differences".

The title of the study is "Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes" and it was published in Nature Medicine.

Published on: 03 September 2020