Study identifies impact of gene mutations on severity of myelodysplastic syndrome

The Myelodysplastic Syndromes Group of Josep Carreras Leukaemia Research Institute, led by Dr. Francesc Solé, has participated in the first international study that confirms that having two mutated copies of the TP53 gene, as opposed to a single mutated copy, is associated with a worse prognosis in patients diagnosed with myelodysplastic syndrome (MDS).

This study, published in the prestigious scientific journal Nature Medicine, has been conducted by researchers from the Memorial Sloan Kettering in the USA, involving 25 research centers in 12 countries and has been supervised by the international working group for the prognosis of MDS, whose aim is to develop new international guidelines for the diagnosis and treatment of this disease. This is a preliminary result in order to define a prognostic score based on molecular changes.

Considered the "guardian of the genome," TP53 is the most commonly mutated gene in cancer. The normal function of TP53 is to detect DNA damages and prevent cells from passing this damage to daughter cells. When TP53 is mutated, the protein resulting from this gene (called p53) can no longer perform this protective function and a cancer may be the result. In most cancers, TP53 mutations are associated with a worse prognosis, such as disease relapse, poor response to treatments and shorter survival.

TP53 exists in duplicate in each of our cells, just like all other genes: one copy from our mother and one copy from our father. Until now, it was not clear whether a mutation of a single copy of TP53 was enough to cause a worse prognosis of the disease, or whether mutations in both copies were necessary.

This study has confirmed for the first time that having the two mutated copies of the TP53 gene is associated with worse results for myelodysplastic syndromes (MDS), a group of blood cancers whose common characteristic is that the stem cells in the bone marrow, in charge of manufacturing all the blood cells, have a defect that makes them produce abnormal cells, unable to perform their usual functions, and in a lower quantity.

From the Josep Carreras Institute we have actively participated by providing more than a hundred samples from patients with the diagnosis of MDS, in the comparative analysis of cytogenetic (karyotype) results versus those obtained by mass sequencing, and in the final discussion of the findings obtained. The results of this study will allow a great advance in the diagnosis and treatment of myelodysplastic syndromes. Current guidelines do not consider genomic data, such as the mutational status of TP53 and other genes to assess prognosis in patients with MDS or to determine appropriate treatment for this disease. However, studies like this show that we should include this information to improve the diagnosis and treatment of patients".

Dr. Francesc Solé, leader of the Josep Carreras Institute's Myelodysplastic Syndromes group, member of the Spanish Myelodysplastic Syndromes Group (GESMD) and member of the international working group for the prognosis of MDS

By using new computational methods in a serie of 4,444 patients with MDS, the researchers found that a third of the patients with TP53 mutations had only a mutated copy of this gene. These patients had similar results to patients who did not have a TP53 mutation, that is to say good response to treatment, low rates of disease progression and long-term survival. However, two-thirds of patients had both mutated copies of TP53 and these patients had worse results, including resistance to treatment, rapid disease progression, and short-term survival.

In fact, the researchers found that the TP53 mutation status (0, 1, or 2 mutated copies of the gene), was the most important variable in predicting the clinical course of the disease.

Given the frequency of TP53 mutations in cancer, these results also advocate to examine the impact of one or two mutations on other types of cancer, both hematologic and solid tumors, and reveal the need of clinical trials specifically designed with these molecular differences.