Dr. Vivienne Rebel reviews a recent study about p53 protein levels as a prognostic factor in MDS | Aplastic Anemia and MDS International Foundation

Dr. Vivienne Rebel reviews a recent study about p53 protein levels as a prognostic factor in MDS

PubMed Abstract: 
Original Publication Date: 
Tuesday, September 30, 2014

Patients with a subtype of MDS that is characterized by a molecular signature showing a deletion of the long arm of chromosome 5 - or (del)5q MDS - were traditionally considered to have a good prognosis compared to patients with other subtypes of MDS.  However, recent DNA sequencing studies have shown that if the 5q deletion is accompanied by a mutation in the p53 gene (the official name of this gene in TP53), there is a significantly increased risk for leukemic progression, which carries a poor prognosis.  The increased risk was clear even if the number of cells showing this mutation was relatively small.  The method currently used to identify p53 mutations is called DNA sequencing, which is a sophisticated and expensive method to decipher our genetic code.  However, this technology is not generally accepted yet, nor is it readily available in all hospitals.  Since knowledge about the presence of a mutated p53 gene may have important consequences for designing a treatment plan, this study investigated whether alternative, simpler methods which can easily be implemented in hospitals can be used instead.

For a variety of cancers it has been demonstrated that strong staining of the p53 protein (which is encoded by the p53 gene) in the nucleus of a cell can function as a surrogate marker for a mutated p53 gene.  The method used to stain p53 protein is called immunohistochemistry (IH).  The goal of this study was to determine if IH for the p53 protein on bone marrow cells obtained from (del)5q MDS patients has the same predictive value as sequencing the p53 gene for the presence of mutations.

All patients studied were classified as low to intermediate risk and were enrolled in a randomized trial, for which they received lenalidomide or a placebo.  P53 staining was performed on samples prior to any treatment and in some cases at several time points thereafter.  This study found that strong p53 protein staining in 1% or more of the bone marrow cells of this patient group was significantly associated with an increased risk to develop leukemia, a shorter overall survival and a lower cytogenetic response rate to lenalidomide treatment (i.e., the disappearance of cells with abnormal chromosomes, in this case cells that harbored a deletion of the long arm of chromosome 5) compared to patients that did not show a strong p53 staining.  Subsequent sequencing of cells that had demonstrated strong p53 protein staining confirmed the presence of mutations in the p53 gene, whereas cells that had shown moderate to no p53 staining had a normal p53 gene.  Interestingly, in a few cases, where there were only a few cells that showed strong p53 protein staining by IH, sequencing of individual cells confirmed a p53 gene mutation, but sequencing bulk bone marrow cells did not.  Thus, this suggests that IH is a more sensitive technology for identifying patients with a small clone of p53 mutated cells.  A disadvantage of IH is that it will not detect mutations that result in no protein expression.  In these cases, the p53-mutated cells cannot be distinguished from normal cells, which express no to very low levels of p53 protein.  However, such mutations are very rare in lower-risk (del)5q MDS patients.  Therefore, the authors conclude that IH for p53 protein is a useful and predictive tool in the clinic to assess patients with lower-risk (del)5q MDS.

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