The p53 gene (TP53) is one of the most characterized and validated tumor suppressor genes studied in cancer. P53 promotes cell-cycle arrest following DNA damage and, through several of its down-stream target genes, also promotes apoptosis if significant cellular injury is present. Genetic deletion of p53 results in a predisposition to cancer that is further enhanced by the additional presence of activated oncogenes or carcinogens. In tumors, p53 function can be lost through gene deletion, mutation, or epigenetic silencing. Additionally, up-regulation of proteins that promote p53 protein degradation, such as MDM2, can also disrupt its function. Whereas a broad role for p53 gene loss has been documented in solid tumors, its role in hematologic malignancies is less common.
Early studies in chronic lymphocytic leukemia (CLL) identified deletion of one p53 allele [del(17p13.1)] and mutation of the other in a small proportion of patients. Deletion and mutation were generally considered to occur in parallel to each other, and in multiple studies were demonstrated to be associated with more rapid disease progression, inferior survival, and poor response to traditional therapies such as chlorambucil and fludarabine. Despite these studies, the general importance of p53 gene abnormalities in CLL pathogenesis has been questioned because of the low frequency of deletion/mutation at disease diagnosis (3% to 8%) and incomplete association with resistance that eventually develops in this disease.
Additionally, loss of p53 either by deletion or mutation has often been associated with CLL cases that have a complex karyotype and evidence of genomic instability, suggesting that this gene might be a passenger in the pathogenesis of CLL rather than a true contributor to it. Zenz and colleagues from the German CLL Study Group now take this story a little further by demonstrating in a large set of well-characterized patient samples treated with either fludarabine or fludarabine and cyclophosphamide that, although uncommon, both loss of the del(17p) locus with accompanying p53 mutation on the alternative allele and even p53 mutation on one allele without the accompanying deletion predicts both poor response to therapy and inferior outcome. The relative number of the sole p53 mutation (without accompanying deletion) is small, making firm conclusions relative to the data difficult. The authors are appropriately cautious in their conclusions and call for larger studies or combining results of different trials to definitively elucidate the importance of this biomarker.
In Brief
The importance of this paper as related to CLL and other malignancies points to how we interpret the importance of relatively uncommon biomarkers that could eventually result in direct personalized therapy. For instance, if in this case standard therapy for patients with p53 mutations or deletions did not work, initiating alternative agents that are independent of p53 could be considered. A key point is that we have to be absolutely certain that isolated mutations are equivalent to full gene loss promoted by deletion of the 17p allele combined with mutation. Given that this represents only a subset of an already common abnormality, combination of data sets from multiple large studies will be required before definitive conclusions can be made. An initiative to do such a meta-analysis among different U.S. and European CLL studies is underway and will hopefully answer this important question.
Competing Interests
Dr. Byrd indicated no relevant conflicts of interest.
