Considered the “guardian of the genome,” TP53 is the most commonly mutated gene in patients with cancer. 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. Across many cancer types, mutations in TP53 are associated with worse outcomes, like disease recurrence and shorter survival.
Up until now, it has not been clear whether a mutation in one or both copies of TP53 would affect cancer outcomes. A new study published by Bernard et al in Nature Medicine definitively answers this question for patients with myelodysplastic syndromes (MDS).
“Our study is the first to assess the impact of having one vs two dysfunctional copies of TP53 on cancer outcomes,” said molecular geneticist lead study author Elli Papaemmanuil, PhD, a member of Memorial Sloan Kettering Cancer Center’s Epidemiology and Biostatistics Department, in a statement. “From our results, it's clear that you need to lose function of both copies to see evidence of genome instability and a high-risk clinical phenotype in MDS.”
The consequences for cancer diagnosis and treatment are immediate and profound, she added.
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, which was conducted under the aegis of the International Working Group for the Prognosis of MDS, whose goal is to develop new international guidelines for the treatment of this disease. The findings were independently validated using data from the Japanese MDS working group.
“Currently, the existing MDS guidelines do not consider genomic data such as TP53 and other acquired mutations when assessing a person's prognosis or determining appropriate treatment for this disease,” said study coauthor Peter Greenberg, MD, Director of Stanford University's MDS Center, Chair of the National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines Panel for MDS. “That needs to change.”
Using new computational methods, the investigators found that about one-third of patients with MDS had only one mutated copy of TP53. These patients had similar outcomes as patients who did not have a TP53 mutation: a good response to treatment, low rates of disease progression, and better survival rates. On the other hand, the two-thirds of patients who had two mutated copies of TP53 had much worse outcomes: treatment-resistant disease, rapid disease progression, and low overall survival. In fact, the researchers found that TP53 mutation status—zero, one, or two mutated copies of the gene—was the most important variable when predicting outcomes.
“Our findings are of immediate clinical relevance to [patients with] MDS,” said Dr. Papaemmanuil. “Going forward, all patients [with MDS] should have their TP53 status assessed at diagnosis.”
As for why it takes two “hits” to TP53 to see an effect on cancer outcomes, the study's first author Elsa Bernard, PhD, a postdoctoral scientist in the Papaemmanuil lab, speculated that one normal copy is enough to provide adequate protection against DNA damage. This would explain why having only one mutated copy was not associated with genome instability or any worse survival rates than having two normal copies.
Given the frequency of TP53 mutations in cancer, these results make a case for examining the impact of one vs two mutations on other cancers as well. They also reveal the need for clinical trials designed specifically with these molecular differences in mind.
“With the increasing adoption of molecular profiling at the time of cancer diagnosis, we need large, evidence-based studies to inform how to translate these molecular findings into optimal treatment strategies,” said Dr. Papaemmanuil.
The study authors concluded, “This study shows that consideration of TP53 allelic state is critical for diagnostic and prognostic precision in MDS as well as in future correlative studies of treatment response.”
Disclosure: For full disclosures of the study authors, visit nature.com.The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.