TP53 Mutations May Play a Role in Treatment‑Related Acute Myeloid Leukemia and Myelodysplastic Syndrome
A genomic study of cancer patients previously treated with chemotherapy or radiation therapy found that TP53 mutations may play a role in the development of treatment-related acute myeloid leukemia (AML) and myelodysplastic syndrome, according to a report by Wong et al in Nature. However, the investigators noted that TP53 mutations seem to accumulate randomly as part of the aging process and thus are present in blood stem cells long before a patient is diagnosed with therapy-related AML and myelodysplastic syndrome.
AML and myelodysplastic syndrome are well-recognized treatment complications associated with cytotoxic chemotherapy and/or radiotherapy. These disorders typically develop 1 to 5 years after patients receive these treatments.
For oncologists, it is important to recognize the occurrence of these treatment-related complications and to determine the differences between them and the similar de novo forms of these conditions. These differences include a higher incidence of TP53 mutations and chromosome abnormalities, and a reduced response to chemotherapy. What is most complex for oncologists to determine is the mechanism by which TP53 mutations are selectively enriched in treatment-related AML and myelodysplastic syndrome.
With that in mind, the investigators conducted a study to identify the role of TP53 in the origin and evolution of treatment-related AML and myelodysplastic syndrome. Their basic approach was to sequence the genomes of 22 cases of treatment-related AML.
Cancer Therapy May Not Cause Widespread DNA Damage
For the whole-genome sequencing study, the investigators selected 22 cases of treatment-related AML with few cytogenetic abnormalities. All patient samples were selected from a larger cohort of adult AML and myelodysplastic syndrome patients enrolled in a single-institution tissue banking protocol. In all of the cases, the TP53 mutation was clonal in the treatment-related AML diagnostic sample.
Four cases of treatment-related AML or myelodysplastic syndrome were identified in which the exact TP53 mutation found at diagnosis was also present at low frequencies (0.003%–0.7%) in mobilized blood leukocytes or bone marrow 3 to 6 years before the development of treatment-related AML and myelodysplastic syndrome. Moreover, functional TP53 mutations were identified in small populations of peripheral blood cells of healthy chemotherapy-naive elderly individuals. Thus, these data suggest that cytotoxic therapy does not directly induce TP53 mutations.
Study patients had similar numbers and types of genetic mutations in their leukemia cells as other patients who developed AML without exposure to chemotherapy or radiation therapy. After analyzing blood samples from 19 healthy patients (aged 68–89) with no history of cancer or chemotherapy, the researchers found that nearly 50% had mutations in one copy of TP53.
Therefore, they hypothesized that TP53 mutations seem to accumulate randomly as part of the aging process and are present in blood stem cells long before a patient is diagnosed with therapy-related AML or myelodysplastic syndrome. Thus, even though chemotherapy and radiation therapy may be associated with the development of AML and myelodysplastic syndrome in certain patients, they may not cause widespread DNA damage.
Closing Thoughts
According to the investigators, their findings open new avenues for research to predict which patients are at risk of developing therapy-related AML and to find ways to prevent it.
“Until now, we’ve understood very little about therapy-related AML and why it is so difficult to treat,” they remarked. “This gives us some important clues for further studies aimed at treatment and prevention.”
Daniel C. Link, MD, of the Department of Medicine, Oncology Division, Washington University School of Medicine, St Louis, is the corresponding author of this article in Nature.
The research is funded by grants from the National Institutes of Health, the National Human Genome Research Institute, and the Leukemia and Lymphoma Society. The authors disclosed no potential conflicts of interest.
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®.
