In a study reported in the Journal of Clinical Oncology, Zampini et al identified a proportion of patients with myelodysplastic syndromes who had nonmutational TP53 but p53 dysfunction, which was associated with poor disease outcomes.
Study Details
The study involved data from a cohort of 6,204 patients. Subsets of patients included those with available information on RNA sequencing of tumor cells, high-dimensional phenotype of immune cells, and multiomics analysis (RNA sequencing and proteomics) on single cells.
Key Findings
Biallelic TP53 inactivation was a potent driver of disease progression and identified high-risk patients irrespective of variant allele frequency. Monoallelic and biallelic inactivation represented disease stages occurring as a multihit process in myelodysplastic syndromes with TP53 mutations; as stated by the investigators, this finding could refine the optimal timing of therapeutic interventions in these patients.
A subset of patients with myelodysplastic syndromes (5%) was identified with wild-type TP53 and hyperexpression of abnormal p53 protein in bone marrow progenitors, with these characteristics being associated with “dismal outcome.” These patients exhibited upstream p53 signaling aberrations in PI3K cascade, RAS, WNT, and NF-KB pathways, MDM2 gene amplification, and downstream dysregulation of p53 targets. Myelodysplastic syndrome with p53 dysfunction was associated with immune dysregulation involving myeloid-derived inflammation and impaired antigen presentation; as stated by the investigators, these characteristics may be a driver of poor prognosis and provide the groundwork for innovative immunotherapies.
The investigators concluded: “The identification of nonmutational p53 dysfunction in [myelodysplastic syndromes] may lay the foundation for a mechanistic classification of myeloid neoplasms, moving beyond a purely molecular stratification. The recognition of patients with p53 dysfunction is relevant to provide correct disease-risk assessment and interventions, as well as to refine the design of clinical trials.”
Matteo Giovanni Della Porta, MD, of the IRCCS Humanitas Research Hospital, Milan, Italy, is the corresponding author of the Journal of Clinical Oncology article.
Disclosure: The study was supported by the European Union-Horizon 2020/2023 program and Innovative Health Initiative and others. For full disclosures of all study authors, visit the Journal of Clinical Oncology.
