A study performed among 3,324 patients with myelodysplastic syndromes (MDS) with analysis of TP53 mutations and allelic imbalances 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. The findings are published on 3 August in the Nature Medicine by a group of international researchers. Seishi Ogawa of the Department of Pathology and Tumor Biology, Kyoto University in Kyoto, Japan and Elli Papaemmanuil of the Computational Oncology Service, Department of Epidemiology & Biostatistics, and Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA jointly supervised this work.
The authors wrote in the study background that TP53 is the most frequently mutated gene in cancer. In patients with MDS, TP53 mutations are associated with high-risk disease, rapid transformation to acute myeloid leukaemia, resistance to conventional therapies and dismal outcomes.
Consistent with the tumour suppressive role of TP53, patients harbour both mono- and biallelic mutations. However, the biological and clinical implications of TP53 allelic state have not been fully investigated in MDS.
The study team delineated two subsets of patients with distinct phenotypes and outcomes. One-third of TP53-mutated patients had monoallelic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting.
Established associations with complex karyotype, few co-occurring mutations, high-risk presentation and poor outcomes were specific to multi-hit patients only. TP53 multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System.
Monoallelic patients did not differ from TP53 wild-type patients in outcomes and response to therapy.
The authors concluded that their study shows that TP53 allelic state is critical for diagnostic and prognostic precision in MDS.
Clinical, copy number and mutation data from this work are available here. Databases used in the study are gnomAD, COSMIC, cBioPortal for Cancer Genomics, OncoKB Precision Oncology Knowledge Base, ClinVar and the IARC TP53 Database.
This work was supported in part by grants from the Celgene Corporation through the MDS Foundation. It was also supported by multiple grants to individual investigators.
Reference
Bernard E, Nannya Y, Hasserjian RP, et al. Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes. Nature Medicine; Published online 3 August 2020. DOI: https://doi.org/10.1038/s41591-020-1008-z
