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Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes.

ABSTRACT: Tumor protein p53 (TP53) is the most frequently mutated gene in cancer^1,2. In patients with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk disease^3,4, rapid transformation to acute myeloid leukemia (AML)⁵, resistance to conventional therapies^6-8 and dismal outcomes⁹. Consistent with the tumor-suppressive role of TP53, patients harbor both mono- and biallelic mutations¹⁰. However, the biological and clinical implications of TP53 allelic state have not been fully investigated in MDS or any other cancer type. We analyzed 3,324 patients with MDS for TP53 mutations and allelic imbalances and 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 (IPSS-R)¹¹. Surprisingly, monoallelic patients did not differ from TP53 wild-type patients in outcomes and response to therapy. 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.

SUBMITTER: Bernard E

PROVIDER: S-EPMC8381722 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell disorders for which allogeneic hematopoietic cell transplantation (HCT) is currently the sole curative treatment. Epigenetic lesions are considered a major pathogenetic determinant in many cancers, and in MDS, epigenetic-based interventions have emerged as life-prolonging therapies. However, the impact of epigenomic aberrations on HCT outcomes among patients with MDS are not well understood. We hypothesized that epigenomic signatures in MDS patients before undergoing HCT serve as a novel prognostic indicator of the risk of post-HCT MDS relapse. To evaluate these epigenomic signatures in MDS patients, we analyzed reduced representation bisulfite sequencing profiles in a matched case-control population of 94 patients. Among these HCT recipients, 47 patients with MDS who relapsed post-HCT (cases) were matched 1:1 to patients with MDS who did not relapse (controls). Only patients with wild-type TP53, RAS pathway, and JAK2 mutations were included in this study to promote the discovery of novel factors. Cases were matched with controls based on conditioning regimen intensity, age, sex, Revised International Prognostic Scoring System, Karnofsky Performance Status, graft type, and donor type. Pre-HCT whole-blood samples from cases and matched controls were obtained from the Center for International Blood and Marrow Transplant Research repository. We comprehensively identified differentially methylated regions (DMRs) by comparing the methylation patterns among matched cases and controls. Our findings show that cases displayed more hyper-DMRs pretransplantation compared with controls, even after adjusting for pre-HCT use of hypomethylating agents. Hyper-DMRs specific to cases were mapped to the transcription start site of 218 unique genes enriched in 5 different signaling pathways that may serve as regions of interest and factors to consider as prognostic determinants of post-HCT relapse in MDS patients. Interestingly, although patients selected for this cohort were wild-type for the TP53 gene, cases showed significantly greater levels of methylation at TP53 compared with controls. These findings indicate that previously identified prognostic genes for MDS, such as TP53, may affect disease relapse not only through genetic mutation, but also through epigenetic methylation mechanisms.

Project description:BackgroundThe molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear.MethodsWe enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients. An extension cohort included 32 additional patients who received decitabine in different protocols.ResultsOf the 116 patients, 53 (46%) had bone marrow blast clearance (<5% blasts). Response rates were higher among patients with an unfavorable-risk cytogenetic profile than among patients with an intermediate-risk or favorable-risk cytogenetic profile (29 of 43 patients [67%] vs. 24 of 71 patients [34%], P<0.001) and among patients with TP53 mutations than among patients with wild-type TP53 (21 of 21 [100%] vs. 32 of 78 [41%], P<0.001). Previous studies have consistently shown that patients with an unfavorable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes. However, in this study of 10-day courses of decitabine, neither of these risk factors was associated with a lower rate of overall survival than the rate of survival among study patients with intermediate-risk cytogenetic profiles.ConclusionsPatients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk, TP53 mutations, or both had favorable clinical responses and robust (but incomplete) mutation clearance after receiving serial 10-day courses of decitabine. Although these responses were not durable, they resulted in rates of overall survival that were similar to those among patients with AML who had an intermediate-risk cytogenetic profile and who also received serial 10-day courses of decitabine. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT01687400 .).

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Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes.

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