Novel scheme for defining the clinical implications of TP53 mutations in myeloid neoplasia

Journal of Hematology & Oncology

Research

Suresh K. Balasubramanian¹  Yazan Madanat²  Taha Bat²  Ishani Pandit³  Yasuo Kubota³  Jaroslaw P. Maciejewski³  Ramsha Ahmed³  Misam Zawit³  Olisaemeka D. Ogbue³  Arda Durmaz³  Hussein Awada³  Valeria Visconte³  Ben Ponvilawan³  Minako Mori³  Carmelo Gurnari⁴  Tariq Kewan⁵  Waled Bahaj⁶  Manja Meggendorfer⁷  Torsten Haferlach⁷ 

[1] Department of Hematology and Oncology, Wayne State University, Detroit, MI, USA;Department of Internal Medicine, Division of Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA;Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, 9620 Carnegie Ave N Building, Building NE6-250, 44106, Cleveland, OH, USA;Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, 9620 Carnegie Ave N Building, Building NE6-250, 44106, Cleveland, OH, USA;Department of Biomedicine and Prevention, Ph.D. in Immunology, Molecular Medicine and Applied Biotechnology, University of Rome Tor Vergata, Rome, Italy;Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, 9620 Carnegie Ave N Building, Building NE6-250, 44106, Cleveland, OH, USA;Division of Hematology & Oncology, Yale School of Medicine, New Haven, CT, USA;Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, 9620 Carnegie Ave N Building, Building NE6-250, 44106, Cleveland, OH, USA;Division of Medical Oncology & Hematology, School of Medicine, University of Louisville, Louisville, KY, USA;MLL Munich Leukemia Laboratory, Munich, Germany;

关键词: TP53;    Allelic inactivation;    Myeloid neoplasia;    Next-generation sequencing;    Single-cell DNA sequencing;   

DOI  :  10.1186/s13045-023-01480-y

 received in 2023-03-05, accepted in 2023-07-14,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundTP53 mutations (TP53MT) occur in diverse genomic configurations. Particularly, biallelic inactivation is associated with poor overall survival in cancer. Lesions affecting only one allele might not be directly leukemogenic, questioning the presence of cryptic biallelic subclones in cases with dismal prognosis.MethodsWe have collected clinical and molecular data of 7400 patients with myeloid neoplasms and applied a novel model by identifying an optimal VAF cutoff using a statistically robust strategy of sampling-based regression on survival data to accurately classify the TP53 allelic configuration and assess prognosis more precisely.ResultsOverall, TP53MT were found in 1010 patients. Following the traditional criteria, 36% of the cases were classified as single hits, while 64% exhibited double hits genomic configuration. Using a newly developed molecular algorithm, we found that 579 (57%) patients had unequivocally biallelic, 239 (24%) likely contained biallelic, and 192 (19%) had most likely monoallelic TP53MT. Interestingly, our method was able to upstage 192 out of 352 (54.5%) traditionally single hit lesions into a probable biallelic category. Such classification was further substantiated by a survival-based model built after re-categorization. Among cases traditionally considered monoallelic, the overall survival of those with probable monoallelic mutations was similar to the one of wild-type patients and was better than that of patients with a biallelic configuration. As a result, patients with certain biallelic hits, regardless of the disease subtype (AML or MDS), had a similar prognosis. Similar results were observed when the model was applied to an external cohort. In addition, single-cell DNA studies unveiled the biallelic nature of previously considered monoallelic cases.ConclusionOur novel approach more accurately resolves TP53 genomic configuration and uncovers genetic mosaicism for the use in the clinical setting to improve prognostic evaluation.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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