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Proposal of a new genomic framework for categorization of pediatric acute myeloid leukemia associated with prognosis.

ABSTRACT: Recent studies on pediatric acute myeloid leukemia (pAML) have revealed pediatric-specific driver alterations, many of which are underrepresented in the current classification schemas. To comprehensively define the genomic landscape of pAML, we systematically categorized 895 pAML into 23 molecular categories that are mutually distinct from one another, including new entities such as UBTF or BCL11B, covering 91.4% of the cohort. These molecular categories were associated with unique expression profiles and mutational patterns. For instance, molecular categories characterized by specific HOXA or HOXB expression signatures showed distinct mutation patterns of RAS pathway genes, FLT3, or WT1, suggesting shared biological mechanisms. We show that molecular categories were strongly associated with clinical outcomes using two independent cohorts, leading to the establishment of a prognostic framework for pAML based on molecular categories and minimal residual disease. Together, this comprehensive diagnostic and prognostic framework forms the basis for future classification of pAML and treatment strategies.

SUBMITTER: Umeda M

PROVIDER: S-EPMC10312943 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Proposal of a new genomic framework for categorization of pediatric acute myeloid leukemia associated with prognosis.

Umeda Masayuki M Ma Jing J Westover Tamara T Ni Yonghui Y Song Guangchun G Maciaszek Jamie L JL Rusch Michael M Rahbarinia Delaram D Foy Scott S Huang Benjamin J BJ Walsh Michael P MP Kumar Priyadarshini P Liu Yanling Y Fan Yiping Y Wu Gang G Baker Sharyn D SD Ma Xiaotu X Wang Lu L Rubnitz Jeffrey E JE Pounds Stanley S Klco Jeffery M JM

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Recent studies on pediatric acute myeloid leukemia (pAML) have revealed pediatric-specific driver alterations, many of which are underrepresented in the current classification schemas. To comprehensively define the genomic landscape of pAML, we systematically categorized 895 pAML into 23 molecular categories that are mutually distinct from one another, including new entities such as <i>UBTF</i> or <i>BCL11B</i>, covering 91.4% of the cohort. These molecular categories were associated with unique ...[more]

PMID: 37398194

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Project description:BackgroundRecent studies have provided a detailed census of genes that are mutated in acute myeloid leukemia (AML). Our next challenge is to understand how this genetic diversity defines the pathophysiology of AML and informs clinical practice.MethodsWe enrolled a total of 1540 patients in three prospective trials of intensive therapy. Combining driver mutations in 111 cancer genes with cytogenetic and clinical data, we defined AML genomic subgroups and their relevance to clinical outcomes.ResultsWe identified 5234 driver mutations across 76 genes or genomic regions, with 2 or more drivers identified in 86% of the patients. Patterns of co-mutation compartmentalized the cohort into 11 classes, each with distinct diagnostic features and clinical outcomes. In addition to currently defined AML subgroups, three heterogeneous genomic categories emerged: AML with mutations in genes encoding chromatin, RNA-splicing regulators, or both (in 18% of patients); AML with TP53 mutations, chromosomal aneuploidies, or both (in 13%); and, provisionally, AML with IDH2(R172) mutations (in 1%). Patients with chromatin-spliceosome and TP53-aneuploidy AML had poor outcomes, with the various class-defining mutations contributing independently and additively to the outcome. In addition to class-defining lesions, other co-occurring driver mutations also had a substantial effect on overall survival. The prognostic effects of individual mutations were often significantly altered by the presence or absence of other driver mutations. Such gene-gene interactions were especially pronounced for NPM1-mutated AML, in which patterns of co-mutation identified groups with a favorable or adverse prognosis. These predictions require validation in prospective clinical trials.ConclusionsThe driver landscape in AML reveals distinct molecular subgroups that reflect discrete paths in the evolution of AML, informing disease classification and prognostic stratification. (Funded by the Wellcome Trust and others; ClinicalTrials.gov number, NCT00146120.).

Project description:Acute myeloid leukemia (AML) is the most common childhood cancer and is a major cause of morbidity among adults with hematologic malignancies. Several novel genetic alterations, which target critical cellular pathways, including alterations in lymphoid development-regulating genes, tumor suppressors and oncogenes that contribute to leukemogenesis, have been identified. The present study aimed to identify molecular markers associated with the occurrence and poor prognosis of AML. Information on these molecular markers may facilitate prediction of clinical outcomes. Clinical data and RNA expression profiles of AML specimens from The Cancer Genome Atlas database were assessed. Mutation data were analyzed and mapped using the maftools package in R software. Kyoto Encyclopedia of Genes and Genomes, Reactome and Gene Ontology analyses were performed using the clusterProfiler package in R software. Furthermore, Kaplan-Meier survival analysis was performed using the survminer package in R software. The expression data of RNAs were subjected to univariate Cox regression analysis, which demonstrated that the mutation loads varied considerably among patients with AML. Subsequently, the expression data of mRNAs, microRNAs (miRNAs/miR) and long non-coding RNAs (lncRNAs) were subjected to univariate Cox regression analysis to determine the the 100 genes most associated with the survival of patients with AML, which revealed 48 mRNAs and 52 miRNAs. The top 1,900 mRNAs (P<0.05) were selected through enrichment analysis to determine their functional role in AML prognosis. The results demonstrated that these molecules were involved in the transforming growth factor-β, SMAD and fibroblast growth factor receptor-1 fusion mutant signaling pathways. Survival analysis indicated that patients with AML, with high MYH15, TREML2, ATP13A2, MMP7, hsa-let-7a-2-3p, hsa-miR-362-3p, hsa-miR-500a-5p, hsa-miR-500b-5p, hsa-miR-362-5p, LINC00987, LACAT143, THCAT393, THCAT531 and KHCAT230 expression levels had a shorter survival time compared with those without these factors. Conversely, a high KANSL1L expression level in patients was associated with a longer survival time. The present study determined genetic mutations, mRNAs, miRNAs, lncRNAs and signaling pathways involved in AML, in order to elucidate the underlying molecular mechanisms of the development and recurrence of this disease.

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Proposal of a new genomic framework for categorization of pediatric acute myeloid leukemia associated with prognosis.

Publications

Proposal of a new genomic framework for categorization of pediatric acute myeloid leukemia associated with prognosis.

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