Abstract
<h3>Context:</h3> The genomic characterization of acute myeloid leukemia (AML) in adults, both at diagnosis and relapse, has been extensively reported. Previous work has shown a clear difference between AML in adults and children, yet the genetic changes associated with relapsed disease in children have yet to be fully described. <h3>Objective:</h3> To elucidate the genetic background of pediatric AML at relapse and identify gene alterations related to poor prognosis. <h3>Design:</h3> Transcriptomic and genetic analyses were performed on relapsed AML from multiple clinical studies held in St. Jude Children's Research Hospital from 2002 to 2020. No blinding was performed in this study. <h3>Patients or Other Participants:</h3> RNA sequencing was performed from 136 patients (median age of 9.2 years) with relapsed pediatric AML. Ninety-one of these samples were also studied by tumor–normal-paired whole-genome sequencing. Additional transcriptomic data from pediatric AML at diagnosis (n=417) were also obtained from previous reports to define the molecular alterations common in relapsed pediatric AML. The clinical outcome of each molecular category is confirmed using clinical data of the diagnosis cohort of the TARGET pediatric AML study. <h3>Results:</h3> Genomic profiling of relapsed pediatric AML demonstrated an increase in KMT2A (n=36, 26.5%) and NUP98 rearrangements (n=18, 13.2%) when compared to <i>de novo</i> pediatric AML, as well as an increase in WT1 mutations (n=33, 24.3%). Comprehensive characterization of pediatric AML with extension RNA transcriptome data revealed 18 molecular categories with unique expression patterns and mutually exclusive gene alteration patterns. These molecular categories included rare categories with structural variants involving oncogenes of MECOM (n=3, 2.2%) or BCL11B (n=2, 1.5%), which led to the upregulation and allele-specific expression (ASE) of each gene. The entire molecular categories showed unique distribution in the relapse cohort compared to the TARGET cohort (p<0.001) and were associated with clinical outcomes. <h3>Conclusions:</h3> Integrated genomic profiling of pediatric AML identified unique molecular categories associated with relapsed disease and poor outcome.
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