Highlights
- •ERGamp is a unique driver of myeloid malignancy with a signature genetic profile with loss of 5q, chromothripsis and TP53 loss of function variants.
- •Chromosome structure with copy number analysis (CNA) and loss of heterozygosity (LOH) should be standard of care to risk stratify myeloid malignancies.
Abstract
ETS-related gene (ERG) amplification, observed in 4–6% of acute myeloid leukemia (AML), is associated with
unfavorable prognosis. To determine coincident effects of additional genomic abnormalities
in AML with ERG amplification (ERGamp), we examined 11 ERGamp cases of 205 newly diagnosed AML using chromosomal microarray analysis and next
generation sequencing. ERGamp cases demonstrated a distinct pattern of high genetic complexity: loss of 5q,
chromothripsis and TP53 loss of function variants. Remarkably, allelic TP53 loss or
loss of heterozygosity (LOH) co-occurring with TP53 inactivating mutation dramatically
effected ERGamp tumor patient outcome. In the presence of homozygous TP53 loss of function, ERGamp patients demonstrated no response to induction chemotherapy with median overall
survival (OS) of 3.8 months (N = 9). Two patients with heterozygous loss of TP53 function underwent alloSCT without
evidence of relapse at one year. Similarly, a validation TCGA cohort, 6 of the 8 ERGamp cases with TP53 loss of function demonstrated median OS of 2.5 months. This suggests
that with TP53 mutant ERGamp AML, successive loss of the second TP53 allele, typically by 17p deletion or LOH
identifies a specific high-risk subtype of AML patients who are resistant to standard
induction chemotherapy and need novel approaches to avert the very poor prognosis.
Keywords
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Article info
Publication history
Published online: January 17, 2023
Accepted:
January 10,
2023
Received in revised form:
December 21,
2022
Received:
July 13,
2022
Identification
Copyright
© 2023 Elsevier Inc. All rights reserved.
