TP53 Copy Number and Protein Expression Inform Mutation Status Across Risk Categories in Acute Myeloid Leukemia

Authors

Mehrnoosh Tashakori
Tapan Kadia
Sanam Loghavi
Naval Daver
Rashmi Kanagal-Shamanna
Sherry Pierce
Dawen Sui
Peng Wei
Farnoosh Khodakarami
Zhenya Tang
Mark Routbort
Carol A Bivins
Elias J Jabbour
L Jeffrey Medeiros
Kapil Bhalla
Hagop M Kantarjian
Farhad Ravandi
Joseph D Khoury

Publication Date

7-7-2022

Journal

Blood

Abstract

Mutant TP53 is an adverse risk factor in acute myeloid leukemia (AML), but large-scale integrated genomic-proteomic analyses of TP53 alterations in patients with AML remain limited. We analyzed TP53 mutational status, copy number (CN), and protein expression data in AML (N = 528) and provide a compilation of mutation sites and types across disease subgroups among treated and untreated patients. Our analysis shows differential hotspots in subsets of AML and uncovers novel pathogenic variants involving TP53 splice sites. In addition, we identified TP53 CN loss in 70.2% of TP53-mutated AML cases, which have more deleterious TP53 mutations, as well as copy neutral loss of heterozygosity in 5/32 (15.6%) AML patients who had intact TP53 CN. Importantly, we demonstrate that mutant p53 protein expression patterns by immunohistochemistry evaluated using digital image-assisted analysis provide a robust readout that integrates TP53 mutation and allelic states in patients with AML. Expression of p53 by immunohistochemistry informed mutation status irrespective of TP53 CN status. Genomic analysis of comutations in TP53-mutant AML shows a muted landscape encompassing primarily mutations in genes involved in epigenetic regulation (DNMT3A and TET2), RAS/MAPK signaling (NF1, KRAS/NRAS, PTPN11), and RNA splicing (SRSF2). In summary, our data provide a rationale to refine risk stratification of patients with AML on the basis of integrated molecular and protein-level TP53 analyses.

Keywords

DNA Copy Number Variations, Epigenesis, Genetic, Humans, Leukemia, Myeloid, Acute, Mutation, Prognosis, Proteomics, Tumor Suppressor Protein p53

DOI

10.1182/blood.2021013983

PMID

35390143

PMCID

PMC9346958

PubMedCentral® Posted Date

7-7-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes