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    Mutant TP53 is an adverse risk factor in acute myeloid leukemia (AML), but large-scale integrated genomic-proteomic analyses of p53 alterations in AML patients 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 uncovered novel pathogenic variants involving TP53 splice sites. In addition, we identified TP53 CN loss in 70.2% of TP53-mutated AML, which had more deleterious TP53 mutations and 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 (sensitivity=94.49%, specificity=90.48%). Protein expression of p53 by immunohistochemistry informed mutation status irrespective of TP53 CN status. Genomic analysis of co-mutations in TP53-mutant AML showed a muted landscape that encompassed 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 provides a rationale to refine risk stratification of AML patients on the basis of integrated molecular and protein-level TP53 analyses. Copyright © 2022 American Society of Hematology.

    Citation

    Mehrnoosh Tashakori, Tapan M Kadia, Sanam Loghavi, Naval G Daver, Rashmi Kanagal-Shamanna, Sherry R Pierce, Dawen Sui, Peng Wei, Farnoosh Khodakarami, Zhenya Tang, Mark Routbort, Carol Bivins, Elias J Jabbour, L Jeffrey Medeiros, Kapil N Bhalla, Hagop M Kantarjian, Farhad Ravandi, Joseph D Khoury. TP53 Copy Number and Protein Expression Inform Mutation Status across Risk Categories in Acute Myeloid Leukemia. Blood. 2022 Apr 07


    PMID: 35390143

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