神经母细胞瘤RAS病毒癌基因同源物
PTPN11型
髓系白血病
生物
克拉斯
癌症研究
突变
拷贝数变化
净现值1
杂合子丢失
白血病
表观遗传学
遗传学
基因
等位基因
基因组
核型
染色体
作者
Mehrnoosh Tashakori,Tapan M. Kadia,Sanam Loghavi,Naval Daver,Rashmi Kanagal‐Shamanna,Sherry Pierce,Dawen Sui,Peng Wei,Farnoosh Khodakarami,Zhenya Tang,Mark J. Routbort,Carol Bivins,Elias Jabbour,L. Jeffrey Medeiros,Kapil N. Bhalla,Hagop M. Kantarjian,Farhad Ravandi,Joseph D. Khoury
出处
期刊:Blood
[American Society of Hematology]
日期:2022-07-07
卷期号:140 (1): 58-72
被引量:47
标识
DOI:10.1182/blood.2021013983
摘要
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.
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