Genomic Classification and Prognosis in Acute Myeloid Leukemia

Abstract

BACKGROUNDRecent studies have provided a detailed census of genes that are mutated in acute myeloid leukemia (AML). Our next challenge is to understand how this genetic diversity defines the pathophysiology of AML and informs clinical practice. METHODSWe enrolled a total of 1540 patients in three prospective trials of intensive therapy. Combining driver mutations in 111 cancer genes with cytogenetic and clinical data, we defined AML genomic subgroups and their relevance to clinical outcomes. RESULTSWe identified 5234 driver mutations across 76 genes or genomic regions, with 2 or more drivers identified in 86% of the patients. Patterns of co-mutation compartmentalized the cohort into 11 classes, each with distinct diagnostic features and clinical outcomes. In addition to currently defined AML subgroups, three heterogeneous genomic categories emerged: AML with mutations in genes encoding chromatin, RNAsplicing regulators, or both (in 18% of patients); AML with TP53 mutations, chromosomal aneuploidies, or both (in 13%); and, provisionally, AML with IDH2 R172 mutations (in 1%). Patients with chromatin-spliceosome and TP53-aneuploidy AML had poor outcomes, with the various class-defining mutations contributing independently and additively to the outcome. In addition to class-defining lesions, other co-occurring driver mutations also had a substantial effect on overall survival. The prognostic effects of individual mutations were often significantly altered by the presence or absence of other driver mutations. Such gene-gene interactions were especially pronounced for NPM1-mutated AML, in which patterns of co-mutation identified groups with a favorable or adverse prognosis. These predictions require validation in prospective clinical trials. CONCLUSIONSThe driver landscape in AML reveals distinct molecular subgroups that reflect discrete paths in the evolution of AML, informing disease classification and prognostic stratification. (Funded by the Wellcome Trust and others; ClinicalTrials.gov number, NCT00146120.) a bs tr ac t

CIN and Aneuploidy: Different Concepts, Different Consequences

“…[2] Furthermore, aneuploidy is associated with poor patient survival. [80][81][82][83][84][85][86][87][88][89] The karyotypes observed in cancer are not random, as different cancer types display specific karyotypes. [36,72,90] While certain forms of aneuploidy can be beneficial to tumor growth, the relationship between cancer and CIN remains paradoxical.…”

P53 deletion and NrasG12D cooperate for AML

“…However, recent studies have shown that P53 mutations were associated with therapy-related AML with a very poor prognosis. 4 Of note, frequent alterations in post-BCR-ABL-positive and -negative MPN leukemia involve P53 mutations (in ;30% of cases) or P53 repression by negative regulators (MDM4 gene amplification [18% of cases] or posttranslational MDM2 upregulation). 5,6 In the present study, Zhang et al identified P53 mutations, RAS mutations, or both mutations in 6%, 17%, and 0.6% of AML cases, respectively (see figure).…”

“…The recommendations are based not only on clinical experience and retrospective data, but also are supported by a large prospective randomized study comparing showing equivalent disease control with 24 Gy (in 2-Gy fractions) compared with the old standard of 40 to 45 Gy. 4 The dose recommended for MZLs (nodal or extranodal) by the National Comprehensive Cancer Network is 24 to 30 Gy. 5 The International Lymphoma Radiation Oncology Group recommendations specifically for orbital MZL are in the range of 24 to 25 Gy, with a preference to smaller fractions of 1.5 to 1.8 Gy.…”

Pharmacogenetics and Personalized Medicine in Hematology

“…A landmark NEJM publication in 2016 [10] sequenced 111 genes in over 1500 AML patients and revealed a staggering 5234 driver mutations in 76 genes or regions. The proposed ''genomic'' classification of AML identified new molecular subgroups including AML with mutations in genes encoding chromatin and/or RNA-splicing factors; AML with TP53 mutations and/or chromosomal aneuploidies and AML with IDH2R172 mutations.…”