The mutational oncoprint of recurrent cytogenetic abnormalities in adult patients with de novo acute myeloid leukemia

Abstract

Recurrent chromosomal abnormalities and gene mutations detected at the time of diagnosis of acute myeloid leukemia (AML) are associated with particular disease features, treatment response and survival of AML patients, and are used to denote specific disease entities in the World Health Organization classification of myeloid neoplasms and acute leukemia. However, large studies that integrate cytogenetic and comprehensive mutational information are scarce. We created a comprehensive oncoprint of mutations associated with recurrent cytogenetic findings by combining the information on mutational patterns of 80 cancer- and leukemia-associated genes with cytogenetic findings in 1603 adult patients with de novo AML. We show unique differences in the mutational profiles among major cytogenetic subsets, identify novel associations between recurrent cytogenetic abnormalities and both specific gene mutations and gene functional groups, and reveal differences in cytogenetic and mutational features between patients younger than 60 years and those aged 60 years or older. The identified associations between cytogenetic and molecular genetic data may help guide mutation testing in AML, and result in more focused application of targeted therapy in patients with de novo AML.

Mutations associated with a 17-gene leukemia stem cell score and the score’s prognostic relevance in the context of the European LeukemiaNet classification of acute myeloid leukemia

“…To obtain more detailed insights into the mutational patterns associated with the 17-gene LSC signature, we analyzed 81 cancer and leukemia-associated genes. 19 We found that 77 genes were mutated in at least one patient (Online Supplementary Table S4). Patients with a 17-gene low score had fewer mutations compared with patients with a 17-gene high score (median: 2 vs. 3; P<0.001).…”

“…We, therefore, derived the 17-gene score from a set of samples from adults with AML and determined associations between the signature and known prognosticators 1,17,18 as well as mutational data of 81 cancer-and leukemia-associated genes. 19 Moreover, we validated the prognostic impact of the 17-gene signature alone and in the context of the 2017 ELN genetic-risk classification. 1…”

“…Next, we looked for differences in the mutational patterns of 81 cancer-and leukemia-associated genes 19 between 17-gene low and 17-gene high score patients. Patients 17-gene LSC score: mutations and outcome in AML haematologica | 2020; 105(3) 727 with a 17-gene low score had a lower median number of mutations and only three genes, namely, GATA2, CEBPA and KIT, were found to be mutated more frequently in this group.…”

Distinct mutation spectrum, clinical outcome and therapeutic responses of typical complex/monosomy karyotype acute myeloid leukemia carrying TP53 mutations

“…Second, next‐generation sequencing (NGS) revealed a unique mutational spectrum associated with TP53 mutation in CK/MK AML. In particular, the mutual exclusivity between TP53 mutations and FLT3 ‐TKD and the rare occurrence of DNMT3A , NPM1 , KRAS , EZH2 , TET2 and SETBP1 have also been reported in different cohorts and may suggest their possible detrimental effects on TP53 mutant cells. NOTCH1 mutations, which are rarely reported in AML, were identified in 16% cases.…”

Emerging therapies for acute myeloid leukemia: translating biology into the clinic

“…While some mutations such as FMS-related tyrosine kinase 3 (FLT3), nucleophosmin (NPM1), and isocitrate dehydrogenase 1 and 2 (IDH1/2) had already been reported in AML, other mutations such as U2AF1 and others involved in spliceosome pathways were discovered. The pattern of AML mutations was subsequently validated in additional cohorts with larger numbers of adult patients (5,10). The presence and prognostic significance of genetic mutations have also been examined in pediatric AML and show trends similar to those of adult AML.…”