# Impact of Somatic Gene Mutations on Prognosis Prediction in De Novo AML: Unraveling Insights from a Systematic Review and Meta-Analysis

## TL;DR

This study reviews how gene mutations affect survival in AML patients, identifying which mutations worsen or improve outcomes.

## Contribution

A comprehensive meta-analysis of 80 studies reveals the prognostic impact of 53 somatic mutations in de novo AML.

## Key findings

- NPM1 is the most frequent mutation (27%) in de novo AML.
- CSF3R, TET2, TP53, ASXL1, DNMT3A, and RUNX1 mutations are linked to worse survival outcomes.
- CEBPA biallelic mutations are associated with better overall and relapse-free survival.

## Abstract

This systematic review and meta-analysis aimed to evaluate the prevalence and prognostic impact of somatic gene mutations in de novo Acute Myeloid Leukemia (AML) patients. Data from 80 studies involving 20,048 patients and 53 somatic mutations were analyzed. The most frequent mutation was NPM1 (27%). Mutations in CSF3R, TET2, TP53, ASXL1, DNMT3A, and RUNX1 were associated with worse overall survival (OS) and relapse-free survival (RFS), while CEBPA biallelic mutations were linked to favorable outcomes. FLT3-ITD mutations showed a consistently poor prognostic impact across all subgroups. No significant associations with OS or RFS were found for GATA2, FLT3-TKD, KRAS, NRAS, IDH1, and IDH2. The results of this study enhance the understanding of the genetic landscape of AML and support improved risk stratification and clinical decision-making.

Background: Wide application of genome sequencing technologies has highlighted extensive genetic diversity in Acute Myeloid Leukemia (AML), yet the specific roles of individual genes remain unclear. This systematic review and meta-analysis aims to provide robust evidence for the prognostic impact of somatic gene mutations in de novo AML patients, while also exploring the prevalence of these mutations. Methods: Eligible studies were identified from PubMed and Scopus, with a focus on those reporting the prognostic influence of somatic gene mutations on overall survival (OS) or relapse-free survival (RFS) when compared to wild-type carriers. We calculated the pooled prevalence with 95% confidence intervals to assess the frequency of these mutations, and the pooled Hazard Ratio (HR) to compare OS and RFS associated with specific gene mutations. Results: We evaluated 53 somatic gene mutations using 80 studies, involving 20,048 de novo AML patients. The analysis revealed that the most prevalent affected genes were NPM1 (27%), DNMT3A (26%), and FLT3-ITD (24%). Mutations in CSF3R, TET2, and TP53 were significantly associated with poorer OS or RFS (p < 0.05). Sensitivity analysis confirmed that ASXL1, DNMT3A, and RUNX1 mutations were consistently linked to inferior OS or RFS. In contrast, CEBPAdm mutations were associated with favorable OS [HR = 0.39 (0.30–0.50)] and RFS [HR = 0.44 (0.37–0.54)]. Subgroup analysis showed that FLT3-ITD mutations were consistently associated with worse OS or RFS across all subgroups, though no significant subgroup differences were noted. No significant impact on OS or RFS was observed for mutations in GATA2, FLT3-TKD, KRAS, NRAS, IDH1, and IDH2. Conclusions: These findings provide critical insights into AML prognosis, aiding clinical decision-making and improving risk stratification strategies.