Data from Somatic Exonic Deletions in <i>RUNX1</i> Constitutes a Novel Recurrent Genomic Abnormality in Acute Myeloid Leukemia

Abstract

<div>AbstractPurpose:<p>In acute myeloid leukemia (AML), somatic mutations (commonly missense, nonsense, and frameshift indels) in <i>RUNX1</i> are associated with a dismal clinical outcome. Inherited <i>RUNX1</i> mutations cause familial platelet disorder. As approximately 5%–10% of germline <i>RUNX1</i> mutations are large exonic deletions, we hypothesized that such exonic <i>RUNX1</i> aberrations may also be acquired during the development of AML.</p>Experimental Design:<p>Sixty patients with well-characterized AML were analyzed with multiplex ligation-dependent probe amplification (<i>n</i> = 60), microarray (<i>n</i> = 11), and/or whole-genome sequencing (<i>n</i> = 8).</p>Results:<p>In total, 25 (42% of the cohort) <i>RUNX1</i>-aberrant patients (defined by the presence of classical mutations and/or exonic deletions) were identified. Sixteen patients (27%) carried only exonic deletions, 5 (8%) carried classical mutations, and 4 (7%) carried both exonic deletions and mutations. No significant difference was observed between patients with classical <i>RUNX1</i> mutations and <i>RUNX1</i> exonic deletions in median overall survival (OS, 53.1 vs. 38.8 months, respectively, <i>P</i> = 0.63). When applying the European Leukemia Net (ELN) classification including the <i>RUNX1</i>-aberrant group, 20% of the patients initially stratified as intermediate-risk (5% of the whole cohort) were reassigned to the high-risk group, which improved the performance of ELN classification regarding OS between intermediate- and high-risk groups (18.9 vs. 9.6 months, <i>P</i> = 0.09).</p>Conclusions:<p>Somatic <i>RUNX1</i> exonic deletions constitute a novel recurrent aberration in AML. Our findings have important clinical implications regarding AML classification, risk stratification, and treatment decision. Moreover, they argue in favor of further investigating such genomic aberrations not only in <i>RUNX1</i> but also in other genes implicated in cancer biology and management.</p><p><i><a href="https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-23-1065" target="_blank">See related commentary by Chakraborty and Stengel, p. 2742</a></i></p></div>