Analysis of <i>MDM2</i> Amplification: Next-Generation Sequencing of Patients With Diverse Malignancies.

Abstract

<i>MDM2</i> amplification can promote tumorigenesis directly or indirectly through p53 inhibition. <i>MDM2</i> has increasing clinical relevance because inhibitors are under evaluation in clinical trials, and <i>MDM2</i> amplification is a possible genomic correlate of accelerated progression, known as hyperprogression, after anti-PD-1/PD-L1 immunotherapy. We used next-generation sequencing (NGS) to ascertain <i>MDM2</i> amplification status across a large number of diverse cancers. We interrogated the molecular profiles of 102,878 patients with diverse malignancies for <i>MDM2</i> amplification and co-altered genes using clinical-grade NGS (182 to 465 genes). <i>MDM2</i> amplification occurred in 3.5% of patients (3,650 of 102,878). The majority of tumor types had a small subset of patients with <i>MDM2</i> amplification. Most of these patients (99.0% [3,613/3,650]) had co-alterations that accompanied <i>MDM2</i> amplification. Various pathways, including those related to tyrosine kinase (37.9% [1,385 of 3,650]), <i>PI3K</i> signaling (25.4% [926 of 3,650]), <i>TP53</i> (24.9% [910 of 3,650]), and <i>MAPK</i> signaling (23.6% [863 of 3,650]), were involved. Although infrequent, mismatch repair genes and <i>PD-L1</i> amplification also were co-altered (2.2% [79 of 3,650]). Most patients (97.6% [3,563 of 3,650]) had one or more co-alterations potentially targetable with either a Food and Drug Administration-approved or investigational agent. <i>MDM2</i> amplifications were less frequently associated with high tumor mutation burden compared with the <i>MDM2</i> wild-type population (2.9% <i>v</i> 6.5%; <i>P</i> < .001). An illustrative patient who harbored <i>MDM2</i> amplification and experienced hyperprogression with an immune checkpoint inhibitor is presented. <i>MDM2</i> amplification was found in 3.5% of 102,878 patients, 97.6% of whom harbored genomic co-alterations that were potentially targetable. This study suggests that a small subset of most tumor types have <i>MDM2</i> amplification as well as pharmacologically tractable co-alterations.