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Analysis of MDM2 Amplification: Next-Generation Sequencing of Patients With Diverse Malignancies

Shumei Kato1, Jeffrey S Ross2, Laurie Gay2

  • 1University of California, San Diego, Moores Cancer Center, La Jolla.

JCO Precision Oncology
|August 28, 2018
PubMed
Abstract

Insights

MDM2 amplification occurs in 3.5% of diverse cancers and is often accompanied by targetable co-alterations. This finding is crucial for understanding cancer progression and developing new therapies.

Area of Science:

  • Oncology
  • Genomics
  • Molecular Biology

Background:

  • MDM2 amplification promotes tumorigenesis via p53 inhibition.
  • MDM2 inhibitors are in clinical trials, and MDM2 amplification correlates with hyperprogression after immunotherapy.
  • Assessing MDM2 amplification is clinically relevant for diverse cancers.

Purpose of the Study:

  • To determine the frequency of MDM2 amplification across a large cohort of diverse cancer types.
  • To identify co-altered genes and pathways associated with MDM2 amplification.
  • To evaluate the potential for targeted therapies in patients with MDM2 amplification.

Main Methods:

  • Next-generation sequencing (NGS) was used to analyze the molecular profiles of 102,878 patients.
  • MDM2 amplification status and co-alterations were interrogated in 182 to 465 genes.
  • Analysis included diverse malignancies.

Main Results:

  • MDM2 amplification was found in 3.5% of patients (3,650/102,878).
  • 99.0% of these patients had co-alterations in pathways like tyrosine kinase, PI3K, TP53, and MAPK signaling.
  • 97.6% of patients with MDM2 amplification had potentially targetable co-alterations, while MDM2 amplifications were less associated with high tumor mutation burden.

Conclusions:

  • MDM2 amplification occurs in a small subset of most tumor types.
  • The majority of patients with MDM2 amplification harbor potentially targetable genomic co-alterations.
  • This highlights MDM2 amplification as a significant biomarker with therapeutic implications.

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