Reference Detail

Ref Type

Journal Article

PMID

(30237864)

Authors

Dembla V, Somaiah N, Barata P, Hess K, Fu S, Janku F, Karp DD, Naing A, Piha-Paul SA, Subbiah V, Tsimberidou AM, Shaw K, Meric-Bernstam F, Hong DS

Title

Prevalence of MDM2 amplification and coalterations in 523 advanced cancer patients in the MD Anderson phase 1 clinic.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Oncotarget	9	69	2018 Sep 04	33232-33243	Oncotarget

URL

Abstract Text

TP53 is the most commonly mutated gene in cancer and codes for the best studied tumor suppressor, p53. MDM2 is involved in the negative regulation of p53 and itself serves as an oncogene, reported to be overexpressed in several cancer tumor types. In this retrospective study, we assessed the occurrence of MDM2 amplification among patients with various types of cancers and its association with clinical factors, other genetic aberrations, and response to targeted therapy in a phase I clinical trial setting.Samples from patients with advanced solid tumors who had been referred to the MD Anderson phase I clinical trials program between January 2011 and January 2016 were collected and analyzed for MDM2 amplification using FoundationOne's genomic profiling assay. Patients whose tumors expressed MDM2 amplification were compared to those with tumors of the same histologic types without MDM2 amplification.We tested tumors from 523 patients, of which 23 (4.4%) had MDM2 amplification. The highest prevalence of MDM2 amplification was in sarcoma (57%), breast cancer (13%) and bladder cancer (9%). Six patients with liposarcoma were treated on phase I protocol with an MDM2 inhibitor. The most common molecular aberrations co-occurring with MDM2 amplification was CDK4 amplification (70%). TP53 mutation was also detected in 7 patients (30%).MDM2 amplification was most commonly associated with liposarcoma. Concomitant alterations in additional genes such as CDK4 amplification and TP53 mutations, along with variable responses to targeted therapies including MDM2 inhibitors, suggest that further combinational studies are needed to target this population.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
MDM2	NCBI	ACTFS\|hdm2\|HDMX\|LSKB		MDM2, MDM2 proto-oncogene, is an E3 ubiquitin protein ligase that mediates Tp53 degradation and therefore, regulates apoptosis and cell-cycle (PMID: 27993876). Amplification and/or overexpression of MDM2 has been identified in several cancer types (PMID: 23303139, PMID: 31440117) and amplification is common in liposarcoma (PMID: 30237864) and has been observed with Mdm2 overexpression in anaplastic lymphoma kinase (ALK)-negative inflammatory myofibroblastic tumors (PMID: 32195970).	Oncogene

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
MDM2 amp	liposarcoma	predicted - sensitive	unspecified MDM2 inhibitor	Phase I	Actionable	In a Phase I trial, treatment with an unspecified MDM2 inhibitor resulted in clinical efficacy in six patients with liposarcoma harboring MDM2 amplification, including three patients with a partial response and two patients with stable disease for 15.7 months and 4.7 months (PMID: 30237864).	30237864