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. 2018 Sep 4;9(69):33232-33243.
doi: 10.18632/oncotarget.26075.

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

Vikas Dembla  1 , Neeta Somaiah  2 , Pedro Barata  3 , Kenneth Hess  4 , Siqing Fu  1 , Filip Janku  1 , Daniel D Karp  1 , Aung Naing  1 , Sarina Anne Piha-Paul  1 , Vivek Subbiah  1 , Apostolia M Tsimberidou  1 , Kenna Shaw  5 , Funda Meric-Bernstam  1 , David S Hong  1
Affiliations

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

Vikas Dembla et al. Oncotarget. .

Abstract

Background: 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.

Methods: 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.

Results: 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%).

Conclusion: 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.

Keywords: CDK4 amplification; MDM2 amplification; TP53 mutation; phase I trials; solid tumors.

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Conflict of interest statement

CONFLICTS OF INTEREST The following authors declare no potential conflicts of interest: Dr. Dembla, Dr. Barata, Dr. Hess, Dr. Fu, Dr. Karp, Dr. Subbiah, and Dr. Shaw. Dr. Naing has received research funding from NCI, EMD Serono, Medimmune, Healios Oncology Nutrition, ATTEROCOR, Amplimmune, ARMO Biosciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, and Baxter (spouse). Dr. Somaiah has a consulting or advisory role with Bayer. Dr. Piha-Paul’s funding sources include Genentech, GlaxoSmithKline, Puma Biotechnology, Inc., Novartis, Merck Sharp and Dohme, Medivation, Inc., Principia Biopharma, Inc., AbbVie, XuanZhu Biopharma, Helix BioPharma Corp., Incyte, Inc., Hoffman LaRoche, Curis, and Cerulean. She has received an honorarium from Genentech. Dr. Janku has research funding from Novartis, Astellas, Agios, BioMed Valley Discoveries, Array, Roche, Plexxikon, Deciphera, Trovagene, and Biocartis. He has a consulting or advisory role with Sequenom, Trovagene, Deciphera, Novartis, and Foundation One. Dr. Tsimberidou has received funding from Foundation Medicine, Merck Serono, Onyx, Baxalta, and Bayer. Dr. Meric-Bernstam has received grant and research support from Novartis and Aileron. Dr. Hong has stock or other ownership in Oncoresponse and Molecular Match. He has received honoraria from Adaptimmune, Baxter, Bayer, and Merrimack. He has a consulting or advisory role with Baxter and Bayer. He has received research funding from Bayer, Lilly, Genentech, LOXO, Pfizer, Amgen, Mirati, Ignyta, Merck, Daichi-Sanka, and Eisai. His travel accommodations or other expenses have been paid or reimbursed from LOXO and MiRNA. He is the founder of Oncoresponse.

Figures

Figure 1
Figure 1. Overall survival according to MDM2 amplification status: After adjusting for RMH score, OS with MDM2 amplification = 13.6 months vs OS without MDM2 amplification= 10.6 months, hazard ratio = 0.6, confidence interval (CI) = (0.4, 1.1); p = 0.12. The median refers to months of survival
See this image and copyright information in PMC

References

    1. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, Xie M, Zhang Q, McMichael JF, Wyczalkowski MA, Leiserson MD, Miller CA, Welch JS, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502:333–9. doi: 10.1038/nature12634. - DOI - PMC - PubMed
    1. Farmer G, Bargonetti J, Zhu H, Friedman P, Prywes R, Prives C. Wild-type p53 activates transcription in vitro. Nature. 1992;358:83–6. doi: 10.1038/358083a0. - DOI - PubMed
    1. Funk WD, Pak DT, Karas RH, Wright WE, Shay JW. A transcriptionally active DNA-binding site for human p53 protein complexes. Mol Cell Biol. 1992;12:2866–71. - PMC - PubMed
    1. Muller PA, Vousden KH. Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell. 2014;25:304–17. doi: 10.1016/j.ccr.2014.01.021. - DOI - PMC - PubMed
    1. Fakharzadeh SS, Trusko SP, George DL. Tumorigenic potential associated with enhanced expression of a gene that is amplified in a mouse tumor cell line. EMBO J. 1991;10:1565–69. - PMC - PubMed