Amplification of Cellular Oncogenes in Solid Tumors

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Abstract

The term gene amplification refers to an increase in copy number of a gene. Upregulation of gene expression through amplification is a general mechanism to increase gene dosage. Oncogene amplifications have been shown in solid human cancers and they are often associated with progression of cancer. Defining oncogene amplification is useful since it is used as a prognostic marker in clinical oncology nowadays, especially v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 ( HER2) targeted agents are used in breast cancer patients with high level of HER2 overexpression as a therapeutic approach. However, patients without HER2 overexpression do not appear to benefit from these agents. We concluded that determination of oncogene amplification in solid tumors is an important factor in treatment of human cancers with many unknowns. We have referred to PubMed and some databases to prepare this article.

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Most cited references 38

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Minireview: Cyclin D1: normal and abnormal functions.

Maofu Fu, Chenguang Wang, Zhiping Li … (2004)

Cyclin D1 encodes the regulatory subunit of a holoenzyme that phosphorylates and inactivates the retinoblastoma protein and promotes progression through the G1-S phase of the cell cycle. Amplification or overexpression of cyclin D1 plays pivotal roles in the development of a subset of human cancers including parathyroid adenoma, breast cancer, colon cancer, lymphoma, melanoma, and prostate cancer. Of the three D-type cyclins, each of which binds cyclin-dependent kinase (CDK), it is cyclin D1 overexpression that is predominantly associated with human tumorigenesis and cellular metastases. In recent years accumulating evidence suggests that in addition to its original description as a CDK-dependent regulator of the cell cycle, cyclin D1 also conveys cell cycle or CDK-independent functions. Cyclin D1 associates with, and regulates activity of, transcription factors, coactivators and corepressors that govern histone acetylation and chromatin remodeling proteins. The recent findings that cyclin D1 regulates cellular metabolism, fat cell differentiation and cellular migration have refocused attention on novel functions of cyclin D1 and their possible role in tumorigenesis. In this review, both the classic and novel functions of cyclin D1 are discussed with emphasis on the CDK-independent functions of cyclin D1.

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The MDM2 gene amplification database.

J Momand, D Jung, S Wilczynski … (1998)

The p53 tumor suppressor gene is inactivated in human tumors by several distinct mechanisms. The best characterized inactivation mechanisms are: (i) gene mutation; (ii) p53 protein association with viral proteins; (iii) p53 protein association with the MDM2 cellular oncoprotein. The MDM2 gene has been shown to be abnormally up-regulated in human tumors and tumor cell lines by gene amplification, increased transcript levels and enhanced translation. This communication presents a brief review of the spectrum of MDM2 abnormalities in human tumors and compares the tissue distribution of MDM2 amplification and p53 mutation frequencies. In this study, 3889 samples from tumors or xenografts from 28 tumor types were examined for MDM2 amplification from previously published sources. The overall frequency of MDM2 amplification in these human tumors was 7%. Gene amplification was observed in 19 tumor types, with the highest frequency observed in soft tissue tumors (20%), osteosarcomas (16%) and esophageal carcinomas (13%). Tumors which showed a higher incidence of MDM2 amplification than p53 mutation were soft tissue tumors, testicular germ cell cancers and neuro-blastomas. Data from studies where both MDM2 amplification and p53 mutations were analyzed within the same samples showed that mutations in these two genes do not generally occur within the same tumor. In these studies, 29 out of a total of 33 MDM2 amplification-positive tumors had wild-type p53. We hypothesize that heretofore uncharacterized carcinogens favor MDM2 amplification over p53 mutations in certain tumor types. A database listing the MDM2 gene amplifications is available on the World Wide Web at http://www. infosci.coh.org/mdm2 . Charts of MDM2 amplification frequencies and comparisons with p53 genetic alterations are also available at this Web site.

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The epidermal growth factor receptor: from development to tumorigenesis.

Maria Sibilia, Renate Kroismayr, Beate M Lichtenberger … (2007)

The epidermal growth factor receptor (EGFR) is activated by many ligands and belongs to a family of tyrosine kinase receptors, including ErbB2, ErbB3, and ErbB4. These receptors are de-regulated in many human tumors, and EGFR amplification, overexpression, and mutations are detected at a high frequency in carcinomas and glioblastomas, which are tumors of epithelial and glial origin, respectively. From the analysis of EGFR-deficient mice, it seems that the cell types mostly affected by the absence of EGFR are epithelial and glial cells, the same cell types where the EGFR is found to be overexpressed in human tumors. Therefore, it is important to define molecularly the function of EGFR signaling in the development of these cell types, because this knowledge will be of fundamental importance to understand how aberrant EGFR signaling can lead to tumor formation and progression. A molecular understanding of the pathways that control the development of a given tissue or cell type will also provide the basis for developing better combination therapies targeting different key components of the EGFR signaling network in the respective cancerous cells. Here, we will review the current knowledge, mostly derived from the analysis of genetically modified mice and cells, about the function of the EGFR in specific organs and tissues and in sites where the EGFR is found to be overexpressed in human tumors.

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Author and article information

Journal

Journal ID (nlm-ta): N Am J Med Sci

Journal ID (iso-abbrev): N Am J Med Sci

Journal ID (publisher-id): NAJMS

Title: North American Journal of Medical Sciences

Publisher: Medknow Publications & Media Pvt Ltd (India )

ISSN (Print): 2250-1541

ISSN (Electronic): 1947-2714

Publication date (Print): August 2015

Volume: 7

Issue: 8

Pages: 341-346

Affiliations

[1] Department of Medical Genetics, Suleyman Demirel University, School of Medicine, Isparta, Turkey

Author notes

Address for correspondence: Dr. Ozkan Bagci, Department of Medical Genetics, Suleyman Demirel University, Medical Faculty, Isparta, Turkey. E-mail: ozkanbagci@ 123456sdu.edu.tr

Article

Publisher ID: NAJMS-7-341

DOI: 10.4103/1947-2714.163641

PMC ID: 4561439

PubMed ID: 26417556

SO-VID: b1dbbb0d-02c3-419e-b0be-565379ce086b

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Amplification of Cellular Oncogenes in Solid Tumors

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International Journal of Applied Technology in Medical Sciences

Most cited references 38

Minireview: Cyclin D1: normal and abnormal functions.

The MDM2 gene amplification database.

The epidermal growth factor receptor: from development to tumorigenesis.

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