Characterization of the Chromosome 17q23 Amplicon

Project: Research project

Project Details

Description

DESCRIPTION: (provided by applicant) In cancer, gene amplification represents a
type of genetic alteration that results in increased copy number of a gene or
genes and subsequent increases in protein expression. When the target of
amplification is a cellular oncogene, the corresponding increases in
oncoprotein expression often result in tumor development and/or progression. To
date, all comprehensively studied regions of amplification have been found to
contain oncogenes, suggesting that characterization of novel amplicons will
lead to identification of novel oncogenes that contribute directly to
development of breast cancer.

Over the last two years we have characterized the structure of an amplicon on
chromosome 17q23 in breast cancer cell lines and breast tumors. We have
identified seven independently amplified regions within the amplicon suggesting
that as many as seven different oncogenes may reside in this amplicon. We have
identified a total of twelve highly amplified genes in these seven amplified
regions, including the TBX2 candidate oncogene that functions as an oncogene by
inhibiting senescence and inducing immortalization. We have also noted that at
least one of these twelve genes is amplified in 42 percent of all breast
tumors, including DCIS. Together, these data strongly suggest that the amplicon
contains several other genes with oncogenic properties, perhaps one from each
of the seven amplification peaks, and that these oncogenes may have an
important role in early progression of breast tumors.

In this study we propose to follow up on these observations by identifying and
characterizing the oncogenes in the amplicon. In order to achieve this
objective we aim to: 1) determine the level and frequency of expression of the
genes in the amplified regions in breast tumors to verify that the selected
candidates are overexpressed as a result of amplification; 2) characterize the
oncogenic activity of the overexpressed candidate genes using a series of
oncogenicity assays; 3) investigate the prognostic potential of the oncogenes
from the region.

To address these aims, we will measure the expression level of the twelve
highly and frequently amplified genes from the amplicon in tumors and cell
lines by microarray analysis and quantitative RT-PCR. The candidate oncogenes
with the best correlation between amplification and overexpression will be
assessed for oncogenic activity in a series of immortalization, transformation,
tumorigenesis, invasion, and metastasis assays. Finally, the prognostic
relevance of amplification of the validated oncogenes from the region will be
studied by correlating patient outcome with amplification, as measured by
fluorescence in situ hybridization, in node negative, node positive, and DCIS
breast tumors.

The importance of this project derives from the potential for identification of
novel oncogenes that will further our understanding of breast tumor
progression. It must be noted that we are taking a comprehensive approach to
the identification of oncogenes in the region so that a full understanding of
the relevance of amplification of the region to tumor progression can be
developed. The study is also important because it may result in discovery of
clinically useful molecular markers of prognosis that may lead to
individualized treatment regimens. Thus, the project may involve a complete
transition from benchtop to bedside. Finally, the amplified and overexpressed
genes may prove useful as important targets of gene, pharmacological, and
immunological therapy in the future.
StatusFinished
Effective start/end date6/5/025/31/09

ASJC

  • Medicine(all)