|Gene's Position in the Nucleus Can be Used
to Distinguish Cancerous from Normal Breast Tissue
Researchers have identified several genes whose spatial position
inside the cell nucleus is altered in invasive breast cancer when
compared to normal breast tissue. The findings suggest that cancer
cells may have disease-specific, three-dimensional gene arrangements
and raise the possibility that such gene positioning patterns could
be used as a new diagnostic strategy to distinguish cancer tissue
from normal tissue. The study, by researchers at the National Cancer
Institute (NCI), part of the National Institutes of Health, appeared
online Dec. 7, 2009, and will appear in print on Dec. 14, 2009
in the Journal of Cell Biology.
Chromosomes and individual genes have been found to occupy specific
locations relative to one another and to landmarks within the cell
nucleus. The spatial organization of genes can change during a
number of normal bodily processes. Alterations of spatial organization
also occur in disease states such as cancer. The distinctive changes
in shape and size of the cell nucleus, which pathologists use routinely
as indicators of whether or not cancer is present, suggest that
major changes in spatial gene organization also occur in cancer
"In our study, we set out to identify genes which are differentially
positioned in breast cancer tissues and we explored the possibility
that disease-specific spatial organization of genes might be used
as a new diagnostic strategy to distinguish malignant from normal
tissue," said senior author Tom Misteli, Ph.D., of NCI's Center
for Cancer Research.
To identify genes which occupy distinct positions inside the nucleus
in normal and malignant cells, the researchers visualized a set
of 20 genes using fluorescent in situ hybridization (FISH), a technique
to detect and localize specific DNA sequences in intact cells in
a set of 11 normal human breast and 14 invasive cancer tissue specimens.
The scientists identified eight genes with a high frequency of
repositioning in cancer specimens. Only a minority of tested genes
underwent significant repositioning in a given cancer tissue, suggesting
that repositioning is gene-specific and does not reflect a large-scale
alteration in gene organization. The repositioning events were
also not due to a common cellular occurrence known as genomic instability,
which is often associated with cancer, because repositioning did
not correlate with changes in the number of copies of the gene
present in the cell.
The scientists next used the tissue specimens to test whether
gene repositioning could distinguish cancer from normal and non-cancerous
tissues. They found that the position of a single gene, HES5, allowed
identification of invasive breast cancer tissue with nearly 100
percent accuracy. HES5 is a gene commonly associated with cancer
and affects biological pathways that have been implicated in cancer.
Additionally, several combinations of two or three genes allowed
identification of cancerous tissues with low false-negative and
false-positive rates (that is, the combinations identified most
cancer tissues as cancer and few non-cancerous tissues as cancer).
This approach compares favorably with current standard breast cancer
diagnostic tests that rely on fine needles or larger core needles
to biopsy small amounts of tissue for examination.
Identification of genes that are localized differently in normal
and cancer cells allows the possibility of using spatial gene positioning
as a novel diagnostic tool, although the authors note that the
findings will need to be replicated in a set of larger tissue samples.
As required for such an application, the researchers found low
variability of gene positioning among individuals. They also found
that cancer tissues could accurately be identified by comparison
to a standardized normal gene distribution.
A distinct advantage of this approach over existing methods is
the very small quantity of material required. Differences in spatial
positioning were routinely detected by analysis of 100 to 200 cells
despite the lack of uniformity in cancer samples. Furthermore,
this approach is suitable for adaptation in a routine laboratory
setting because all individual steps of the procedure rely on standard
methods, including embedding of biopsy material and FISH detection.
The use of spatial genome positioning for detection of tumors could
reduce human error in making a diagnosis because the method gives
a quantifiable readout and is not based on subjective criteria
or the individual expertise of the pathologist who performs an
evaluation with a microscope.
"If validated in a larger number of samples, we envision
that this approach may be a useful first molecular indicator of
cancer after an abnormal mammogram," said Misteli. "Our
method of cancer diagnosis is not limited to breast cancer and
may be applied to any cancer type in which repositioned genes can
For more information on Dr. Misteliís research, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=5819.
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Reference: Meaburn KJ, Gudla PR, Sameena K, Lockett
SJ, and Mistli T. Disease-specific gene repositioning in breast cancer.
Online Dec. 7, 2009. In print Dec. 14, 2009. Vol. 187, Issue 6. Journal
of Cell Biology.