NCI Creates Gene Expression Database of Normal Human Organ Tissue
Researchers at the National Cancer Institute (NCI), part of the
National Institutes of Health (NIH), have built the largest open-source
database
for normal tissue from human organs. Scientists searching for
genes that go awry and cause disease can use the NCI database as
a crucial point
of reference because it pinpoints which genes are expressed in
many of the body’s major organs under normal conditions (without known disease).
Scientists can compare the genes from their own biological samples to
this dictionary of normal expression. “Genes identified by the database
as abnormally active in a particular disease could become potential targets,
guiding researchers to better candidates for new drug therapies, immune-based
vaccine treatments, and potential biomarkers to help with diagnosis,” explained
Javed Khan, M.D., chief of the Oncogenomics Section of NCI’s Pediatric
Oncology Branch. A study validating the database appears in the
March 2005 issue of Genome Research.*
“The NCI database is an important addition to the growing body
of knowledge about gene expression in normal human tissues,” added
James Jacobson, Ph.D., acting branch chief of the Diagnostics Research
Branch in NCI’s Division of Cancer Treatment and Diagnosis. “These
data give investigators a baseline against which to compare gene expression
data obtained from tumor or other disease specimens, and should be a
valuable resource for the research community.”
The normal organ database uses a technology known as gene expression
microarrays, more commonly known as gene chips, to provide a kind of
fingerprint that researchers and clinicians can use to compare cells
and tissue they suspect may have cancerous or other malfunctioning genes.
To create these fingerprints, Khan and his team assembled a complementary
DNA (cDNA) microarray, using a pair of glass slides on which thousands
of known genes have been printed in tiny spots. Cells can be tested
by manipulating them so that genes activated in the cell will match
up with the known gene samples, like two pieces of Velcro attaching
to each other. The cellular genes are treated with fluorescence and
literally light up the gene dots on the chip. The light pattern is then
measured with a special type of microscope and the results are fed into
a computer for analysis.
Gene expression microarrays have been used in numerous applications,
including identifying novel genes associated with certain cancers, classifying
tumors, and predicting patient outcome. Another NCI-funded study recently
demonstrated that microarray analysis of identical tissue samples at
geographically separate laboratories can produce the same quality of
results as those done within a single lab**. The normal organ database
takes that one step further, enabling scientists and clinicians to compare
the gene expression results for their own tissue or genes of interest
to a baseline standard that represents a generic picture of normal gene
activity, organ by organ, in the human body. Users of the array on the
new NCI web site (http://home.ccr.cancer.gov/oncology/oncogenomics/) will find expression profiles for 18,927 genes, which include most
of the genes that are known to help direct basic activities of the human
body.
Recently the Human Genome Project revealed a surprisingly low number
of human genes (20,000-25,000), and Khan said it had been previously
reported that “only a fraction of that, perhaps 10,000 genes,
are actively transcribed in normal cell processes.” Thus it becomes
strategically useful to characterize this essential backdrop. “The
normal organ database provides a platform that may help scientists find
new targets in the cells of previously incurable cancers. The driving
force of research in our section is to translate genomic information
to the clinic. The goal is to save lives and improve the quality of
life for children with high-risk cancer.”
Until now, no publicly available, normal human organ database has used
so many tissue samples (158), or included samples of tissue from different
parts of the same organs from multiple donors. Tissue samples were harvested
an average of 11 hours after death, from males and females of different
ethnic groups, ranging from ages 3 months to 39 years old.
The very large cDNA microarray they constructed has more than 42,000
detectors built into two chips using verified cDNA libraries upon which
many other researchers currently rely. Analyzing the organ tissue with
this tool allowed Khan and his team to identify 18,927 genes that constitute
their database. “We found that each organ had a unique expression
level profile,” said Khan, “and, remarkably, any truly random
subset of 1,000 genes could distinguish one organ from another.”
Each organ revealed a very distinct profile of active genes, different
from all others. However, the gene profiles from different
organs that share similar biological functions also showed
patterns of expression.
For example, though the cerebrum and the cerebellum are two
distinct parts of the brain, located apart from each other
and doing very different
jobs, their gene expression profiles reflected their commonality
as part of the nervous system. Similarly, “muscle contraction” genes
were found in skeletal muscle, smooth muscle tissue, and the
heart – all
organs that share a common way of functioning.
To illustrate the kind of useful data that can emerge from using this
tool, Khan’s team analyzed 100 samples of the most common pediatric
solid tumor cancer, neuroblastoma (NB), which accounts for 7 percent
to 10 percent of all childhood cancers. Even though the tumor samples
were taken from a variety of patients with different stages of cancer,
the database kicked out a list of 19 genes that were consistently overexpressed
compared to normal brain tissue.
“All of these genes are involved in one way or another with the
kinds of activities associated with the development of cancer – processes
such as apoptosis, growth, proliferation and transcription,” said
Khan. These results provide scientists studying and treating
NB with a focused set of genes to explore.
For more information about cancer, please visit the NCI home page at http://www.cancer.gov or
call NCI ’s Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
* Son, C.G., Bilke, S., Davis, S., Greer, B.T., Wei, J.S., Whiteford,
C.C., Chen, Q.-R., Cenacchi, N., Khan, J. 2005. Database of mRNA gene
expression profiles of multiple human organs. Genome Research 15: 443-450.
(http://www.genome.org/).
** Dobbin, K.K., et. al., 2005. Clinical
Cancer Research 11:565-572. |