Gene Expression Profiling in Mice Can Predict
Risk of Skin Lesions Progressing to Cancer
A new study has shown that microarray technology, which allows
researchers to simultaneously compare the degree to which hundreds
of genes are expressed (converted into proteins), now makes it
possible to more definitively identify skin lesions in mice that
are thought to be at high risk of progressing to a type of cancer
known as squamous cell carcinoma (SCC). It is hoped that this technique
will eventually lead to identification of high-risk SCC tumors
in humans. This study appears in the online version of the journal
Oncogene on May 21, 2007, and was conducted by researchers from
the American University of Beirut (Lebanon), Pennsylvania State
University, and the National Cancer Institute (NCI), part of the
National Institutes of Health.
Researchers compared the gene expression profiles of four different
types of mouse skin cells: low-risk and high-risk papillomas (benign
tumors) that had been chemically induced, as well as normal skin
and SCC. The investigators demonstrated that precancerous lesions
can be separated into subgroups according to distinct patterns
of gene activities — namely, which genes were turned on or
off. A specific pattern of activity, sometimes called a molecular
signature, was present in the precancerous lesions, and correlated
with a higher risk for malignant conversion.
“Today’s clinicians are in need of a straightforward method of
determining which precancerous lesions are at high risk of developing
into cancer,” said NCI Director John E. Niederhuber, M.D. “The
data suggest that if this same correlation holds true for humans,
then gene expression analysis of precancerous skin lesions could
lead to the development of diagnostic tools for squamous cell carcinoma
risk.”
Microarrays, also known as gene chips, are glass slides that have
been coated with thousands of spots of DNA, each representing a
different known gene. Microarray technology is often used in gene
expression profiling because it allows researchers to quickly and
efficiently identify the multiple genes that are simultaneously
expressed in a particular type of cell. Microarray-based comparisons
of cancer gene expression patterns in humans have been used to
discover subgroups within cancer types as well as to associate
specific expression profiles with disease outcomes.
The researchers used microarray technology to test the hypothesis
that high-risk papillomas share a similar gene expression pattern
with SCC, and therefore represent the likely precursor lesion to
SCC. For the analysis, genetic materials which had been isolated
from six adult-mouse normal skins, ten low-risk papillomas, ten
high-risk papillomas and six SCC were added to the gene chips.
“While we had done previous marker studies to suggest that the
high-risk papillomas were the precursors to SCC, the degree of
similarity in gene expression patterns between these very early
benign lesions and SCC was amazing” said Adam Glick, Ph.D., associate
professor, Center for Molecular Toxicology and Carcinogenesis at
Pennsylvania State University and formerly of NCI’s Laboratory
of Cancer Biology and Genetics. “This suggests that prior to any
overt microscopic changes, some lesions have a molecular signature
similar, in part, to a malignant tumor.”
Several different tests were conducted in this study. One analysis
showed that the high-risk papillomas and SCC had very similar molecular
signatures or gene patterns, while the low-risk papillomas had
very different ones. Another test identified a pattern consisting
of 87 genes that distinguished low-risk from high-risk papillomas.
This test showed similarities in the expression patterns of the
high-risk papillomas and SCC. It also showed that the high-risk
papillomas and SCC had reduced expression of genes associated with
immune response at an early stage in their development.
A third analysis used the distinguishing set of genes, including
the immune function genes, to correctly classify unknown precancerous
lesions as low or high risk. Together, these results show that
this methodology can predict the risk potential of benign skin
lesions with high accuracy in mice. Additional research is needed
to see if the genes identified in this study could serve as predictive
markers for human cancer.
“In many organs, lesions that turn out to be benign are far more
common than those that progress to cancer,” said Stuart H. Yuspa,
M.D., Chief of NCI’s Laboratory of Cancer Biology and Genetics. “Being
able to preemptively determine which lesions are likely to progress
to cancer provides a strategy both for cancer prevention and for
informed follow-up.”
For more information about cancer, visit http://www.cancer.gov.,
or call NCI's Cancer Information Service at 1-800-4 CANCER.
For more information on the Laboratory of Cancer Biology and
Genetics, which is part of NCI’s Center for Cancer Research, go
to http://ccr.cancer.gov/labs/lab.asp?labid=90.
For more information about NCI’s Center for Cancer Research, go
to http://ccr.cancer.gov.
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Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
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