Matthew Breen
Dept of Molecular Biomedical Sciences, College of Veterinary Medicine
North
Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606
The
genome of a dog is comprised of 78 chromosomes. These chromosomes are nature’s
filing cabinets and contain all the genes (‘files’) that are required to inform cells what to do and how to behave. Many genes are associated with the regulation of cell growth, division and even death. Cancer is a term that describes a multitude of conditions with an enormous range of
clinical outcomes.
One key aspect of cancer biology is the recurrent
involvement of changes to chromosome structure and/or organization within the cell.
These changes are referred to as chromosome aberrations. Many forms of
human cancer are so closely associated with specific chromosome aberrations that the aberrations are regarded as diagnostic
for the cancer. Some chromosome aberrations result in the gain or loss of chromosomal
material (numerical changes), whilst others result in a reorganization of chromosomal material (structural changes). Numerical changes alter the copy number of genes in the genome and numerical changes
bring together genes that are usually separated within the non-cancer genome. The
interaction between these new ‘neighbors’ often leads to the generation of gene products that drive the cell to
form a cancer. Knowledge of such gene products provides an opportunity to develop
new therapies for treatment of cancers. In addition, for many human cancers there
is a correlation between the presence of certain chromosome aberrations and the clinical outcome of the tumor and/or the tumor’s
response to therapy. For this reason many chromosome aberrations have prognostic
value and this information may be used by clinicians to determine the most appropriate therapy.
Molecular cytogenetics is an exciting area of research
that combines molecular biology, cytogenetics and fluorescence in situ hybridization (FISH). This approach, which makes use of sophisticated fluorescence microscopy techniques, allows us to look closely
at the chromosomal organization of individual tumors and thus to identify cancer-associated chromosome aberrations.
Cytogenetic studies of dog cancers have been hindered
by difficulties in identifying the chromosomes. We have developed a series of
reagents and techniques that allow us to identify all dog chromosomes with confidence.
These reagents include a set of whole chromosome paint probes and a genome-wide panel of single locus FISH probes. We have also isolated a number of canine cancer-associated genes.
We are now using our reagents to look closely at
the chromosomal changes associated with a variety of canine cancers. We have
conducted a detailed cytogenetic analysis of canine lymphoma and have identified chromosomal aberrations that suggest some
of the mechanisms leading to pathogenetically important events are evolutionarily conserved.
We have also identified chromosome aberrations that have not been reported for the corresponding human disease. These regions of the genome may thus contain novel cancer-associated genes. In addition, we have identified chromosome aberrations that appear to be correlated with increased survival
and so may soon be in a position to offer prognostic aides to cancer diagnoses.
(This work is supported
by CHF grants 2038, 2214 and 2254.)
