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Breen, Matthew, PhD. C.Biol. M.I.Biol
Associate Professor of Genomics
Gene expression profiling of canine brain neoplasia
Primary tumors of the central nervous system are common in dogs and are histologically similar to those found in humans. Brain tumors occur in all dog breeds, although some breeds have a predisposition for certain tumor types. Meningiomas are the most common type of brain tumor found in dogs and glial tumors are the second most frequent reported type. cDNA microarrays are useful tools for the analysis of differentially expressed genes in tumorsand have led to the identification of genes and pathways involved in tumorigenesis. To analyze gene expressions in canine brain tumors, we developed a cDNA microarray specific for genes expressed in the canine brain. Our custom microarray contains approximately 4,000 genes that were PCR amplified from a canine brain specific cDNA library. We analyzed several different types of canine brain tumors and found expression patterns similar to that present in human brain tumors. This indicates that canine brain tumors not only share similarities with human brain tumors at a morphological level, but also on a molecular level.
Figure 1 . Brain specific cDNA expression microarray.
A Cy-3 labeled canine meningioma sample and a Cy-5 labeled normal canine brain reference sample were co- hybridized to our custom canine brain cDNA array. This image shows a scan of the resulting data. To compare gene expression of meningioma samples to that of normal tissue, meninges from a clinically healthy dog were also included in this study. Gene expression differences between the meningioma samples and the normal meninges were calculated using a two-step mixed model analysis of variance in SAS version 7.1.
Hierarchical cluster analysis of canine brain tumor samples is another method for further classification of tumor types. In our analysis we found two distinct sub-types of meningiomas. These findings are useful in determining treatment options and remission status as well as in the development of tumor type specific drugs.
Figure 2. Hierarchical clustering of canine meningioma samples.
M-1 to M-6 are meningioma samples taken from six different dogs. N-1 and N-2 are data obtained from normal meninges. The datat divided canine meningioma expression profiles into two distinct subtypes: samples 1, 5, 6, and 7 and samples 2, 3, and 4. This study also included a granular cell tumor (GCT), which clusters with the normal meninges samples, indicating that it might have a mesenchymal origin but shows distinct gene expression differences compared to the meningioma
Comparative studies between human and canine brain tumors enable us to further our understanding in tumorigenesis and epidemiology, and ultimately lead to the development of new therapeutic cancer treatments for humans and dogs. Human tumor samples are often heterogeneous and identification of genes specifically involved in tumor formation can be troublesome. Dogs represent a more genetically homogenous population and allow us to more easily identify genes directly involved in tumorigenesis as well as to identify new genes previously not associated with cancer. Since our finding indicate that dogs can provide an excellent animal model for cancer research and this technology can be applied to a variety of tumors, development of other canine cDNA microarrays will allow us to expand our studies to other types of cancers as well.