Oncology Current Research
Canine mast cell tumours
Using molecular genetics to help predict whether canine mast cell tumours will metastasise
Mast cell tumours (MCTs) are the most common skin tumour in dogs, and display variable behaviour. MCTs are classified by histological grade, with the majority categorised as intermediate grade. Intermediate grading does not accurately predict how an individual MCT will behave. A study at the AHT demonstrated that frequency of expression of the proliferation marker Ki-67 was a more accurate predictor of survival, but a subset of MCTs did not behave as predicted, and a less subjective prognostic method is desirable. For human cancers, gene expression ‘signatures’ are predictive of metastatic outcome. Identification of genes most likely to stratify MCTs according to whether they metastasise is the first step towards developing an assay that will accurately predict whether a MCT will metastasise, and therefore whether a patient would benefit from chemotherapy.
In this study, a whole genome microarray will be used to screen RNA from biopsies of 15 MCTs to identify genes that exhibit differential expression between tumours that metastasised and tumours that did not. Since clinically-relevant mRNA profiling-based tumour classification is possible using fine needle tissue aspirates (FNAs), expression profiles will be generated for FNAs of 3 of the MCTs to investigate whether they are representative of the tumours.
Identification of the gene mutations responsible for the susceptibility of Boxers and Weimaraners to developing mast cell tumours
Certain breeds of dog are much more likely to develop cancer than other breeds, with some families within these breeds being particularly susceptible. A study in 2004 of the incidence of mast cell tumours in dogs diagnosed at the AHT between 1997 and 1999 identified the highest prevalence in Boxers and Weimaraners. The inherited susceptibility probably results from the combined effects of many modified genes, each of which alone, confers a low to moderate increase in risk. The risk of developing a cancer is thought to increase according to the number of altered genes carried.
We are seeking to identify the genes that, when mutated, are associated with the increased risk of Boxers and Weimaraners developing mast cell tumours. As these breeds develop these tumours more often than other breeds, the gene mutations that confer the increased risk will be more common than in other breeds, and thus easier to identify. Future work would aim to investigate whether the same gene mutations conferred susceptibility to developing this cancer upon other breeds.
In the long term, we hope that the research will lead to the development of diagnostic tests to identify the gene mutations that confer an increased risk of developing mast cell tumours, allowing breeders to take these gene mutations into consideration in their breeding programmes. A realistic objective would be to attempt to reduce the incidence of dogs affected with these cancers. Identification of ‘cancer susceptibility genes’ will also improve our understanding of how these tumours develop, thereby ultimately assisting the development of new therapies.
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Canine lymphoma
Evaluation of the classification of canine lymphoma by gene expression profiling
The diagnosis and prognostication of the human equivalent of canine lymphoma, non-Hodgkin’s lymphoma (NHL), has been revolutionised by gene expression profiling-based classification. For example, gene expression signatures have been identified that distinguish phenotypically indistinct forms of the most common type of NHL in adults (diffuse large B-cell lymphoma, DLBCL), and predict the survival rate for DLBCL patients in receipt of cyclophosphamide, adriamycin, vincristine and prednisone-based chemotherapy.
If a gene expression profile-based prognostic assay for canine lymphoma is to be deployed as a routine clinical test, it would be optimal to find an alternative to the collection of tumour tissue by surgical resection for RNA extraction. Collection of an excisional biopsy will not always be easy, particularly so in animals that are hypercalcaemic or thrombocytopenic. Consequently, we are seeking to investigate the feasibility of developing a classification scheme (hopefully ultimately clinically relevant) for canine lymphoma based upon the messenger RNA profiles of lymph node fine needle aspirates (FNAs). In a preliminary study, we have found a high degree of similarity between FNA and excisional biopsy-derived lymph node expression profiles, suggesting that the FNAs are as representative of the tumours as the excisional biopsies. We are now keen to investigate the potential of lymph node FNAs in a larger study.
Identification of the gene mutations responsible for the susceptibility of Bulldogs, Bullmastiffs, and Boxers to developing lymphoma
In 2003, the AHT examined the occurrence of lymphoma in 20 breeds within a UK population of 130,684 dogs and found that the incidence of lymphoma in Bullmastiff, Bulldog and Boxer was significantly higher than in other breeds. We are seeking to identify the genes that, when mutated, are associated with the increased risk of Bulldogs, Bullmastiffs, and Boxers developing lymphoma.
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Canine brain tumours
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Feline oral squamous cell carcinoma
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Canine soft tissue sarcoma
Can tumour gene expression profiles distinguish between metastatic and non-metastatic soft-tissue sarcomas?
Histological grade does not predict whether a canine soft tissue sarcoma (STS) will metastasise. A number of studies of human STS (including tumours located on the limbs and trunk wall, and in the abdomen) have identified gene expression signatures that discriminate between metastatic and non-metastatic tumours, and/or are predictive of the development of metastasis. We plan to investigate whether metastatic and non-metastatic canine STSs can be distinguished on the basis of gene expression profile.
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Canine ocular melanoma
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Canine osteosarcoma
Identification of the gene mutations responsible for the susceptibility of Irish Wolfhounds to developing osteosarcoma
Canine osteosarcoma is associated with increasing height (and weight) and therefore the highest incidence is in large and giant breeds. However, some families within these breeds are particularly susceptible, suggesting an inherited predisposition. An American Kennel Club survey (2004) of the most frequent 10 diseases of 78 dog breeds (diagnosed at veterinary teaching hospitals over a 30 year period) demonstrated that although the risk of an Irish Wolfhound developing an osteosarcoma is low the risk was 27.5 x the risk of all other breeds combined. In the USA, it is estimated that osteosarcoma is the cause of death for 25% of Irish Wolfhounds. We are seeking to identify the genes that, when mutated, are associated with the increased risk of Wolfhounds developing osteosarcomas.
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