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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.

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Identification of the inherited gene mutations responsible for the susceptibility of Boxers, Golden Retrievers, Labrador Retrievers, 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 a high prevalence in Boxers, Golden Retrievers, Labrador Retrievers, 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 the four breeds 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, it is hoped that the research will lead to the development of tests to identify dogs that carry the gene mutations conferring an increased risk. This information will be useful to vets as it will identify dogs who may benefit from careful monitoring for early detection of cancer, and thereby early treatment. These tests will also assist breeders to reduce the incidence of dogs affected with these cancers. The research will also increase understanding of how these tumours develop, 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.

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Identification of the inherited 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.

In the long term, it is hoped that the research will lead to the development of tests to identify dogs that carry the gene mutations conferring an increased risk. This information will be useful to vets as it will identify dogs who may benefit from careful monitoring for early detection of cancer, and thereby early treatment. These tests will also assist breeders to reduce the incidence of dogs affected with these cancers. The research will also increase understanding of how these tumours develop, ultimately assisting the development of new therapies.

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Canine brain tumours

Application of molecular genetics to predict which canine meningiomas are likely to respond to radiation therapy following surgical resection

Intracranial meningiomas in dogs are an important clinical problem. A whole genome microarray will be used to screen RNA from biopsies of meningiomas, representative of tumours that are sensitive and resistant to radiotherapy. Tumours will be grouped on the basis of their expression profiles and multivariate statistical analysis performed to assess whether molecular subtype is associated with radiotherapy response.

Analysis of genomic abnormalities in canine meningiomas

The detection of recurrent chromosome copy number abnormalities in tumours is a strategy for the identification of genes associated with tumour development and progression. Specific DNA copy number alterations may underpin key pathogenetic events. Dominantly acting oncogenes, that encode proteins that accelerate cell growth, are typically altered by an activating mutation, chromosomal rearrangement, or by gene amplification. Conversely, tumour suppressor genes that encode proteins that negatively regulate cell growth are typically inactivated by mutation, promoter hypermethylation, or deletion of one or both alleles. When considered in concert with clinical data, the identification of unbalanced genomic aberrations in tumours also represents a means of identifying markers of prognosis. In this study, metaphase chromosome Comparative Genomic Hybridisation (CGH) and oligonucleotide array-CGH will be used to screen DNA from biopsies of meningiomas.

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Identification of the inherited gene mutations responsible for the susceptibility of Boxers to developing glial cell tumours

Clinicians in the AHT Neurology Unit have noted a disproportinately high incidence of Boxers with glial cell tumours, suggesting that the breed carries genetic ‘risk factors’. Consequently, we are seeking to identify the genes that, when mutated, are associated with the increased risk of Boxers developing glial cell tumours.

In the long term, it is hoped that the research will lead to the development of tests to identify dogs that carry the gene mutations conferring an increased risk. This information will be useful to vets as it will identify dogs who may benefit from careful monitoring for early detection of cancer, and thereby early treatment. These tests will also assist breeders to reduce the incidence of dogs affected with these cancers. The research will also increase understanding of how these tumours develop, ultimately assisting the development of new therapies.

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Canine haemangiosarcoma

Identification of the inherited gene mutations responsible for the susceptibility of German Shepherd Dogs to developing haemangiosarcomas

German Shepherd Dogs are reported to have an elevated risk of developing haemangiosarcomas of both the skin and internal organs. We are seeking to identify the one, or more, inherited genetic mutations responsible for German Shepherd Dogs having an increased risk of developing haemangiosarcomas. The research study is being lead by Dr. David Sargan at the University of Cambridge Veterinary School, and is part of the European Union-funded LUPA project (http://www.eurolupa.org/), a 4-year initiative involving 20 veterinary schools from 12 European countries.

In the long term, it is hoped that the research will lead to the development of tests to identify dogs that carry the gene mutations conferring an increased risk. This information will be useful to vets as it will identify dogs who may benefit from careful monitoring for early detection of cancer, and thereby early treatment. These tests will also assist breeders to reduce the incidence of dogs affected with these cancers. The research will also increase understanding of how these tumours develop, ultimately assisting the development of new therapies.

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Canine histiocytic sarcoma

Identification of the inherited gene mutations responsible for the susceptibility of Rottweilers to developing histiocytic sarcomas

Rottweilers are amongst a number of breeds (including Bernese Mountain Dogs, Golden Retrievers, and Flat-coated Retrievers) that appear to be more susceptible to developing disseminated histiocytic sarcomas. We are seeking to identify the one, or more, inherited genetic mutations responsible for Rottweilers having an increased risk of developing histiocytic sarcomas. The research study is part of the European Union-funded LUPA project (http://www.eurolupa.org/), a 4-year initiative involving 20 veterinary schools from 12 European countries.

In the long term, it is hoped that the research will lead to the development of tests to identify dogs that carry the gene mutations conferring an increased risk. This information will be useful to vets as it will identify dogs who may benefit from careful monitoring for early detection of cancer, and thereby early treatment. These tests will also assist breeders to reduce the incidence of dogs affected with these cancers. The research will also increase understanding of how these tumours develop, ultimately assisting the development of new therapies.

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Canine mammary tumours

Identification of the inherited gene mutations responsible for the susceptibility of Boxers, Cocker Spaniels, English Springer Spaniels, and German Shepherd Dogs to developing mammary tumours

An increased risk of developing malignant mammary tumours has been reported for several breeds, including Boxers, Cocker Spaniels, English Springer Spaniels, and German Shepherd Dogs, suggesting that these breeds carry genetic risk factors. We are seeking to identify the one, or more, inherited genetic mutations responsible for the four breeds having an increased risk of developing mammary tumours. The research study is part of the European Union-funded LUPA project (http://www.eurolupa.org/), a 4-year initiative involving 20 veterinary schools from 12 European countries.

In the long term, it is hoped that the research will lead to the development of tests to identify dogs that carry the gene mutations conferring an increased risk. This information will be useful to vets as it will identify dogs who may benefit from careful monitoring for early detection of cancer, and thereby early treatment. These tests will also assist breeders to reduce the incidence of dogs affected with these cancers. The research will also increase understanding of how these tumours develop, ultimately assisting the development of new therapies.

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Canine melanoma

Identification of the inherited gene mutations responsible for the susceptibility of Schnauzers and Scottish Terriers to developing cutaneous melanomas

Black coated breeds appear to be more susceptible to developing cutaneous melanomas, with Schnauzers in particular showing a relatively high incidence of mainly cutaneous melanomas. We are seeking to identify the one, or more, inherited genetic mutations responsible for Schnauzers and Scottish Terriers having an increased risk of developing cutaneous melanomas.

Identification of the inherited gene mutations responsible for the susceptibility of Poodles, Golden Retrievers, Labrador Retrievers and and Scottish Terriers to developing oral melanomas

Several breeds appear to have an increased risk of developing oral melanomas, with Poodles displaying the highest risk. We are seeking to identify the one, or more, inherited genetic mutations responsible for Poodles, Golden Retrievers and Labrador Retrievers having an increased risk of developing oral melanomas.

The two research studies are part of the European Union-funded LUPA project (http://www.eurolupa.org/), a 4-year initiative involving 20 veterinary schools from 12 European countries.

In the long term, it is hoped that the research studies will lead to the development of tests to identify dogs that carry the gene mutations conferring an increased risk. This information will be useful to vets as it will identify dogs who may benefit from careful monitoring for early detection of cancer, and thereby early treatment. These tests will also assist breeders to reduce the incidence of dogs affected with these cancers. The research will also increase understanding of how these tumours develop, ultimately assisting the development of new therapies.

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Canine uveal melanoma and ocular melanosis project

The primary aim of the project is to evaluate the potential of a fine needle aspirate-based assay to predict the metastatic/malignant outcome for canine uveal melanomas. In addition, we will evaluate the utility of the assay for distinguishing between uveal melanomas and ocular melanosis, and between primary uveal melanomas and melanoma (oral, ungual and cutaneous) metastases.

For a variety of human tumours it is possible to predict biological behaviour by measuring the number of copies of specific messenger RNA molecules in the tumour prior to treatment. A mRNA-based gene expression profile that distinguishes metastasising and non-metastasising uveal melanoma has been developed (Onken et al., 2004; Cancer Res. 64: 7205-7209). Expression profiles of fine needle aspirates of uveal melanoma shown to be highly similar to those of matching biopsies from enucleated eyes (Onken et al., 2006; J. Mol. Diagn. 8: 567-573).

In this project, canine whole genome microarrays will be used to compare gene expression in fine needle aspirates of uveal melanoma that display the histopathological criteria for malignancy and uveal melanoma for which histopathology is indicative of low metastatic potential. The gene expression profiles of uveal melanomas will also be compared to gene expression profiles derived from fine needle aspirates of aqueous fluid from ocular melanosis cases, and biopsies of oral, ungual and cutaneous melanomas (which metastasised), respectively.

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Canine osteosarcoma

Identification of the gene mutations responsible for the susceptibility of Irish Wolfhounds to developing osteosarcoma

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. In 2006, a UK Kennel Club/British Small Animal Veterinary Association Purebred Dog Health Survey (http://www.thekennelclub.org.uk/item/549) reported that osteosarcoma was the most common cause of death of Irish Wolfhounds in the UK. The inherited susceptibility to developing osteosarcoma probably results from the combined effects of a number of gene defects, each of which alone, confers a low to moderate increase in risk. The risk of developing cancer is thought to increase according to the number of altered genes carried.

With the support in the UK of The Irish Wolfhound Society and The Irish Wolfhound Club and their members, since June 2005 we have been collecting samples from Wolfhounds to enable a study of the genetics of this disease. We wish to identify the genes that, when mutated, are associated with the increased risk of Wolfhounds developing osteosarcomas.

In the long term, it is hoped that the research will lead to the development of tests to identify dogs that carry the gene mutations conferring an increased risk. This information will be useful to vets as it will identify dogs who may benefit from careful monitoring for early detection of cancer, and thereby early treatment. These tests will also assist breeders to reduce the incidence of dogs affected with these cancers. The research will also increase understanding of how these tumours develop, ultimately assisting the development of new therapies.

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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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Identification of the inherited gene mutations responsible for the susceptibility of Golden Retrievers and Labrador Retrievers to developing soft tissue sarcomas

There is some evidence to suggest that Golden Retrievers and Labrador Retrievers are susceptible to developing soft tissue sarcomas. In Golden Retrievers there appears to be a higher incidence of a specific subtype (‘fibrosarcoma’) of the mouth and upper jaw. We are seeking to identify the one, or more, inherited genetic mutations responsible for Golden Retrievers and Labrador Retrievers having an increased risk of developing soft tissue sarcomas. The research study is part of the European Union-funded LUPA project (http://www.eurolupa.org/), a 4-year initiative involving 20 veterinary schools from 12 European countries.

In the long term, it is hoped that the research will lead to the development of tests to identify dogs that carry the gene mutations conferring an increased risk. This information will be useful to vets as it will identify dogs who may benefit from careful monitoring for early detection of cancer, and thereby early treatment. These tests will also assist breeders to reduce the incidence of dogs affected with these cancers. The research will also increase understanding of how these tumours develop, ultimately assisting the development of new therapies.

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