WP1 Cancer

WP1.1 Mammary Tumours – Leader : University of Uppsala

Canine mammary tumour shows similarity to human breast cancer, which is a devastating disease diagnosed in 1.2 million persons worldwide each year. So far only a small fraction of human breast cancer cases can be explained by single gene mutations. Other cases may have a more complex inheritance, since the incidence of clearly hereditary breast cancer range from 5 to 10 percent to as many as 27 percent of all breast cancers. Our goal is the identification of genetic factors important in canine carcinogenesis that can provide a unique opportunity to improve prevention, diagnosis and treatment of human breast cancer.

Mammary tumours (MT) are the most common tumour in the female dog. It is well established that estrogenic stimulation increases the risk of mammary tumours in dogs, as well as other species including humans. Around half of the canine mammary tumours are malignant, and have a high probability of developing distant metastases to lungs, central nervous system, abdominal organs and the skeleton. The other half are benign. 4% are sarcomas (mostly osteo- and fibrosarcomas), 4% are inflammatory carcinomas and 42% are adenocarcinomas. In Sweden, an overwhelming 36% of English Springer Spaniels are diagnosed with MT, making them a high-risk breed. An increased risk for malignant MT has been reported also in other breeds, including Cocker Spaniels, German Shepherds and Boxers, suggesting that these breeds may carry genetic risk factors for MT. Often multiple tumour types are found segregating within a family suggesting that the different tymor types may be a continuum of stages within the disease. Here we aim to identify genetic risk factors for MT in English Springer Spaniels and other breeds with a similar disease phenotype.

WP1.2 Melanoma – Leader : CNRS-Rennes

The canine melanoma shares many features with human melanomas, but also presents some interesting differences. In the dog, melanomas represent 10 to 15% of cutaneous tumours with an evident correlation with the phototype. Black-coated dogs are more predisposed, especially for cutaneous melanoma. Cutaneous melanomas can be benign (>50%) or malignant and can metastasize or not, in part dependent upon stage and treatment. This heterogeneity should make it possible to identify genes involved in malignancy and metastatic pathways. Oral melanomas represent a homologue of human mucosal melanomas. Most are malignant. Taken together, the variety in localisations and in behaviour and breed predisposition in canines are likely to reflect the various forms of human melanoma.

Elucidation of causative genes and pathways involved in canine melanoma may be of great importance in better understanding human melanoma. We aim to identify the genetic bases of oral and cutaneous melanoma in two high-risk breeds. Schnauzers show a high frequency of melanomas (5%), the majority being cutaneous and even ungeal. Poodles show a 3% melanoma frequency, the majority being oral. In the two breeds, malignant versus melanocytomas and metastatic versus non-metastatic tumours will be analyzed.

WP1.3 Soft tissue sarcoma (STS) – Leader : University of Utrecht

The incidence of soft tissue sarcoma in humans in the developed world is around 18 per million per annum accounting for 7% of paediatric tumours. Although these tumours have a variety of presentations many are associated with high morbidity and mortality. The various types of STS include extensive infiltration at varying rates of distant metastasis. The study of the genetic background in the human is severely hampered by the fact that STS constitute a heterogenous group of tumours, where the overall incidence is fairly low and that family sizes are small. Golden Retrievers carry a breed predisposition to soft tissue sarcomas and Rottweilers to the subtype of histiocytic sarcomas (HS) suggesting genetic components.

In the dog, STS comprise more than 10% of all malignant tumours. The higher number of STS in the dog over that in the human, the larger families and the shorter generation interval, make the study of canine STS of interest as a comparative model. In both species there are many similarities in presentation and biological characteristics of these tumours. Furthermore, subtypes of STS often share defects in biochemical pathways and genetic programs and some of these defects are constitutional and provide a familial predisposition. By establishing immunohistochemical and molecular profiles for STS to improve sub-classification and by identifying genomic loci predisposing to major types of STS in Golden Retriever and Rottweiler, we aim to find both general risk factors as well as those predisposing to malignancy and infiltration.

WP1.4 Hemangiosarcoma (HAS) – Leader : University of Cambridge

Hemangiosarcomas account for about 1% of soft tissue sarcomas in human adults, as well as in juveniles. The tumour is found at many locations in the body, but with predilection for extremities, head and neck, breast or cardiac tissue. In both dogs and humans HAS is often accompanied by a disseminated coagulopathy, local oxygenation problems and increased blood clotting times. In workers exposed to vinyl chloride or arsenic, there is an increased incidence in the liver, whilst hepatic and splenic presentations in the absence of known carcinogenesis are more typical in juveniles and thus more similar to the canine model. Although rather rare and thus difficult to study in humans, HAS tumours are aggressive and malignant with a dismal prognosis and 5 year survival rate of < 20%.

In dogs hemangiosarcomas are tumours derived from blood vessel endothelial precursor cells. They are common tumours in medium and large breeds of dogs and may represent more than 2% of all canine malignancies. Again they are often diagnosed late, and have a very bleak prognosis. Both subcutaneous and visceral HAS show breed specificity to German Shepherd Dogs and Golden retrievers, whilst subcutaneous HAS are more prevalent in Greyhounds, Italian Greyhounds and generally in dogs with short hair and light colour. The increase in relative risk for all types of HAS in German Shepherds compared with the whole canine population is about three fold. We will establish immunochemical and molecular profiles for HAS originating in the viscera or dermis/subcutis to see whether these tumours can be treated as a uniform entity, to identify genomic loci associated with HAS and to identify the genes, mutations and pathways associated with disease.