Malignant Histiocytosis in the Bernese Mountain Dog

Malignant histiocytosis (MH) belongs to a group of histiocitic disorders, which represent a broad range of clinical symptoms, from the simple cutaneous histiocytoma to the severe malignant histiocytosis. MH itself is an aggressive histiocytic neoplasm which arises in multiple sites simultaneously. While clinical signs may vary, lethargy, anorexia, weight loss, and respiratory and CNS abnormalities predominate in the initial diagnosis and the lungs are almost always the primary site of tumor involvement. The disease is associated with both high incidence and rapid mortality. In 1995 Padgett et al. reported that 25.4% of tumors diagnosed in the Bernese Mountain Dog (BMD) were MH. Perhaps more strikingly, the vast majority of MH cases reported in the US are diagnosed in the BMD.

We have been very interested in finding the genes that predispose the BMD to malignant histiocytosis (MH) for three reasons. First, we are interested in improving the health of this increasingly popular breed, which is severely affected by this deadly disease. Finding the underlying disease gene will lead to the development of genetic tests that can ultimately generate improvements in breeding programs. Second, once we know the underlying cause of MH, we can begin to work towards targeted therapies that improve both life, quality and duration. Finally, we are interested in the genetics of similar disorders affecting humans.

To date we have collected and validated DNA samples from over 400 BMD including a set of about 75 dogs which reportedly have the disease. We initially did a 5 cM genome scan using 55 validated cases and a matched set of aged controls using a set of nearly 500 microsatellite markers. Analysis of this data suggests a small number of key regions where MH genes may lie. But additional validation is needed before proceeding.

We have thus selected a set of key cases and controls that we are currently genotyping using the Affymetrix Version two 127,000 SNP chip. This chip density of markers on this chip is so great that it should allow us to quickly weed out any false positives from our initial data set and focus on the small number of regions where a gene is likely to lie and begin positional cloning efforts.

We are working in collaboration with Catherine Andre at the University of Rennes. Her group has assembled a large pedigree of BMD, a subset of which have MH. We are comparing prepublication results with her group in order to validate results between the two groups. The Ostrander and Andre groups will work together, sharing data prior to publication in order to focus on the regions of the genome where the strongest statistical evidence lies. Positional cloning efforts are currently underway at two genomic regions, based on analysis to date. We will keep the community up to date with any critical findings that result from these efforts.

Elaine Ostrander
NHGRI/National Institutes of Health
June 11, 2007

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