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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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