GRANT PROGRESS REPORT REVIEW
Grant: 00935A&B: Positional Cloning of Two
Genes for Malignant Histiocytosis (MH) in the Bernese Mountain Dog
Principal Investigator: Dr. Elaine Ostrander, PhD: Dr.
Catherine Andre, PhD
Research Institution: National Human Genome Research Institute;
CNRS University of Rennes
Grant Amount: $166,400.00
Start Date: 9/1/2008 End Date: 8/31/2010
Progress Report: 12 month
Report Due: 8/31/2009 Report Received: 8/31/2009
Recommended for Approval: Approved
(Content of this report is not confidential)
Original Project Description:
histiocytosis (MH) belongs to a group of histiocyitic disorders,
which represent a broad array of clinical symptoms. The disease is
found in excess in Bernese Mountain Dogs (BMD), Flat Coated
Retrievers (FCR), and a small number of other breeds. MH is an
aggressive tumor from which affected dogs die quickly. Working
together, the Ostrander and Andre labs have each clearly identified
two regions of the genome (on chromosomes 8 and 20) with genes
causing MH in the BMD.
researchers are working to find the exact genes and genetic variants
responsible for the disease. It involves finding a common piece of
each chromosome that affected dogs likely inherited from a single
affected ancestor. Whether the disease is caused by the same
mutations in breeds other then the BMD is unknown. Preliminary data
suggest they are distinct. As studies are most advanced in the BMD,
once genes are identified the researchers will move to the FCR and
other breeds to determine if the same, or different mutations are
responsible for the disease. Their long- term goal is to produce the
information needed for genetic test development.
Objective 1: Develop
haplotypes across the chromosome regions of interest.
Objective 2: Determine
haplotype associated with disease status.
Objective 3: Test
candidate genes of interest for mutations by direct sequencing of
exons, intron/exon boundaries, known regulatory elements, and
multiply conserved regions.
Objective 4: Extend
mutation/haplotype analysis to other breeds of dog.
Publications: Abadie, J.,
Hedan B., Cadieu, E., DeBrito, E., Devauchelle, P., Bourgain, C.,
Parker, H.G., Vaysse, A., Margaritte-Jeannin, P., Galibert, F.,
Ostrander E.A., André, C. (2009). Epidemiology, pathology,
and genetics of histiocytic sarcoma in the Bernese mountain dog
breed, J. Heredity. 100 Supp 1, S19-27. Shearin, A.L., and
Ostrander, E.A., Leading the Way: Canine Models of Genomics and
Disease. (2009), Disease Models and Mechanisms, Submitted.
Report to Grant Sponsor
Histiocytic sarcoma (HS)
refers to a highly aggressive and frequently disseminated neoplastic
disease belonging to the class of canine histiocytic proliferative
disorders. Disseminated HS (previously called malignant
histiocytosis) is highly breed specific, with Bernese mountain dogs
(BMDs), rottweilers, and retrievers having a high prevalence with a
frequency of approximately 25% in the BMD breed. We collected DNA
samples and clinical information from 800 BMDs, of which 200 are
affected by HS. To better characterize the physiopathology and
epidemiology, an in-depth analysis of 89 BMD cases has been
performed. The mean age of onset was 6.5 years, males and females
being equally affected. The clinical features, biochemical
parameters, and pathological features have been determined. The life
span after diagnosis has been estimated to be 49 days. A large BMD
pedigree of 327 dogs, 121 of which are affected, was assembled.
Using a subset of 160 BMDs, encompassing 21 complete sibships, we
now propose an oligogenic transmission mode of the disease.
Whole-genome linkage scans as well as association studies using a
case/control analysis, in parallel with expression profiling of
neoplastic versus normal histiocytes, are all underway. Altogether,
these complementary approaches are expected to localize the genes
for HS in the BMD, leading to advances in our knowledge of
histiocyte diseases in dogs and humans.