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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:

Background: Malignant 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.

Objective: The 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.

Original Grant Objectives:
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 from Investigator:
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.

Thank you for your support! --

Joye Neff and Nicky "BG #38330" (and Will)
Berner Fundraiser
Mt. Lebanon,
Pittsburgh, PA

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