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PLoS Genet. 2015 Feb 2;11(2):e1004922. doi: 10.1371/journal.pgen.1004922. eCollection 2015 Feb.

Genome-wide association study identifies shared risk loci common to two malignancies in golden retrievers.

Author information

1
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America; Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, United States of America.
2
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America; Science for Life Laboratory, Dept. of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
3
Department of Molecular Biomedical Sciences, College of Veterinary Medicine, & Center for Comparative Medicine and Translational Research, North Carolina State University, Raleigh, North Carolina, United States of America.
4
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
5
Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota, United States of America.
6
Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota, United States of America; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America.
7
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America; Department of Laboratory Medicine, Boston Children's Hospital, Boston, Massachusetts, United States of America.
8
Science for Life Laboratory, Dept. of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
9
Department of Microbiology, Immunology, and Pathology, Colorado State University College of Veterinary Medicine and Biomedical Sciences, Fort Collins, Colorado, United States of America; Animal Cancer Center, Colorado State University College of Veterinary Medicine and Biomedical Sciences, Fort Collins, Colorado, United States of America.
10
Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, United States of America.
11
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America; FAS Center for Systems Biology, Harvard University, Cambridge, Massachusetts, United States of America.
12
Department of Molecular Biomedical Sciences, College of Veterinary Medicine, & Center for Comparative Medicine and Translational Research, North Carolina State University, Raleigh, North Carolina, United States of America; Cancer Genetics Program, University of North Carolina Lineberger Comprehensive Cancer Center, Raleigh, North Carolina, United States of America.

Abstract

Dogs, with their breed-determined limited genetic background, are great models of human disease including cancer. Canine B-cell lymphoma and hemangiosarcoma are both malignancies of the hematologic system that are clinically and histologically similar to human B-cell non-Hodgkin lymphoma and angiosarcoma, respectively. Golden retrievers in the US show significantly elevated lifetime risk for both B-cell lymphoma (6%) and hemangiosarcoma (20%). We conducted genome-wide association studies for hemangiosarcoma and B-cell lymphoma, identifying two shared predisposing loci. The two associated loci are located on chromosome 5, and together contribute ~20% of the risk of developing these cancers. Genome-wide p-values for the top SNP of each locus are 4.6×10-7 and 2.7×10-6, respectively. Whole genome resequencing of nine cases and controls followed by genotyping and detailed analysis identified three shared and one B-cell lymphoma specific risk haplotypes within the two loci, but no coding changes were associated with the risk haplotypes. Gene expression analysis of B-cell lymphoma tumors revealed that carrying the risk haplotypes at the first locus is associated with down-regulation of several nearby genes including the proximal gene TRPC6, a transient receptor Ca2+-channel involved in T-cell activation, among other functions. The shared risk haplotype in the second locus overlaps the vesicle transport and release gene STX8. Carrying the shared risk haplotype is associated with gene expression changes of 100 genes enriched for pathways involved in immune cell activation. Thus, the predisposing germ-line mutations in B-cell lymphoma and hemangiosarcoma appear to be regulatory, and affect pathways involved in T-cell mediated immune response in the tumor. This suggests that the interaction between the immune system and malignant cells plays a common role in the tumorigenesis of these relatively different cancers.

PMID:
25642983
PMCID:
PMC4333733
DOI:
10.1371/journal.pgen.1004922
[Indexed for MEDLINE]
Free PMC Article

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