Change search
ReferencesLink to record
Permanent link

Direct link
Genome-wide Association Study Identifies Shared Risk Loci Common to Two Malignancies in Golden Retrievers
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Show others and affiliations
2015 (English)In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 2, e1004922Article in journal (Refereed) Published
Abstract [en]

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 similar to 20% of the risk of developing these cancers. Genome-wide p-values for the top SNP of each locus are 4.6x10(-7) and 2.7x10(-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 hemangio-sarcoma 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.

Place, publisher, year, edition, pages
2015. Vol. 11, no 2, e1004922
National Category
URN: urn:nbn:se:uu:diva-252254DOI: 10.1371/journal.pgen.1004922ISI: 000352081800010OAI: diva2:809836
Available from: 2015-05-05 Created: 2015-05-04 Last updated: 2015-05-05Bibliographically approved

Open Access in DiVA

fulltext(988 kB)86 downloads
File information
File name FULLTEXT01.pdfFile size 988 kBChecksum SHA-512
Type fulltextMimetype application/pdf

Other links

Publisher's full text

Search in DiVA

By author/editor
Elvers, IngegerdArendt, Maja
By organisation
Department of Medical Biochemistry and MicrobiologyScience for Life Laboratory, SciLifeLab
In the same journal
PLOS Genetics

Search outside of DiVA

GoogleGoogle Scholar
Total: 86 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 323 hits
ReferencesLink to record
Permanent link

Direct link