Genome-wide Association Study Identifies Shared Risk Loci Common to Two Malignancies in Golden Retrievers

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.

Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background

“…Such genetic backgrounds may be exemplified by the two loci predisposing to B-cell lymphoma and hemangiosarcoma in golden retrievers (found by genome-wide association mapping), which are associated with differential expression of immune-related genes, including BIRC3 (Tonomura et al 2015). These results point to a mechanism involving altered T-cell activation as a strong predisposing factor in this breed.…”

Safe and Effective Sarcoma Therapy through Bispecific Targeting of EGFR and uPAR

“…The federal project was begun in 2005 to catalog genetic mutations responsible for cancer using genome sequencing and bioinformatics. To perform a similar analysis in dogs, we used next generation RNA sequencing (RNAseq) data from canine hemangiosarcoma and canine lymphoma samples that were reported previously [24, 25]. RNAseq for 31 canine osteosarcoma samples was performed as described [24, 26, 27].…”

Comparative oncology: what dogs and other species can teach us about humans with cancer

“…More comparison work is currently underway. The most recent canine cancer GWAS explored the genetic risk for haematologic malignancy in the dog, specifically B-cell lymphoma and haemangiosarcoma in golden retrievers [55]. These cancers occur at high rates in this breed (B-cell lymphoma 6% and haemangiosarcoma 20%), and the investigators looked at 148 haemangiosarcoma cases versus 41 B-cell lymphoma cases versus 172 cancer-free controls.…”

“…The authors investigated gene expression in B-cell lymphoma tumours and concluded that these germline-risk alleles affect T-cell regulatory pathways and immune-mediated responses. Based on their canine GWAS findings, the authors conclude that the immune system and malignant cells may interact in tumour risk and development [55], a hypothesis that now can be explored in other haematologic malignancy models and even primary tumours in humans. In support of this concept, recent human GWAS in diffuse large B-cell lymphoma [56], follicular lymphoma [57] and marginal zone lymphoma [58] have all demonstrated a role for immune recognition and immune function, with lymphoma risk strongly linked to HLA and other regions [56 -58].…”