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

摘要

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 Ca~(2+)-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. Author Summary To shed light on the genetic predisposition to cancers of the hematologic system, we performed genome-wide association analysis of affected and non-affected pet dogs. Dogs naturally develop the same diseases as humans, including cancer, and the relatively limited genetic diversity within different breeds makes genetic studies easier compared to in humans. By doing genome-wide association, we identified loci predisposing to hemangiosarcoma and B-cell lymphoma. To our surprise, we found two shared loci predisposing to both diseases. Within these two regions we identified several partially overlapping haplotypes, predisposing somewhat differently to the two cancers. We found no coding mutations that followed the risk or non-risk haplotypes suggesting that regulatory mutations exert the effect on disease. We also looked at gene expression in B-cell lymphomas, comparing samples from individuals with risk or non-risk haplotypes. This analysis showed differential expression associated with the haplotypes at both loci, suggesting the risk haplotypes are associated with an effect on T-cell response.