TY - JOUR

T1 - Genome-wide association study identifies shared risk loci common to two malignancies in golden retrievers

AU - Tonomura, Noriko

AU - Elvers, Ingegerd

AU - Thomas, Rachael

AU - Megquier, Kate

AU - Turner-Maier, Jason

AU - Howald, Cedric

AU - Sarver, Aaron L

AU - Swofford, Ross

AU - Frantz, Aric M

AU - Ito, Daisuke

AU - Mauceli, Evan

AU - Arendt, Maja

AU - Noh, Hyun Ji

AU - Koltookian, Michele

AU - Biagi, Tara

AU - Fryc, Sarah

AU - Williams, Christina

AU - Avery, Anne C

AU - Kim, Jong-Hyuk

AU - Barber, Lisa

AU - Burgess, Kristine

AU - Lander, Eric S

AU - Karlsson, Elinor K

AU - Azuma, Chieko

AU - Modiano, Jaime F

AU - Breen, Matthew

AU - Lindblad-Toh, Kerstin

PY - 2015/2

Y1 - 2015/2

N2 - 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.

AB - 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.

KW - Animals

KW - B-Lymphocytes/pathology

KW - Breeding

KW - Carcinogenesis/genetics

KW - Dogs

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Genotype

KW - Germ-Line Mutation

KW - Haplotypes/genetics

KW - Hemangiosarcoma/genetics

KW - Humans

KW - Lymphoma, B-Cell/genetics

KW - Polymorphism, Single Nucleotide

KW - Risk Factors

U2 - 10.1371/journal.pgen.1004922

DO - 10.1371/journal.pgen.1004922

M3 - Journal article

C2 - 25642983

VL - 11

JO - P L o S Genetics

JF - P L o S Genetics

SN - 1553-7390

IS - 2

M1 - e1004922

ER -