Genome-wide association study identifies shared risk loci common to two malignancies in golden retrievers
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Genome-wide association study identifies shared risk loci common to two malignancies in golden retrievers. / Tonomura, Noriko; Elvers, Ingegerd; Thomas, Rachael; Megquier, Kate; Turner-Maier, Jason; Howald, Cedric; Sarver, Aaron L; Swofford, Ross; Frantz, Aric M; Ito, Daisuke; Mauceli, Evan; Arendt, Maja; Noh, Hyun Ji; Koltookian, Michele; Biagi, Tara; Fryc, Sarah; Williams, Christina; Avery, Anne C; Kim, Jong-Hyuk; Barber, Lisa; Burgess, Kristine; Lander, Eric S; Karlsson, Elinor K; Azuma, Chieko; Modiano, Jaime F; Breen, Matthew; Lindblad-Toh, Kerstin.
In: PLOS Genetics, Vol. 11, No. 2, e1004922, 02.2015.Research output: Contribution to journal › Journal article › Research › peer-review
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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 -
ID: 209172578