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

Noriko Tonomura; Ingegerd Elvers; Rachael Thomas; Kate Megquier; Jason Turner-Maier; Cedric Howald; Aaron L Sarver; Ross Swofford; Aric M Frantz; Daisuke Ito; Evan Mauceli; Maja Arendt; Hyun Ji Noh; Michele Koltookian; Tara Biagi; Sarah Fryc; Christina Williams; Anne C Avery; Jong-Hyuk Kim; Lisa Barber; Kristine Burgess; Eric S Lander; Elinor K Karlsson; Chieko Azuma; Jaime F Modiano; Matthew Breen; Kerstin Lindblad-Toh

doi:10.1371/journal.pgen.1004922

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

Noriko Tonomura, Ingegerd Elvers, Rachael Thomas, Kate Megquier, Jason Turner-Maier, Cedric Howald, Aaron L Sarver, Ross Swofford, Aric M Frantz, Daisuke Ito, Evan Mauceli, Maja Arendt, Hyun Ji Noh, Michele Koltookian, Tara Biagi, Sarah Fryc, Christina Williams, Anne C Avery, Jong-Hyuk Kim, Lisa BarberKristine Burgess, Eric S Lander, Elinor K Karlsson, Chieko Azuma, Jaime F Modiano, Matthew Breen, Kerstin Lindblad-Toh

40 Citationer (Scopus)

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.

Originalsprog	Engelsk
Artikelnummer	e1004922
Tidsskrift	PLOS Genetics
Vol/bind	11
Udgave nummer	2
ISSN	1553-7390
DOI	https://doi.org/10.1371/journal.pgen.1004922
Status	Udgivet - feb. 2015
Udgivet eksternt	Ja

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10.1371/journal.pgen.1004922Licens: CC BY

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Tonomura, N., Elvers, I., Thomas, R., Megquier, K., Turner-Maier, J., Howald, C., Sarver, A. L., Swofford, R., Frantz, A. M., Ito, D., Mauceli, E., Arendt, M., Noh, H. J., Koltookian, M., Biagi, T., Fryc, S., Williams, C., Avery, A. C., Kim, J.-H., ... Lindblad-Toh, K. (2015). Genome-wide association study identifies shared risk loci common to two malignancies in golden retrievers. PLOS Genetics, 11(2), Artikel e1004922. https://doi.org/10.1371/journal.pgen.1004922

Tonomura, N, Elvers, I, Thomas, R, Megquier, K, Turner-Maier, J, Howald, C, Sarver, AL, Swofford, R, Frantz, AM, Ito, D, Mauceli, E, Arendt, M, Noh, HJ, Koltookian, M, Biagi, T, Fryc, S, Williams, C, Avery, AC, Kim, J-H, Barber, L, Burgess, K, Lander, ES, Karlsson, EK, Azuma, C, Modiano, JF, Breen, M & Lindblad-Toh, K 2015, 'Genome-wide association study identifies shared risk loci common to two malignancies in golden retrievers', PLOS Genetics, bind 11, nr. 2, e1004922. https://doi.org/10.1371/journal.pgen.1004922

@article{b54fd6a35806444b8cef09462b031c03,

title = "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. ",

keywords = "Animals, B-Lymphocytes/pathology, Breeding, Carcinogenesis/genetics, Dogs, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Germ-Line Mutation, Haplotypes/genetics, Hemangiosarcoma/genetics, Humans, Lymphoma, B-Cell/genetics, Polymorphism, Single Nucleotide, Risk Factors",

author = "Noriko Tonomura and Ingegerd Elvers and Rachael Thomas and Kate Megquier and Jason Turner-Maier and Cedric Howald and Sarver, {Aaron L} and Ross Swofford and Frantz, {Aric M} and Daisuke Ito and Evan Mauceli and Maja Arendt and Noh, {Hyun Ji} and Michele Koltookian and Tara Biagi and Sarah Fryc and Christina Williams and Avery, {Anne C} and Jong-Hyuk Kim and Lisa Barber and Kristine Burgess and Lander, {Eric S} and Karlsson, {Elinor K} and Chieko Azuma and Modiano, {Jaime F} and Matthew Breen and Kerstin Lindblad-Toh",

year = "2015",

month = feb,

doi = "10.1371/journal.pgen.1004922",

language = "English",

volume = "11",

journal = "PLOS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "2",

}

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

SN - 1553-7390

VL - 11

JO - PLOS Genetics

JF - PLOS Genetics

IS - 2

M1 - e1004922

ER -

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

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