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 & 7 others Kristine Burgess, Eric S. Lander, Elinor K. Karlsson, Chieko Azuma, Jaime F. Modiano, Matthew Breen, Kerstin Lindblad-Toh

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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.

Original languageEnglish (US)
Article numbere1004922
Pages (from-to)1-24
Number of pages24
JournalPLoS genetics
Volume11
Issue number2
DOIs
StatePublished - Jan 1 2015

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Golden Retriever
Genome-Wide Association Study
B-Cell Lymphoma
B-lymphocytes
Hemangiosarcoma
lymphoma
genome
hemangiosarcoma
Haplotypes
loci
haplotypes
neoplasms
Neoplasms
cancer
gene
tumor
Genes
gene expression
genes
T-lymphocytes

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Tonomura, N., Elvers, I., Thomas, R., Megquier, K., Turner-Maier, J., Howald, C., ... Lindblad-Toh, K. (2015). Genome-wide Association Study Identifies Shared Risk Loci Common to Two Malignancies in Golden Retrievers. PLoS genetics, 11(2), 1-24. [e1004922]. https://doi.org/10.1371/journal.pgen.1004922

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, 01.01.2015, p. 1-24.

Research output: Contribution to journalArticle

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, JH, 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, vol. 11, no. 2, e1004922, pp. 1-24. https://doi.org/10.1371/journal.pgen.1004922
Tonomura N, Elvers I, Thomas R, Megquier K, Turner-Maier J, Howald C et al. Genome-wide Association Study Identifies Shared Risk Loci Common to Two Malignancies in Golden Retrievers. PLoS genetics. 2015 Jan 1;11(2):1-24. e1004922. https://doi.org/10.1371/journal.pgen.1004922
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. / Genome-wide Association Study Identifies Shared Risk Loci Common to Two Malignancies in Golden Retrievers. In: PLoS genetics. 2015 ; Vol. 11, No. 2. pp. 1-24.
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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

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