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.
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America; Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, United States of America.
authors: Noriko
authors: N
authors: Tonomura
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America; Science for Life Laboratory, Dept. of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors: Ingegerd
authors: I
authors: Elvers
authors: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, & Center for Comparative Medicine and Translational Research, North Carolina State University, Raleigh, North Carolina, United States of America.
authors: Rachael
authors: R
authors: Thomas
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America; Science for Life Laboratory, Dept. of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors: Kate
authors: K
authors: Megquier
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors: Jason
authors: J
authors: Turner-Maier
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors: Cedric
authors: C
authors: Howald
authors: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota, United States of America.
authors: Aaron L
authors: AL
authors: Sarver
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors: Ross
authors: R
authors: Swofford
authors: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota, United States of America; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors: Aric M
authors: AM
authors: Frantz
authors: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota, United States of America; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors: Daisuke
authors: D
authors: Ito
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America; Department of Laboratory Medicine, Boston Children's Hospital, Boston, Massachusetts, United States of America.
authors: Evan
authors: E
authors: Mauceli
authors: Science for Life Laboratory, Dept. of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors: Maja
authors: M
authors: Arendt
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors: Hyun Ji
authors: HJ
authors: Noh
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors: Michele
authors: M
authors: Koltookian
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors: Tara
authors: T
authors: Biagi
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors: Sarah
authors: S
authors: Fryc
authors: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, & Center for Comparative Medicine and Translational Research, North Carolina State University, Raleigh, North Carolina, United States of America.
authors: Christina
authors: C
authors: Williams
authors: Department of Microbiology, Immunology, and Pathology, Colorado State University College of Veterinary Medicine and Biomedical Sciences, Fort Collins, Colorado, United States of America; Animal Cancer Center, Colorado State University College of Veterinary Medicine and Biomedical Sciences, Fort Collins, Colorado, United States of America.
authors: Anne C
authors: AC
authors: Avery
authors: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota, United States of America; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors: Jong-Hyuk
authors: JH
authors: Kim
authors: Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, United States of America.
authors: Lisa
authors: L
authors: Barber
authors: Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, United States of America.
authors: Kristine
authors: K
authors: Burgess
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors: Eric S
authors: ES
authors: Lander
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America; FAS Center for Systems Biology, Harvard University, Cambridge, Massachusetts, United States of America.
authors: Elinor K
authors: EK
authors: Karlsson
authors: Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, United States of America.
authors: Chieko
authors: C
authors: Azuma
authors: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota, United States of America; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors: Jaime F
authors: JF
authors: Modiano
authors: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, & Center for Comparative Medicine and Translational Research, North Carolina State University, Raleigh, North Carolina, United States of America; Cancer Genetics Program, University of North Carolina Lineberger Comprehensive Cancer Center, Raleigh, North Carolina, United States of America.
authors: Matthew
authors: M
authors: Breen
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America; Science for Life Laboratory, Dept. of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors: Kerstin
authors: K
authors: Lindblad-Toh
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology; D001947:Breeding; D063646:Carcinogenesis / Q000235:genetics* / Q000276:immunology; D004285:Dogs; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D018095:Germ-Line Mutation; D006239:Haplotypes / Q000235:genetics; D006394:Hemangiosarcoma / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000662:veterinary; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000662:veterinary; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
references: Immunol Rev. 2010 Nov;238(1):182-94
references: 20969593
references: Cancer Invest. 2000;18(8):781-92
references: 11107448
references: J Hum Genet. 2003;48(3):159-62
references: 12624729
references: Vet Pathol. 2003 Jan;40(1):32-41
references: 12627711
references: Leukemia. 2004 Mar;18(3):589-96
references: 14712286
references: Nature. 2000 Feb 3;403(6769):503-11
references: 10676951
references: Lab Invest. 2004 May;84(5):562-72
references: 15064773
references: Blood. 2004 Jun 1;103(11):4251-8
references: 14976040
references: Biochemistry. 2004 Sep 21;43(37):11701-8
references: 15362854
references: J Natl Cancer Inst. 1976 Aug;57(2):451-4
references: 1034019
references: Mod Pathol. 1990 May;3(3):361-7
references: 2194216
references: Nature. 1990 Oct 18;347(6294):669-71
references: 1699135
references: Ann Oncol. 1998 Jul;9(7):717-20
references: 9739436
references: Nat Rev Genet. 2004 Dec;5(12):900-10
references: 15573122
references: Bioinformatics. 2005 Jan 15;21(2):263-5
references: 15297300
references: J Pathol. 2005 Jul;206(3):328-36
references: 15887291
references: Cancer Res. 2005 Jul 1;65(13):5654-61
references: 15994938
references: Nature. 2005 Dec 8;438(7069):803-19
references: 16341006
references: J Immunol. 2006 May 1;176(9):5153-9
references: 16621978
references: Exp Hematol. 2006 Jul;34(7):870-8
references: 16797414
references: Am J Hum Genet. 2011 Jan 7;88(1):76-82
references: 21167468
references: Vet Pathol. 2011 Jan;48(1):198-211
references: 20861499
references: Nat Rev Genet. 2010 Jul;11(7):459-63
references: 20548291
references: PLoS Genet. 2011 Apr;7(4):e1001378
references: 21533074
references: Nat Genet. 2011 Jun;43(6):519-25
references: 21552263
references: Crit Rev Oncol Hematol. 2011 Nov;80(2):257-63
references: 21055965
references: PLoS Genet. 2011 Oct;7(10):e1002316
references: 22022279
references: Nat Med. 2011;17(11):1437-43
references: 22064433
references: Curr Mol Med. 2011 Nov;11(8):633-49
references: 21902653
references: Biochim Biophys Acta. 2012 Apr;1821(4):618-26
references: 22306362
references: Fly (Austin). 2012 Apr-Jun;6(2):80-92
references: 22728672
references: Immunotherapy. 2012 Sep;4(9):957-69
references: 23046239
references: Immunity. 2013 Jan 24;38(1):13-25
references: 23352221
references: Brief Bioinform. 2013 Mar;14(2):178-92
references: 22517427
references: Nat Genet. 2013 Jul;45(7):804-7
references: 23749188
references: Vet Pathol. 2013 Jul;50(4):693-703
references: 23125145
references: CA Cancer J Clin. 2014 Jan-Feb;64(1):9-29
references: 24399786
references: PLoS One. 2014;9(3):e91172
references: 24625832
references: Am J Hum Genet. 2014 Apr 3;94(4):559-73
references: 24702953
references: Vet Immunol Immunopathol. 2014 Jun 15;159(3-4):192-201
references: 24642290
references: Genome Biol. 2014;15(3):R25
references: 24995881
references: Genome Biol. 2013;14(12):R132
references: 24330828
references: Nat Genet. 2014 Nov;46(11):1233-8
references: 25261932
references: Nat Genet. 2006 Aug;38(8):904-9
references: 16862161
references: Life Sci. 2006 Dec 14;80(2):89-97
references: 16979191
references: Br J Haematol. 2007 May;137(4):364-73
references: 17456059
references: Nature. 2007 Jun 7;447(7145):661-78
references: 17554300
references: Am J Hum Genet. 2007 Sep;81(3):559-75
references: 17701901
references: Clin Cancer Res. 2007 Nov 15;13(22 Pt 1):6666-72
references: 18006767
references: Nat Rev Cancer. 2008 Feb;8(2):147-56
references: 18202698
references: J Immunol. 2008 Dec 15;181(12):8391-401
references: 19050256
references: Acta Physiol (Oxf). 2009 Jan;195(1):3-11
references: 18983454
references: FASEB J. 2009 Feb;23(2):297-328
references: 18940894
references: Bioinformatics. 2009 May 1;25(9):1105-11
references: 19289445
references: Br J Haematol. 2009 Jun;146(1):91-4
references: 19438470
references: Nat Protoc. 2009;4(7):1073-81
references: 19561590
references: J Proteome Res. 2009 Nov;8(11):4943-53
references: 19799413
references: Bioinformatics. 2010 Jan 1;26(1):139-40
references: 19910308
references: Mol Psychiatry. 2010 Jan;15(1):8-10
references: 20029408
references: Nat Genet. 2010 Mar;42(3):250-4
references: 20101241
references: Nat Genet. 2010 Apr;42(4):348-54
references: 20208533
references: Nat Genet. 2011 May;43(5):491-8
references: 21478889