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  • 1.
    Cavalli, Marco
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Pan, Gang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Nord, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Wallerman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Arzt, Emelie Wallén
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Karolinska Inst, Dept Biosci & Nutr, Ctr Biosci, Huddinge, Sweden..
    Berggren, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Elvers, Ingegerd
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst MIT & Harvard, Cambridge, MA USA..
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Toh, Kerstin Lindblad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst MIT & Harvard, Cambridge, MA USA..
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Allele-specific transcription factor binding to common and rare variants associated with disease and gene expression2016In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 135, no 5, p. 485-497Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have identified a large number of disease-associated SNPs, but in few cases the functional variant and the gene it controls have been identified. To systematically identify candidate regulatory variants, we sequenced ENCODE cell lines and used public ChIP-seq data to look for transcription factors binding preferentially to one allele. We found 9962 candidate regulatory SNPs, of which 16 % were rare and showed evidence of larger functional effect than common ones. Functionally rare variants may explain divergent GWAS results between populations and are candidates for a partial explanation of the missing heritability. The majority of allele-specific variants (96 %) were specific to a cell type. Furthermore, by examining GWAS loci we found >400 allele-specific candidate SNPs, 141 of which were highly relevant in our cell types. Functionally validated SNPs support identification of an SNP in SYNGR1 which may expose to the risk of rheumatoid arthritis and primary biliary cirrhosis, as well as an SNP in the last intron of COG6 exposing to the risk of psoriasis. We propose that by repeating the ChIP-seq experiments of 20 selected transcription factors in three to ten people, the most common polymorphisms can be interrogated for allele-specific binding. Our strategy may help to remove the current bottleneck in functional annotation of the genome.

  • 2.
    Elvers, Ingegerd
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst, Cambridge, MA 02142 USA..
    Turner-Maier, Jason
    Broad Inst, Cambridge, MA 02142 USA..
    Swofford, Ross
    Broad Inst, Cambridge, MA 02142 USA..
    Koltookian, Michele
    Broad Inst, Cambridge, MA 02142 USA..
    Johnson, Jeremy
    Broad Inst, Cambridge, MA 02142 USA..
    Stewart, Chip
    Broad Inst, Cambridge, MA 02142 USA..
    Zhang, Cheng-Zhong
    Broad Inst, Cambridge, MA 02142 USA.;Dana Farber Canc Inst, Boston, MA 02215 USA..
    Schumacher, Steven E.
    Broad Inst, Cambridge, MA 02142 USA.;Dana Farber Canc Inst, Boston, MA 02215 USA..
    Beroukhim, Rameen
    Broad Inst, Cambridge, MA 02142 USA.;Dana Farber Canc Inst, Boston, MA 02215 USA..
    Rosenberg, Mara
    Broad Inst, Cambridge, MA 02142 USA..
    Thomas, Rachael
    N Carolina State Univ, Raleigh, NC 27695 USA..
    Mauceli, Evan
    Broad Inst, Cambridge, MA 02142 USA..
    Getz, Gad
    Broad Inst, Cambridge, MA 02142 USA.;Harvard Univ, Sch Med, Boston, MA 02115 USA.;Massachusetts Gen Hosp, Boston, MA 02114 USA..
    Di Palma, Federica
    Broad Inst, Cambridge, MA 02142 USA..
    Modiano, Jaime F.
    Univ Minnesota, Coll Vet Med, Anim Canc Care & Res Program, Minneapolis, MN 55455 USA.;Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA..
    Breen, Matthew
    N Carolina State Univ, Raleigh, NC 27695 USA.;Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27514 USA..
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst, Cambridge, MA 02142 USA..
    Alfoeldi, Jessica
    Broad Inst, Cambridge, MA 02142 USA..
    Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background2015In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 25, no 11, p. 1634-1645Article in journal (Refereed)
    Abstract [en]

    Lymphoma is the most common hematological malignancy in developed countries. Outcome is strongly determined by molecular subtype, reflecting a need for new and improved treatment options. Dogs spontaneously develop lymphoma, and the predisposition of certain breeds indicates genetic risk factors. Using the dog breed structure, we selected three lymphoma predisposed breeds developing primarily T-cell (boxer), primarily B-cell (cocker spaniel), and with equal distribution of B- and T-cell lymphoma (golden retriever), respectively. We investigated the somatic mutations in B- and T-cell lymphomas from these breeds by exome sequencing of tumor and normal pairs. Strong similarities were evident between B-cell lymphomas from golden retrievers and cocker spaniels, with recurrent mutations in TRAF3-MAP3K14 (28% of all cases), FBXW7 (25%), and POT1 (17%). The FBXW7 mutations recurrently occur in a specific codon; the corresponding codon is recurrently mutated in human cancer. In contrast, T-cell lymphomas from the predisposed breeds, boxers and golden retrievers, show little overlap in their mutation pattern, sharing only one of their 15 most recurrently mutated genes. Boxers, which develop aggressive T-cell lymphomas, are typically mutated in the PTEN-mTOR pathway. T-cell lymphomas in golden retrievers are often less aggressive, and their tumors typically showed mutations in genes involved in cellular metabolism. We identify genes with known involvement in human lymphoma and leukemia, genes implicated in other human cancers, as well as novel genes that could allow new therapeutic options.

  • 3. Karlsson, Elinor K
    et al.
    Sigurdsson, Snaevar
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ivansson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Thomas, Rachael
    Elvers, Ingegerd
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wright, Jason
    Howald, Cedric
    Tonomura, Noriko
    Perloski, Michele
    Swofford, Ross
    Biagi, Tara
    Fryc, Sarah
    Anderson, Nathan
    Courtay-Cahen, Celine
    Youell, Lisa
    Ricketts, Sally L
    Mandlebaum, Sarah
    Rivera, Patricio
    von Euler, Henrik
    Kisseberth, William C
    London, Cheryl A
    Lander, Eric S
    Couto, Guillermo
    Comstock, Kenine
    Starkey, Mike P
    Modiano, Jaime F
    Breen, Matthew
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A/B2013In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 14, no 12, article id R132Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Canine osteosarcoma is clinically nearly identical to the human disease, but is common and highly heritable, making genetic dissection feasible.

    RESULTS: Through genome-wide association analyses in three breeds (greyhounds, Rottweilers, and Irish wolfhounds), we identify 33 inherited risk loci explaining 55% to 85% of phenotype variance in each breed. The greyhound locus exhibiting the strongest association, located 150 kilobases upstream of the genes CDKN2A/B, is also the most rearranged locus in canine osteosarcoma tumors. The top germline candidate variant is found at a >90% frequency in Rottweilers and Irish wolfhounds, and alters an evolutionarily constrained element that we show has strong enhancer activity in human osteosarcoma cells. In all three breeds, osteosarcoma-associated loci and regions of reduced heterozygosity are enriched for genes in pathways connected to bone differentiation and growth. Several pathways, including one of genes regulated by miR124, are also enriched for somatic copy-number changes in tumors.

    CONCLUSIONS: Mapping a complex cancer in multiple dog breeds reveals a polygenic spectrum of germline risk factors pointing to specific pathways as drivers of disease.

  • 4.
    Megquier, Katherine
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tonomura, Noriko
    Fall, Tove
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Noh, Hyun Ji
    Broad Institute.
    Turner-Maier, Jason
    Broad Institute.
    Swofford, Ross
    Broad Institute.
    Koltookian, Michele
    Broad Institute.
    Biagi, Tara
    Fryc, Sarah
    Arendt, Maja Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Häggström, Jens
    Barber, Lisa
    Tufts Cummings School of Veterinary Medicine.
    Burgess, Kristine
    Tufts Cummings School of Veterinary Medicine.
    Thomas, Rachael
    NCSU.
    Breen, Matthew
    NCSU.
    Modiano, Jaime
    University of Minnesota.
    Elvers, Ingegerd
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Azuma, Chieko
    University of Massachusetts Medical School.
    Karlsson, Elinor
    Broad Institute.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genome-wide meta-analysis identifies inherited variation contributing to overall risk and age of onset in canine angiosarcomaManuscript (preprint) (Other academic)
  • 5.
    Megquier, Katherine
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Turner-Maier, Jason
    Broad Institute.
    Swofford, Ross
    Broad Institute.
    Kim, Jong Hyuk
    University of Minnesota.
    Sarver, Aaron
    University of Minnesota.
    Wang, Chao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sakthikumar, Sharadha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Johnson, Jeremy
    Broad Institute.
    Lewellen, Mitzi
    University of Minnesota.
    Scott, Milcah
    University of Minnesota.
    Graef, Ashley
    University of Minnesota.
    Tonomura, Noriko
    Fryc, Sarah
    Biagi, Tara
    Alfoldi, Jessica
    Broad Institute.
    Thomas, Rachael
    NCSU.
    Karlsson, Elinor
    Broad Institute.
    Breen, Matthew
    NCSU.
    Modiano, Jaime
    University of Minnesota.
    Elvers, Ingegerd
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Exome sequencing of hemangiosarcomas in the golden retriever reveals frequent mutation of TP53 tumor suppressor and PIK3CA oncogeneManuscript (preprint) (Other academic)
  • 6.
    Megquier, Katherine
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
    Turner-Maier, Jason
    Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
    Swofford, Ross
    Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
    Kim, Jong-Hyuk
    Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota; Animal Cancer Care and Research Program, University of Minnesota, St. Paul, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota..
    Sarver, Aaron L
    Animal Cancer Care and Research Program, University of Minnesota, St. Paul, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; Institute for Health Informatics, University of Minnesota, Minneapolis, Minnesota..
    Wang, Chao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sakthikumar, Sharadha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Institute of Harvard and MIT, Cambridge, Massachusetts..
    Johnson, Jeremy
    Broad Institute of Harvard and MIT, Cambridge, Massachusetts..
    Koltookian, Michele
    Broad Institute of Harvard and MIT, Cambridge, Massachusetts..
    Lewellen, Mitzi
    Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota; Animal Cancer Care and Research Program, University of Minnesota, St. Paul, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota..
    Scott, Milcah C
    Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota; Animal Cancer Care and Research Program, University of Minnesota, St. Paul, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota..
    Schulte, Ashley J
    Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota; Animal Cancer Care and Research Program, University of Minnesota, St. Paul, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota..
    Borst, Luke
    Department of Clinical Sciences, North Carolina State College of Veterinary Medicine, Raleigh, North Carolina..
    Tonomura, Noriko
    Broad Institute of Harvard and MIT, Cambridge, Massachusetts; Tufts Cummings School of Veterinary Medicine, North Grafton, Massachusetts..
    Alfoldi, Jessica
    Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
    Painter, Corrie
    Broad Institute of Harvard and MIT, Cambridge, Massachusetts; Count Me In, Cambridge, Massachusetts.
    Thomas, Rachael
    Department of Molecular Biomedical Sciences, North Carolina State University College of Veterinary Medicine; Comparative Medicine Institute, Raleigh, North Carolina.
    Karlsson, Elinor K
    Broad Institute of Harvard and MIT, Cambridge, Massachusetts; Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, Massachusetts; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.
    Breen, Matthew
    Department of Molecular Biomedical Sciences, North Carolina State University College of Veterinary Medicine; Comparative Medicine Institute, Raleigh, North Carolina..
    Modiano, Jaime F
    Univ Minnesota, Minneapolis, MN USA.
    Elvers, Ingegerd
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
    Comparative Genomics Reveals Shared Mutational Landscape in Canine Hemangiosarcoma and Human Angiosarcoma2019In: Molecular Cancer Research, ISSN 1541-7786, E-ISSN 1557-3125, Vol. 17, no 12, p. 2410-2421Article in journal (Refereed)
    Abstract [en]

    Angiosarcoma is a highly aggressive cancer of blood vessel-forming cells with few effective treatment options and high patient mortality. It is both rare and heterogenous, making large, well-powered genomic studies nearly impossible. Dogs commonly suffer from a similar cancer, called hemangiosarcoma, with breeds like the golden retriever carrying heritable genetic factors that put them at high risk. If the clinical similarity of canine hemangiosarcoma and human angiosarcoma reflects shared genomic etiology, dogs could be a critically needed model for advancing angiosarcoma research. We assessed the genomic landscape of canine hemangiosarcoma via whole-exome sequencing (47 golden retriever hemangiosarcomas) and RNA sequencing (74 hemangiosarcomas from multiple breeds). Somatic coding mutations occurred most frequently in the tumor suppressor TP53 (59.6% of cases) as well as two genes in the PI3K pathway: the oncogene PIK3CA (29.8%) and its regulatory subunit PIK3R1 (8.5%). The predominant mutational signature was the age-associated deamination of cytosine to thymine. As reported in human angiosarcoma, CDKN2A/B was recurrently deleted and VEGFA, KDR, and KIT recurrently gained. We compared the canine data to human data recently released by The Angiosarcoma Project, and found many of the same genes and pathways significantly enriched for somatic mutations, particularly in breast and visceral angiosarcomas. Canine hemangiosarcoma closely models the genomic landscape of human angiosarcoma of the breast and viscera, and is a powerful tool for investigating the pathogenesis of this devastating disease. IMPLICATIONS: We characterize the genomic landscape of canine hemangiosarcoma and demonstrate its similarity to human angiosarcoma.

  • 7.
    Melin, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Rivera, Patricio
    Evidensia Sodra Djursjukhuset, Stockholm, Sweden..
    Arendt, Maja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Univ Cambridge, Dept Vet Med, Cambridge, England..
    Elvers, Ingegerd
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst MIT & Harvard, Cambridge, MA USA..
    Murén, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gustafson, Ulla
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Starkey, Mike
    Anim Hlth Trust, Newmarket, Suffolk, England..
    Borge, Kaja Sverdrup
    Norwegian Univ Life Sci, Dept Basic Sci & Aquat Med, Oslo, Norway..
    Lingaas, Frode
    Norwegian Univ Life Sci, Dept Basic Sci & Aquat Med, Oslo, Norway..
    Haggstrom, Jens
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Saellstrom, Sara
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Ronnberg, Henrik
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst MIT & Harvard, Cambridge, MA USA..
    Genome-Wide Analysis Identifies Germ-Line Risk Factors Associated with Canine Mammary Tumours2016In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, no 5, article id e1006029Article in journal (Refereed)
    Abstract [en]

    Canine mammary tumours (CMT) are the most common neoplasia in unspayed female dogs. CMTs are suitable naturally occurring models for human breast cancer and share many characteristics, indicating that the genetic causes could also be shared. We have performed a genome-wide association study (GWAS) in English Springer Spaniel dogs and identified a genome-wide significant locus on chromosome 11 (p(raw) = 5.6x10(-7), p(perm) = 0.019). The most associated haplotype spans a 446 kb region overlapping the CDK5RAP2 gene. The CDK5RAP2 protein has a function in cell cycle regulation and could potentially have an impact on response to chemotherapy treatment. Two additional loci, both on chromosome 27, were nominally associated (p(raw) = 1.97x10(-5) and p(raw) = 8.30x10(-6)). The three loci explain 28.1 +/- 10.0% of the phenotypic variation seen in the cohort, whereas the top ten associated regions account for 38.2 +/- 10.8% of the risk. Furthermore, the ten GWAS loci and regions with reduced genetic variability are significantly enriched for snoRNAs and tumour-associated antigen genes, suggesting a role for these genes in CMT development. We have identified several candidate genes associated with canine mammary tumours, including CDK5RAP2. Our findings enable further comparative studies to investigate the genes and pathways in human breast cancer patients.

  • 8.
    Sakthikumar, Sharadha
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst, Cambridge, MA USA.
    Elvers, Ingegerd
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Inst, Cambridge, MA USA.
    Kim, Jaegil
    Broad Inst, Cambridge, MA USA.
    Arendt, Maja Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Copenhagen, Dept Vet Clin Sci, Frederiksberg D, Denmark.
    Thomas, Rachael
    North Carolina State Univ, Comparat Med Inst, Raleigh, NC USA;North Carolina State Univ, Coll Vet Med, Raleigh, NC USA.
    Turner-Maier, Jason
    Broad Inst, Cambridge, MA USA.
    Swofford, Ross
    Broad Inst, Cambridge, MA USA.
    Johnson, Jeremy
    Broad Inst, Cambridge, MA USA.
    Schumacher, Steven E.
    Broad Inst, Cambridge, MA USA.
    Alfoldi, Jessica
    Broad Inst, Cambridge, MA USA.
    Axelsson, Erik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Couto, C. Guillermo
    Ohio State Univ, Ctr Vet Med, Columbus, OH 43210 USA;Ohio State Univ, Dept Vet Clin Sci, Columbus, OH 43210 USA;Couto Vet Consultants, Hilliard, OH USA.
    Kisseberth, William C.
    Ohio State Univ, Ctr Vet Med, Columbus, OH 43210 USA;Ohio State Univ, Dept Vet Clin Sci, Columbus, OH 43210 USA.
    Pettersson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Getz, Gad
    Harvard Med Sch, Boston, MA USA;Broad Inst, Cambridge, MA USA;Massachusetts Gen Hosp, Boston, MA 02114 USA.
    Meadows, Jennifer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Modiano, Jaime F.
    Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN USA;Univ Minnesota, Stem Cell Inst, Minneapolis, MN USA;Univ Minnesota, Inst Engn & Med, Minneapolis, MN USA;Univ Minnesota, Ctr Immunol, Minneapolis, MN USA;Coll Vet Med, Dept Vet Clin Sci, St Paul, MN USA;Coll Vet Med, Anim Canc Care & Res Program, St Paul, MN USA.
    Breen, Matthew
    North Carolina State Univ, Comparat Med Inst, Raleigh, NC USA;North Carolina State Univ, Coll Vet Med, Raleigh, NC USA.
    Kierczak, Marcin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Forsberg-Nilsson, Karin
    Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, Uppsala, Sweden.
    Marinescu, Voichita
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Inst, Cambridge, MA USA.
    SETD2 Is Recurrently Mutated in Whole-Exome Sequenced Canine Osteosarcoma2018In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, no 13, p. 3421-3431Article in journal (Refereed)
    Abstract [en]

    Osteosarcoma is a debilitating bone cancer that affects humans, especially children and adolescents. A homologous form of osteosarcoma spontaneously occurs in dogs, and its differential incidence observed across breeds allows for the investigation of tumor mutations in the context of multiple genetic backgrounds. Using whole-exome sequencing and dogs from three susceptible breeds (22 golden retrievers, 21 Rottweilers, and 23 greyhounds), we found that osteosarcoma tumors show a high frequency of somatic copy-number alterations (SCNA), affecting key oncogenes and tumor-suppressor genes. The across-breed results are similar to what has been observed for human osteosarcoma, but the disease frequency and somatic mutation counts vary in the three breeds. For all breeds, three mutational signatures (one of which has not been previously reported) and 11 significantly mutated genes were identified. TP53 was the most frequently altered gene (83% of dogs have either mutations or SCNA in TP53), recapitulating observations in human osteosarcoma. The second most frequently mutated gene, histone methyltransferase SETD2, has known roles in multiple cancers, but has not previously been strongly implicated in osteosarcoma. This study points to the likely importance of histone modifications in osteosarcoma and highlights the strong genetic similarities between human and dog osteosarcoma, suggesting that canine osteosarcoma may serve as an excellent model for developing treatment strategies in both species. Significance: Canine osteosarcoma genomics identify SETD2 as a possible oncogenic driver of osteosarcoma, and findings establish the canine model as a useful comparative model for the corresponding human disease.

  • 9. Tonomura, Noriko
    et al.
    Elvers, Ingegerd
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Thomas, Rachael
    Megquier, Kate
    Turner-Maier, Jason
    Howald, Cedric
    Sarver, Aaron L.
    Swofford, Ross
    Frantz, Aric M.
    Ito, Daisuke
    Mauceli, Evan
    Arendt, Maja
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    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
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genome-wide Association Study Identifies Shared Risk Loci Common to Two Malignancies in Golden Retrievers2015In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 2, article id e1004922Article in journal (Refereed)
    Abstract [en]

    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 similar to 20% of the risk of developing these cancers. Genome-wide p-values for the top SNP of each locus are 4.6x10(-7) and 2.7x10(-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 hemangio-sarcoma 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.

  • 10.
    Vieira, Natassia M.
    et al.
    Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Dept Pediat & Genet, Boston, MA 02115 USA.;Univ Sao Paulo, Biosci Inst, Human Genome & Stem Cell Ctr, BR-05508090 Sao Paulo, Brazil..
    Elvers, Ingegerd
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA..
    Alexander, Matthew S.
    Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Dept Pediat & Genet, Boston, MA 02115 USA.;Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA..
    Moreira, Yuri B.
    Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-05508000 Sao Paulo, Brazil..
    Eran, Alal
    Harvard Univ, Sch Med, Dept Pediat & Genet, Boston, MA 02115 USA..
    Gomes, Juliana P.
    Univ Sao Paulo, Biosci Inst, Human Genome & Stem Cell Ctr, BR-05508090 Sao Paulo, Brazil..
    Marshall, Jamie L.
    Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Dept Pediat & Genet, Boston, MA 02115 USA..
    Karlsson, Elinor K.
    Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA.;Univ Massachusetts, Sch Med, Program Bioinformat & Integrat Biol, Worcester, MA 01605 USA..
    Verjovski-Almeida, Sergio
    Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-05508000 Sao Paulo, Brazil.;Inst Butantan, BR-05508050 Sao Paulo, Brazil..
    Lindblad-Toh, Kerstin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA..
    Kunkel, Louis M.
    Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Dept Pediat & Genet, Boston, MA 02115 USA.;Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA 02115 USA..
    Zatz, Mayana
    Univ Sao Paulo, Biosci Inst, Human Genome & Stem Cell Ctr, BR-05508090 Sao Paulo, Brazil..
    Jagged 1 Rescues the Duchenne Muscular Dystrophy Phenotype2015In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 163, no 5, p. 1204-1213Article in journal (Refereed)
    Abstract [en]

    Duchenne muscular dystrophy (DMD), caused by mutations at the dystrophin gene, is the most common form of muscular dystrophy. There is no cure for DMD and current therapeutic approaches to restore dystrophin expression are only partially effective. The absence of dystrophin in muscle results in dysregulation of signaling pathways, which could be targets for disease therapy and drug discovery. Previously, we identified two exceptional Golden Retriever muscular dystrophy (GRMD) dogs that are mildly affected, have functional muscle, and normal lifespan despite the complete absence of dystrophin. Now, our data on linkage, whole-genome sequencing, and transcriptome analyses of these dogs compared to severely affected GRMD and control animals reveals that increased expression of Jagged1 gene, a known regulator of the Notch signaling pathway, is a hallmark of the mild phenotype. Functional analyses demonstrate that Jagged1 overexpression ameliorates the dystrophic phenotype, suggesting that Jagged1 may represent a target for DMD therapy in a dystrophin-independent manner.

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