title: Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background.
abstract: 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.
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA; Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala SE 751 23, Sweden;
authors.forename: Ingegerd
authors.initials: I
authors.lastname: Elvers
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA;
authors.forename: Jason
authors.initials: J
authors.lastname: Turner-Maier
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA;
authors.forename: Ross
authors.initials: R
authors.lastname: Swofford
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA;
authors.forename: Michele
authors.initials: M
authors.lastname: Koltookian
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA;
authors.forename: Jeremy
authors.initials: J
authors.lastname: Johnson
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA;
authors.forename: Chip
authors.initials: C
authors.lastname: Stewart
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA; Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;
authors.forename: Cheng-Zhong
authors.initials: CZ
authors.lastname: Zhang
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA; Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;
authors.forename: Steven E
authors.initials: SE
authors.lastname: Schumacher
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA; Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA;
authors.forename: Mara
authors.initials: M
authors.lastname: Rosenberg
authors.affiliation: North Carolina State University, Raleigh, North Carolina 27695, USA;
authors.forename: Rachael
authors.initials: R
authors.lastname: Thomas
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA;
authors.forename: Evan
authors.initials: E
authors.lastname: Mauceli
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA; Harvard Medical School, Boston, Massachusetts 02115, USA; Massachusetts General Hospital, Boston, Massachusetts 02114, USA;
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA;
authors.forename: Federica Di
authors.initials: FD
authors.lastname: Palma
authors.affiliation: Animal Cancer Care and Research Program, College of Veterinary Medicine, and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA;
authors.forename: Jaime F
authors.initials: JF
authors.lastname: Modiano
authors.affiliation: North Carolina State University, Raleigh, North Carolina 27695, USA; University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27514, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Breen
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA; Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala SE 751 23, Sweden;
authors.forename: Kerstin
authors.initials: K
authors.lastname: Lindblad-Toh
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA;
authors.forename: Jessica
authors.initials: J
authors.lastname: Alföldi
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics; D056915:DNA Copy Number Variations; D004195:Disease Models, Animal; D004285:Dogs / Q000235:genetics*; D059472:Exome; D044783:F-Box Proteins / Q000235:genetics; D000073979:F-Box-WD Repeat-Containing Protein 7; D000068617:Genetic Background; D006801:Humans; D016393:Lymphoma, B-Cell / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D016415:Sequence Alignment; D000089804:Shelterin Complex; D013601:T-Lymphocytes / Q000378:metabolism; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics; D034501:Telomere-Binding Proteins / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D017346:Protein Serine-Threonine Kinases; D000089804:Shelterin Complex; D048008:TNF Receptor-Associated Factor 3; D034501:Telomere-Binding Proteins; D044767:Ubiquitin-Protein Ligases; D000097782:NF-kappaB-Inducing Kinase; C513273:FBXW7 protein, human; C440849:POT1 protein, human