Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background

• DOI: 10.1101/gr.194449.115
• Publication Date: 2015-10-09T02:29:00Z
• Authors: Ingegerd Elvers; Jason Turner-Maier; Ross Swofford; Michele Koltookian; Jeremy Johnson; Chip Stewart; Cheng-Zhong Zhang; Steven E. Schumacher; Rameen Beroukhim; Mara Rosenberg; Rachael Thomas; Evan Mauceli; Gad Getz; Federica Di Palma; Jaime F. Modiano; Matthew Breen; Kerstin Lindblad-Toh; Jessica Alföldi
• Keywords: F-Box-WD Repeat-Containing Protein 7; Lymphoma, B-Cell; DNA Copy Number Variations; T-Lymphocytes; Ubiquitin-Protein Ligases; Telomere-Binding Proteins; 610; Cell Cycle Proteins; Protein Serine-Threonine Kinases; Biochemistry; Shelterin Complex; 0403 veterinary science; Dogs; Animals; Humans; Exome; Biokemi; Molecular Biology; Cancer och onkologi; B-Lymphocytes; Molekylärbiologi; TNF Receptor-Associated Factor 3; Research; F-Box Proteins; Biochemistry and Molecular Biology; 04 agricultural and veterinary sciences; 3. Good health; Disease Models, Animal; Cancer and Oncology; Mutation; Genetic Background; Sequence Alignment; Biokemi och molekylärbiologi

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.