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

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

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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.

Original languageEnglish (US)
Pages (from-to)1634-1645
Number of pages12
JournalGenome Research
Volume25
Issue number11
DOIs
StatePublished - Nov 1 2015

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Exome
T-Cell Lymphoma
Lymphoma
Dogs
B-Cell Lymphoma
Mutation
Genes
Codon
Neoplasms
TNF Receptor-Associated Factor 3
Hematologic Neoplasms
Developed Countries
Leukemia
B-Lymphocytes
Genetic Background
T-Lymphocytes

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Elvers, I., Turner-Maier, J., Swofford, R., Koltookian, M., Johnson, J., Stewart, C., ... Alföldi, J. (2015). Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background. Genome Research, 25(11), 1634-1645. https://doi.org/10.1101/gr.194449.115

Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background. / Elvers, Ingegerd; Turner-Maier, Jason; Swofford, Ross; Koltookian, Michele; Johnson, Jeremy; Stewart, Chip; Zhang, Cheng Zhong; Schumacher, Steven E.; Beroukhim, Rameen; Rosenberg, Mara; Thomas, Rachael; Mauceli, Evan; Getz, Gad; Di Palma, Federica; Modiano, Jaime F.; Breen, Matthew; Lindblad-Toh, Kerstin; Alföldi, Jessica.

In: Genome Research, Vol. 25, No. 11, 01.11.2015, p. 1634-1645.

Research output: Contribution to journalArticle

Elvers, I, Turner-Maier, J, Swofford, R, Koltookian, M, Johnson, J, Stewart, C, Zhang, CZ, Schumacher, SE, Beroukhim, R, Rosenberg, M, Thomas, R, Mauceli, E, Getz, G, Di Palma, F, Modiano, JF, Breen, M, Lindblad-Toh, K & Alföldi, J 2015, 'Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background', Genome Research, vol. 25, no. 11, pp. 1634-1645. https://doi.org/10.1101/gr.194449.115
Elvers I, Turner-Maier J, Swofford R, Koltookian M, Johnson J, Stewart C et al. Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background. Genome Research. 2015 Nov 1;25(11):1634-1645. https://doi.org/10.1101/gr.194449.115
Elvers, Ingegerd ; Turner-Maier, Jason ; Swofford, Ross ; Koltookian, Michele ; Johnson, Jeremy ; Stewart, Chip ; Zhang, Cheng Zhong ; Schumacher, Steven E. ; Beroukhim, Rameen ; Rosenberg, Mara ; Thomas, Rachael ; Mauceli, Evan ; Getz, Gad ; Di Palma, Federica ; Modiano, Jaime F. ; Breen, Matthew ; Lindblad-Toh, Kerstin ; Alföldi, Jessica. / Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background. In: Genome Research. 2015 ; Vol. 25, No. 11. pp. 1634-1645.
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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.",
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