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Exome sequencing of hemangiosarcomas in the golden retriever reveals frequent mutation of TP53 tumor suppressor and PIK3CA oncogene
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.
Broad Institute.
University of Minnesota.
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(English)Manuscript (preprint) (Other academic)
National Category
Genetics
Identifiers
URN: urn:nbn:se:uu:diva-347164OAI: oai:DiVA.org:uu-347164DiVA, id: diva2:1193428
Available from: 2018-03-27 Created: 2018-03-27 Last updated: 2018-03-27
In thesis
1. Analysis of inherited and somatic variants to decipher canine complex traits
Open this publication in new window or tab >>Analysis of inherited and somatic variants to decipher canine complex traits
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis presents several investigations of the dog as a model for complex diseases, focusing on cancers and the effect of genetic risk factors on clinical presentation.

In Papers I and II, we performed genome-wide association studies (GWAS) to identify germline risk factors predisposing US golden retrievers to hemangiosarcoma (HSA) and B-cell lymphoma (BLSA). Paper I identified two loci predisposing to both HSA and BLSA, approximately 4 megabases (Mb) apart on chromosome 5. Carrying the risk haplotype at these loci was associated with separate changes in gene expression, both relating to T-cell activation and proliferation.

Paper II followed up on the HSA GWAS by performing a meta-analysis with additional cases and controls. This confirmed three previously reported GWAS loci for HSA and revealed three new loci, the most significant on chromosome 18. This locus contains several candidate genes with a clear role in carcinogenesis, including KMT5B and LRP5. Overall, carriers of the risk alleles at the top six loci are diagnosed with HSA earlier in life.

In Paper III we investigated the somatic mutations which occur in HSA tumor tissue by performing tumor-normal exome sequencing of 47 golden retrievers. We identified 7 recurrently mutated genes, including the tumor suppressor TP53 (mutated in 59.6% of tumors) and oncogene PIK3CA (mutated in 29.8% of tumors). Additional somatically mutated genes overlap those found in human angiosarcomas, suggesting that angiosarcomas in dogs and humans are genetically very similar.

In Paper IV, we investigated the variable penetrance of a SOD1 mutation in Pembroke Welsh corgis causing degenerative myelopathy (DM), a model of the human motor neuron disease amyotrophic lateral sclerosis (ALS). We discovered that regulatory variants near the SP110 gene were associated with an increased risk of DM and an earlier age at diagnosis, suggesting a role for immune response in the pathogenesis of the disease.

Taken together, these findings provide new insight into the pathophysiology of both hemangiosarcoma and degenerative myelopathy, which could guide future diagnostics and therapeutic strategies both in humans and veterinary patients. In addition, they demonstrate the power of the dog as a biomedical model for human complex diseases.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 67
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1454
Keyword
dog, genetics, GWAS, exome, cancer, DM
National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-347165 (URN)978-91-513-0310-9 (ISBN)
Public defence
2018-05-21, A1:107a, BMC, Husargatan 3, Uppsala, 13:15 (English)
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Supervisors
Available from: 2018-04-26 Created: 2018-03-27 Last updated: 2018-04-26

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Megquier, KatherineWang, ChaoElvers, IngegerdLindblad-Toh, Kerstin

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