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Biomarkers and Genetics of Canine Visceral Haemangiosarcoma

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Biomarkers and Genetics of Canine Visceral Haemangiosarcoma Biomarkers and genetics of canine visceral haemangiosarcoma Patharee Oungsakul Doctor of Veterinary Medicine, Master of Veterinary Studies 0000-0003-4523-3484 A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in Year 2020 School of Veterinary Science Abstract Visceral haemangiosarcoma (HSA) is a vascular endothelial cell cancer that arises in internal organs, especially in the spleen. HSA carries a very poor prognosis but is also difficult to diagnose. Therefore, dogs with HSA symptoms are often euthanized without full investigation. The goal of the thesis was to improve the diagnosis and prevention of this cancer by exploring several HSA biomarkers. The thesis comprises four independent biomarker studies regarding glycoproteins, genetics and Infrared spectral markers. The aim of the first study (chapter 2) was to validate the candidates for canine visceral HSA serum biomarkers, by performing tissue immuno- and lectin-labelling of HSA (n = 32) and HSA-like (n=26) formalin-fixed paraffin-embedded (FFPE) tissues with C7 (component complement 7), MGAM (maltase-glucoamylase), VTN (vitronectin) antibodies and DSA (Datura stramonium), WGA (Wheat germ agglutinin), SNA (Sambucus nigra) and PSA (Pisum sativum)lectins. The results showed lectin/immuno-positive signal on HSA cells, endothelial cell of the veins and arteries. IHC and LHC signal intensities were heterogeneous across the tissue types, diagnosis groups (HSA vs HSA-like) and tissue markers. A semi-quantitative assay was applied to assess and compare the levels of IHC/LHC signal intensities of each marker. Among the candidates tested, complement component 7 (C7) and DSA binding glycoproteins were considered the most promising tissue markers as they demonstrated the ability to distinguish HSA tissue from HSA-like tissues (e.g. hematoma), by the comparison of glycoprotein expression level. HSA is overrepresented in Golden Retrievers, German Shepherds and Labrador Retrievers which suggested that genetic background plays an important role in this cancer. Inherited germline mutation was hypothesized to be the major factor. The aim of chapter 3 was to identify germline variants/polymorphisms that were related to HSA, allowing for development of HSA predisposing genetic markers in the future. Whole exome sequence data analysis was performed in 28 dogs with HSA. The sources of data included novel whole exome sequencing from the samples collected in this study (n = 11) and database archival data (n = 17). Control data (n = 247) were obtained from sequence read archive databases. Exome variants association scan was performed in parallel with functional annotation analysis. The results showed genetic variants/polymorphisms in four genes, including PLSCR3, FANCM, MRPL40 and ZNF704, were strongly associated with HSA. The allele frequencies were detected in over 80% of HSA cases and were mostly homozygous. While the allele frequencies in the control were around 50%, none was homozygous. Gene set enrichment analysis showed five molecular pathways where genes with HSA-related variants resided, including i Interferon gamma, Complement, Adipogenesis, Genes down-regulated in CD4 T-cells, and Genes down-regulated in marginal zone B-lymphocytes. In chapter 4, somatic mutations were investigated further in five samples, where matched blood- tumour samples were available, by performing whole exome sequencing and bioinformatics data analysis. Gene mutation candidates were manually selected based on; 1) their annotated functions, 2) co-mutated candidates which most HSA tumours have in common, and 3) genes that had high numbers of mutations. Co-mutated (more than 60% of samples) somatic mutations were found in ADCY1, CNN2, ARHGAP45, ATXN2L, CYP1A2, KRT3, SBNO2, TUFM and U6 genes. When considering the severity of molecular functions that were disrupted by gene mutations, genes containing one or more binding sites for MZF1 (myeloid zinc finger 1) in their promoter regions (DUSP6, NFKBID, COPS3, KPNB1, KIF21A, SERF2, PABPC1L and COL24A1) were found to have undergone mutations in canine HSA tumours. Genes with high numbers of mutations included GLUL, RIDA, ESRRA, COL11A2, ZNF296, RSAD2, RIN2, XRCC1, POLRMT, MTFR2 and PSMD4, with high numbers of the mutations occurring in the 3'-UTR. Combining all the mutations, the mitotic spindle pathway was found to be disrupted by mutations in NF1, SASS6, CLASP1, ARHGEF3 and STAU1 genes. The proportion of samples having mutations on gene TP53 and PIK3CA in this study cohort was 20%. The study in chapter 5 explored the capability of Fourier Transform Infrared (FTIR) imaging plus Partial Least Squares-Discriminant analysis (PLS-DA) in discriminating FFPE spleen tissue sections containing HSA (cancer), which could lead to the development of rapid, label-free tissue diagnostic technologies to aid in canine HSA differential diagnosis. FTIR images of 26 splenic HSA and 32 non-HSA splenic lesions were blind tested. The prediction model correctly identified 24 out of 26 HSA samples while 21 non-HSA samples were incorrectly predicted as cancer, which yielded a sensitivity of 92% and 34% specificity. Potential improvement for this technology is suggested. The studies in this thesis contributed to further development of canine visceral HSA biomarkers such as differential diagnostic markers, disease predisposing genetic markers and genomic markers for personalized treatments. ii Declaration by author This thesis is composed of my original work, and contains no material previously published or written by another person except where due reference has been made in the text. I have clearly stated the contribution by others to jointly authored works that I have included in my thesis. I have clearly stated the contribution of others to my thesis as a whole, including statistical assistance, survey design, data analysis, significant technical procedures, professional editorial advice, financial support and any other original research work used or reported in my thesis. The content of my thesis is the result of work I have carried out since the commencement of my higher degree by research candidature and does not include a substantial part of work that has been submitted to qualify for the award of any other degree or diploma in any university or other tertiary institution. I have clearly stated which parts of my thesis, if any, have been submitted to qualify for another award. I acknowledge that an electronic copy of my thesis must be lodged with the University Library and, subject to the policy and procedures of The University of Queensland, the thesis be made available for research and study in accordance with the Copyright Act 1968 unless a period of embargo has been approved by the Dean of the Graduate School. I acknowledge that copyright of all material contained in my thesis resides with the copyright holder(s) of that material. Where appropriate I have obtained copyright permission from the copyright holder to reproduce material in this thesis and have sought permission from co-authors for any jointly authored works included in the thesis. iii Publications included in this thesis No publication included. iv Submitted manuscripts included in this thesis No manuscripts submitted for publication. v Other publications during candidature Conference abstracts 1. Patharee Oungsakul, Caroline O’Leary, Michelle M. Hill, Helle Bielefeldt-Ohmann, David Duffy. (2019) Identifying visceral haemangiosarcoma related germline variants in dogs using whole exome sequencing [Poster presentation and flash talk oral presentation] Proceeding of the 10th International Conference on Canine and Feline Genetics and Genomics (ICCFGG). May 26 – 29, 2019, Bern, Switzerland. 2. Patharee Oungsakul, Caroline O’Leary, Michelle M. Hill, David Duffy, Helle Bielefeldt- Ohmann. (2018) Genetic variations associated with splenic haemangiosarcoma in the dog [Oral presentation, Best oral presentation] at School of Veterinary Science Research Conference. July 20, 2018, the University of Queensland, Gatton Campus 3. Patharee Oungsakul, Caroline O’Leary, Michelle M. Hill, David Duffy, Helle Bielefeldt- Ohmann. (2017) Validation of candidate glycoprotein biomarkers for canine visceral haemangiosarcoma using semi-quantitative lectin/immunohistochemical assay [Oral presentation] School of Veterinary Science Research Conference. September 15, 2017, the University of Queensland, Gatton Campus. 4. Patharee Oungsakul, Caroline O’Leary, Michelle M. Hill, David Duffy, Helle Bielefeldt- Ohmann. (2016) Improving the detection and prognostication of canine haemangiosarcoma [Oral presentation] Program and Abstract of School of Veterinary Science Research Conference. October 27, 2016, the University of Queensland, Gatton Campus. Manuscripts in preparation 1. Patharee Oungsakul, David Perez Guaita, Alok K. Shah, Eunju Choi, David Duffy, Helle Bielefeldt-Ohmann, Bayden Wood, Michelle M. Hill. Use of FTIR imaging for differential diagnosis of splenic canine hemangiosarcoma. [Manuscript in preparation] 2. Patharee Oungsakul, Eunju Choi, Alok K. Shah, Ahmed Mohamed, Caroline O’Leary, David Duffy, Michelle M. Hill, Helle Bielefeldt-Ohmann. Validation of candidate glycoprotein biomarkers for canine visceral hemangiosarcoma using semi-quantitative lectin/immunohistochemical assays. [Manuscript in preparation] vi Contributions by others to the thesis Dr. Helle Bielefeld-Ohmann has contributed to the conceptual design of this PhD research project and has contributed to the pathologic diagnosis for the
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