Comparative Genomics Reveals Shared Mutational Landscape in Canine Hemangiosarcoma and Human Angiosarcoma

Megquier, Kate; Turner-Maier, Jason; Swofford, Ross; Kim, Jong Hyuk; Sarver, Aaron L.; Wang, Chao; Sakthikumar, Sharadha; Johnson, Jeremy; Koltookian, Michele; Lewellen, Mitzi; Scott, Milcah C.; Schulte, Ashley J.; Borst, Luke B.; Tonomura, Noriko; Alföldi, Jessica; Painter, Corrie; Thomas, Rachael; Karlsson, Elinor K.; Breen, Matthew; Modiano, Jaime F.; Elvers, Ingegerd; Lindblad‐Toh, Kerstin

doi:10.1158/1541-7786.mcr-19-0221

Cited by 87 publications

(132 citation statements)

References 61 publications

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“…Over the past decade, the Dog has arisen as a relevant and under used spontaneous model for the analysis of cancer predisposition and progression, as well as development and trials of more efficient therapies for a number of human cancers [1][2][3][4][5][6][7][8][9][10] . With over 4.2 million dogs diagnosed with cancer annually in USA 8 , canine cancers represent a unique source of spontaneous tumors.…”

Section: Introductionmentioning

confidence: 99%

The tree that hides the forest: identification of common predisposing loci in several hematopoietic cancers and several dog breeds

Hédan¹,

Cadieu²,

Rimbault³

et al. 2020

Preprint

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Histiocytic sarcoma (HS) is a rare but aggressive cancer in humans and dogs. The spontaneous canine model, with the clinical, epidemiological and histological similarities with human HS and specific breed predispositions, is a unique model/opportunity to unravel the genetic bases of this cancer. In this study, we aimed to identify germline risk factors associated with the development of HS in canine predisposed breeds. We used a methodology that combined several genome-wide association studies in a multi-breed and multi-cancer approach, as well as targeted next generation sequencing, and imputation combining several breeds (Bernese mountain dog, Rottweiler, flat coated retriever and golden retriever) and three haematopoietic cancers (HS, lymphoma and mast cell tumor). Results showed that we not only refined the previously identified HS risk CDKN2A locus but we identified new loci on canine chromosomes 2, 5, 12, 14, 20, 26 and X. Capture and targeted sequencing of specific loci pointed towards the existence of regulatory variants in non coding regions and/or methylation mechanisms linked to risk haplotypes, leading to strong cancer predispositions in specific dog breeds. Our results showed that these canine cancer predisposing loci appear to be due to the additive effect of several risk haplotype involved also in other haematopoietic cancers such lymphoma or mast cell tumor, illustrating the pleiotropic nature of these canine cancer loci as observed in human oncology, thus reinforcing the interest of predisposed dog breeds to study cancer initiation and progression.

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Section: Introductionmentioning

confidence: 99%

The tree that hides the forest: identification of common predisposing loci in several hematopoietic cancers and several dog breeds

Hédan¹,

Cadieu²,

Rimbault³

et al. 2020

Preprint

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“…We performed a rigorous quality control (QC) on the WES data published for 601 canine cases. The 601 canine cases consist of over six cancer types, including mammary cancer 13 , oral melanoma 11 , osteosarcoma 15 , lymphoma 16 , glioma 12 and hemangiosarcoma 17 (Table S1). They represent over 35 breeds (Table S1A).…”

Section: Resultsmentioning

confidence: 99%

“…They represent over 35 breeds (Table S1A). Their WES data were generated by different groups, using different exome-capturing kits and Illumina sequencing machines [11][12][13][15][16][17] . We hence performed a rigorous QC to ensure that each study met a set of quality standards before any further integrative analysis.…”

Section: Resultsmentioning

confidence: 99%

“…To answer these questions, we performed a pan-cancer and pan-breed study with 710 canine cases with public whole exome sequencing (WES) and/or whole genome sequencing (WGS) data [11][12][13][14][15][16][17][18][19][20][21][22] . We used 601 cases with WES data [11][12][13][15][16][17] for discovery, and 18 with WES data 18,23 and 91 with WGS data [18][19][20][21][22] for validation. We also compared our canine findings to those published for the corresponding human cancers 3,4,[24][25][26][27] .…”

Section: Introductionmentioning

confidence: 99%

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Canine tumor mutation rate is positively correlated with TP53 mutation across cancer types and breeds

Alsaihati

Watson

et al. 2020

Preprint

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Spontaneous canine cancers are a valuable but relatively understudied and underutilized model in cancer research. To enhance their usage, we reanalyzed whole exome sequencing data published for 601 dogs with mammary cancer, osteosarcoma, oral melanoma, lymphoma, glioma or hemangiosarcoma from over 35 breeds, after rigorous quality control, including breed validation. Each cancer type harbors distinct molecular features, with major pathway alterations matching its human counterpart (e.g., PI3K for mammary cancer and p53 for osteosarcoma). On average, mammary cancer and glioma have lower mutation rates (median <0.5 mutation per Mb), whereas oral melanoma, osteosarcoma and hemangiosarcoma have higher mutation rates (median ≥1 mutation per Mb). Across cancer types and across breeds, the mutation rate is strongly associated with TP53 mutation, but not with PIK3CA mutation. The mutation rate is also associated with a mutation signature enriched in osteosarcoma of Golden Retrievers, independent of TP53 mutation. Finally, compared to other breeds examined, DNA repair genes appear to be less conserved in Golden Retriever which is predisposed to numerous cancers.

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“…number gains in KDR (31% in human, 22% in canine) and KIT (17% in both) [15]. These genome-wide studies reveal that, while specific genetic aberrations are associated with HSA in some populations, these alterations are not sufficient to explain the majority of HSA cases.…”

mentioning

confidence: 94%

Chromatin run-on sequencing analysis finds that ECM remodeling plays an important role in canine hemangiosarcoma pathogenesis

Mukai

Choi

Sams

et al. 2020

Preprint

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Background Canine visceral hemangiosarcoma (HSA) is a highly aggressive cancer of endothelial origin that closely resembles visceral angiosarcoma in humans, both clinically and histopathologically. Currently there is an unmet need for new diagnostics and therapies for both forms of this disease. The goal of this study was to utilize ChRO-seq and immunohistochemistry (IHC) to identify gene and protein expression signatures that may be important drivers of HSA progression. Methods Chromatin run-on sequencing (ChRO-seq) was performed on tissue isolated from 17 HSA samples and 4 normal splenic samples. Computational analysis was then used to identify differentially expressed genes and these factors were subjected to gene ontology analysis. Next, RT-PCR was performed on a subset of candidate genes to validate the ChRO-seq data. We then performed Masson’s trichrome, H&E, and IHC staining on these tissues to investigate morphological features of HSA tumor tissue as well as the expression patterns of several proteins identified in our ChRO-seq analysis. Results ChRO-seq analysis revealed over a thousand differentially expressed genes in HSA tissue compared with normal splenic tissue (FDR <0.005). Interestingly, the majority of genes overexpressed in HSA tumor tissue were associated with extracellular matrix (ECM) remodeling. This observation correlated well with our histological analysis, which found that HSA tumors contain a rich and complex collagen network. Additionally, we characterized the protein expression patterns of two highly overexpressed molecules identified in ChRO-seq analysis, podoplanin (PDPN) and laminin alpha 4 (LAMA4). We found that the expression of these two ECM-associated factors appeared to be largely limited to transformed endothelial cells within the HSA lesions. Conclusion Outcomes from this study suggest that ECM remodeling plays an important role in HSA progression. Additionally, our study identified two potential novel biomarkers of HSA, PDPN and LAMA4. Interestingly, given that function-blocking anti-PDPN antibodies have shown anti-tumor effects in mouse models of canine melanoma, our studies raise the possibility that these types of therapeutic strategies could potentially be developed for treating canine HSA.

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Comparative Genomics Reveals Shared Mutational Landscape in Canine Hemangiosarcoma and Human Angiosarcoma

Cited by 87 publications

References 61 publications

The tree that hides the forest: identification of common predisposing loci in several hematopoietic cancers and several dog breeds

The tree that hides the forest: identification of common predisposing loci in several hematopoietic cancers and several dog breeds

Canine tumor mutation rate is positively correlated with TP53 mutation across cancer types and breeds

Chromatin run-on sequencing analysis finds that ECM remodeling plays an important role in canine hemangiosarcoma pathogenesis

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