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Koltookian Michele - One of the best experts on this subject based on the ideXlab platform.
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Data from: A synonymous germline variant in a gene encoding a cell adhesion molecule is associated with cutaneous mast cell tumour development in Labrador and Golden Retrievers
2019Co-Authors: Biasoli Deborah, Compston-garnett Lara, Ricketts Sally, Birand Zeynep, Courtay-cahen Celine, Fineberg Elena, Arendt Maja, Boerkamp Kim, Melin Malin, Koltookian MicheleAbstract:Mast cell tumours are the most common type of skin Cancer in Dogs, representing a significant concern in canine health. The molecular pathogenesis is largely unknown, but breed-predisposition for mast cell tumour development suggests the involvement of inherited genetic risk factors in some breeds. in this study, we aimed to identify germline risk factors associated with the development of mast cell tumours in Labrador Retrievers, a breed with an elevated risk of mast cell tumour development. Using a methodological approach that combined a genome-wide association study, targeted next generation sequencing, and TaqMan genotyping, we identified a synonymous variant in the DSCAM gene on canine chromosome 31 that is associated with mast cell tumours in Labrador Retrievers. DSCAM encodes a cell-adhesion molecule. We showed that the variant has no effect on the DSCAM mRNA level but is associated with a significant reduction in the level of the DSCAM protein, suggesting that the variant affects the dynamics of DSCAM mRNA translation. Furthermore, we showed that the variant is also associated with mast cell tumours in Golden Retrievers, a breed that is closely related to Labrador Retrievers and that also has a predilection for mast cell tumour development. The variant is common in both Labradors and Golden Retrievers and consequently is likely to be a significant genetic contributor to the increased susceptibility of both breeds to develop mast cell tumours. The results presented here not only represent an important contribution to the understanding of mast cell tumour development in Dogs, as they highlight the role of cell adhesion in mast cell tumour tumourigenesis, but they also emphasise the potential importance of the effects of synonymous variants in complex diseases such as Cancer
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A synonymous germline variant in a gene encoding a cell adhesion molecule is associated with cutaneous mast cell tumour development in Labrador and Golden Retrievers
'Public Library of Science (PLoS)', 2019Co-Authors: Biasoli Deborah, Compston-garnett Lara, Birand Zeynep, Courtay-cahen Celine, Fineberg Elena, Boerkamp Kim, Melin Malin, Ricketts, Sally L., Arendt, Maja Louise, Koltookian MicheleAbstract:Mast cell tumours are the most common type of skin Cancer in Dogs, representing a significant concern in canine health. The molecular pathogenesis is largely unknown, but breed-predisposition for mast cell tumour development suggests the involvement of inherited genetic risk factors in some breeds. in this study, we aimed to identify germline risk factors associated with the development of mast cell tumours in Labrador Retrievers, a breed with an elevated risk of mast cell tumour development. Using a methodological approach that combined a genome-wide association study, targeted next generation sequencing, and TaqMan genotyping, we identified a synonymous variant in the DSCAM gene on canine chromosome 31 that is associated with mast cell tumours in Labrador Retrievers. DSCAM encodes a cell-adhesion molecule. We showed that the variant has no effect on the DSCAM mRNA level but is associated with a significant reduction in the level of the DSCAM protein, suggesting that the variant affects the dynamics of DSCAM mRNA translation. Furthermore, we showed that the variant is also associated with mast cell tumours in Golden Retrievers, a breed that is closely related to Labrador Retrievers and that also has a predilection for mast cell tumour development. The variant is common in both Labradors and Golden Retrievers and consequently is likely to be a significant genetic contributor to the increased susceptibility of both breeds to develop mast cell tumours. The results presented here not only represent an important contribution to the understanding of mast cell tumour development in Dogs, as they highlight the role of cell adhesion in mast cell tumour tumourigenesis, but they also emphasise the potential importance of the effects of synonymous variants in complex diseases such as Cancer. Author summary The combination of various genetic and environmental risk factors makes the understanding of the molecular circuitry behind complex diseases, like Cancer, a major challenge. The homogeneous nature of pedigree dog breed genomes makes these Dogs ideal for the identification of both simple disease-causing genetic variants and genetic risk factors for complex diseases. Mast cell tumours are the most common type of canine skin Cancer, and one of the most common Cancers affecting Dogs of most breeds. Several breeds, including Labrador Retrievers (which represent one of the most popular dog breeds), have an elevated risk of mast cell tumour development. Here, by using a methodological approach that combined different techniques, we identified a common inherited synonymous variant, that predisposes Labrador Retrievers to mast cell tumour development. interestingly, we showed that this variant, despite its synonymous nature, appears to have an effect on translation dynamics as it is associated with reduced levels of DSCAM, a cell adhesion molecule. The results presented here reveal dysregulation of cell adhesion to be an important factor in mast cell tumour pathogenesis, and also highlight the important role that synonymous variants can play in complex diseases
Cheryl A London - One of the best experts on this subject based on the ideXlab platform.
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abstract sy28 01 spontaneous Cancer in Dogs opportunities for preclinical evaluation of novel therapies
Cancer Research, 2011Co-Authors: Cheryl A LondonAbstract:Spontaneous Cancers are common in the pet dog population with estimated 60% of Dogs that live to 10 years of age developing neoplasia. These naturally occurring tumors in Dogs possess several clinical and molecular features observed in human Cancers that are challenging to replicate in experimental systems. Therefore, they represent a unique biological resource to answer critical questions in the development of new Cancer diagnostics and therapeutics that are often challenging to evaluate in conventional preclinical models or in human clinical trials (reviewed in [1, 2]). in support of this effort, the NCI has developed the Comparative Oncology Program (http://ccr.nci.nih.gov/resources/cop/) housed within the Center for Cancer Research. The overriding goal of this program is to promote and include companion species with naturally occuring cancesr into preclinical oncology investigations. Components of this program include the Comparative Oncology Trials Consortium (COTC) and the Canine Comparative Oncology and Genomics Consortium (CCOGC). The COTC is an active network of academic comparative oncology centers, centrally managed by the Comparative Oncology Program, that functions to design and execute clinical trials in Dogs with Cancer to assess novel therapies. The primary purpose of the CCOGC is to populate a biospecimen repository (tissue bank) that can be utilized for future molecular and genetic studies of canine Cancers. The COTC has now completed ten studies and several more are scheduled to begin in the next year. Examples include “Evaluation of RGD Targeted Delivery of Phage Expressing TNF-alpha to Tumor Bearing Dogs” and “Evaluation of Immunocytokine Fusion Proteins in Dogs.” The biospecimen repository is now close to being sufficiently populated and release of samples is expected to begin within the next year. Together, these efforts have markedly enhanced the incorporation of Dogs into studies intended to support the development of novel treatment strategies for human Cancers. Several factors contribute to the suitability of spontaneous canine Cancers as a model for human disease. Dogs are an outbred population exposed to environmental factors known to contribute to carcinogenesis, and as such, their tumors closely recapitulate the heterogeneity and tumor-stromal interactions found in human tumors. Unlike most rodent models, Cancers in Dogs consistently exhibit spontaneous metastases and resistance to standard therapeutics including chemotherapy, immunotherapy and radiation therapy. Furthermore, similar druggable targets, angiogenic pathways, and mechanisms of apoptosis are present in dog Cancers (3-6). Dogs that develop Cancer possess an intact immune system shaped by both age and previous immune exposure, permitting a more accurate assessment of immunotherapeutic approaches when compared to rodent models. Importantly, given their larger size, diagnostic imaging (PET/CT, MRI) and treatment modalities typically used in humans (hypofractionated radiation therapy), can be routinely employed. Essential for the evaluation of novel therapeutics, the large size of Dogs provides an opportunity for repeated tissue and fluid sampling over time with more abundant tissue for analysis than that available in rodent models. A significant challenge associated with many human Cancer clinical trials, particularly in the early phases, is the fact that patients have often undergone several prior therapeutic regimens, and as such are heavily pretreated prior to study entry. They may also have significant tumor burdens and a lower performance status thereby influencing the spectrum of clinical toxicities observed. in contrast, clinical trials in pet Dogs are performed using a patient population that is less heavily pretreated, has a higher performance status, and exhibits less acquired resistance providing an opportunity to evaluate a novel treatment approach in a setting more likely to demonstrate activity. A feature unique to trials in Dogs is that toxicity studies are initially performed in normal laboratory Dogs permitting subsequent evaluation in pet Dogs with Cancer to be initiated close to the predicted maximum tolerated dose, resulting in a more rapid toxicity to activity assessment than occurs in human clinical trials. Lastly, the lack of established standards of care for the treatment of canine Cancer allows for early evaluation of therapies in the minimal residual disease setting, providing insight into how a particular treatment may perform in a naturally occurring microscopic metastatic model. The use of spontaneous Cancer in Dogs to inform the human drug development path is not new. Dogs with lymphoma were used for several years to develop protocols for autologous bone marrow transplantation that are currently used in human patients. More recently, a variety of clinical trials have been undertaken in Dogs with Cancer that have directly impacted human drug development. These include evaluation of the multitargeted receptor tyrosine kinase inhibitor SU11654 in Dogs with Cancer (7, 8), targeted AAV-phage vector delivering tumor necrosis factor (RGD-A-TNF) to alphaV integrins on tumor endothelium (9), assessment of the novel acyclic nucleotide analog GS-9219 in Dogs with non-Hodgkin9s lymphoma (10, 11), and development of a xenogeneic tyrosinase DNA vaccine for melanoma (12-14). Such studies have helped to define clinical toxicities and safety of targeted therapeutics, to establish pharmacokinetic and pharmacodynamic relationships, and to identify dosing regimens most likely to demonstrate clinical activity. These efforts have laid the groundwork for enhanced integration of Dogs with naturally occurring tumors into the development path for new Cancer diagnostics and therapeutics. Such an approach has the potential not only to serve as an important bridge from rodent systems to humans, but to assist in the optimization of subsequent human clinical trials. References 1. C. Khanna et al., Nat Biotechnol 24, 1065 (Sep, 2006). 2. C. Khanna, C. London, D. Vail, C. Mazcko, S. Hirschfeld, Clin Cancer Res 15, 5671 (Sep 15, 2009). 3. S. L. Fossey et al., BMC Cancer 9, 81 (2009). 4. M. S. Kent, C. J. Collins, F. Ye, Am J Vet Res 70, 263 (Feb, 2009). 5. J. Kirpensteijn, M. Kik, E. Teske, G. R. Rutteman, Vet Surg 37, 454 (Jul, 2008). 6. C. A. London et al., Exp Hematol 27, 689 (Apr, 1999). 7. C. A. London et al., Clin Cancer Res 9, 2755 (Jul, 2003). 8. N. K. Pryer et al., Clin Cancer Res 9, 5729 (Nov 15, 2003). 9. M. C. Paoloni et al., PLoS One 4, e4972 (2009). 10. H. Reiser et al., Clin Cancer Res 14, 2824 (May 1, 2008). 11. D. M. Vail et al., Clin Cancer Res 15, 3503 (May 15, 2009). 12. P. J. Bergman et al., Vaccine 24, 4582 (May 22, 2006). 13. P. J. Bergman et al., Clin Cancer Res 9, 1284 (Apr, 2003). 14. J. C. Liao et al., Cancer Immun 6, 8 (2006). Citation Format: {Authors}. {Abstract title} [abstract]. in: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY28-01. doi:10.1158/1538-7445.AM2011-SY28-01
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abstract ia5 1 spontaneous Cancer in Dogs opportunities for preclinical investigation of novel therapeutics
Clinical Cancer Research, 2010Co-Authors: Cheryl A LondonAbstract:Spontaneous Cancers occur commonly in the pet dog population. indeed, an estimated 60% of Dogs that live to 10 years of age will develop some form of neoplasia. These naturally occurring tumors in Dogs exhibit several clinical and molecular similarities to human Cancers that are challenging to replicate in experimental systems. As such, they represent a unique opportunity to answer critical questions in the development of new Cancer diagnostics and therapeutics that are difficult to evaluate in conventional preclinical models or in human clinical trials (reviewed in [1, 2]) in support of this effort, the National Cancer institute has initiated the Comparative Oncology Program (http://ccr.nci.nih.gov/resources/cop/) within the Center for Cancer Research, which is designed to promote and include companion species with spontaneous Cancer in preclinical oncology investigations. Components of this program include the Comparative Oncology Trials Consortium (COTC) and the Canine Comparative Oncology and Genomics Consortium (CCOGC). The COTC is an active network of academic comparative oncology centers, centrally managed by the Comparative Oncology Program, that functions to design and execute clinical trials in Dogs with Cancer to assess novel therapies. The primary purpose of the CCOGC is to develop a biospecimen repository that can be utilized for future molecular and genetic studies of canine Cancers. Together, these efforts have markedly enhanced the incorporation of Dogs into studies intended to support the development of novel treatment strategies for human Cancers. Several factors contribute to the suitability of spontaneous canine Cancers as a model. Dogs are an outbred population and as such, their tumors recapitulate the heterogeneity and tumor-stromal interactions found in human tumors. Unlike most rodent models, Cancer in Dogs reliably exhibits spontaneous metastases and resistance to standard therapeutics. Furthermore, similar druggable targets, angiogenic pathways, and mechanisms of apoptosis are present in dog Cancers (3-6). Dogs possess an intact immune system permitting a reliable assessment of immunotherapeutic approaches. Given their larger size, diagnostic imaging and treatment modalities typically used in humans (e.g., radiation therapy), can be routinely employed. Additionally, their size provides an opportunity for repeated tissue and fluid sampling over time with more abundant tissue for analysis than that available in rodent models. One of the challenges of human Cancer clinical trials is the fact that many patients have undergone several prior therapeutic regimens, and as such are often heavily pretreated prior to study entry. in contrast, clinical trials in pet Dogs are performed using a patient population that is less heavily pretreated, has a higher performance status, and exhibits less acquired resistance providing an opportunity to evaluate a novel treatment approach in a setting more likely to demonstrate activity. As toxicity studies are initially performed in normal laboratory Dogs, subsequent studies in pet Dogs with Cancer can be initiated at doses close to the predicted maximum tolerated dose, permitting rapid toxicity to activity assessments. Lastly, the lack of established standards of care for the treatment of canine Cancer allows for early evaluation of therapies in the minimal residual disease setting, providing insight into how a particular treatment may perform in a naturally occurring microscopic metastatic model. The concept of utilizing Cancer in Dogs to inform the human drug development path is not new. For example, Dogs with lymphoma were used to develop protocols for autologous bone marrow transplantation currently used in human patients. More recently, a variety of clinical trials have been undertaken in Dogs with Cancer that have directly impacted human drug development. These include evaluation of the multitargeted receptor tyrosine kinase inhibitor SU11654 in Dogs with Cancer (7, 8), targeted AAV-phage vector delivering tumor necrosis factor (RGD-A-TNF) to alphaV integrins on tumor endothelium (9), assessment of the novel acyclic nucleotide analog GS-9219 in Dogs with non-Hodgkin9s lymphoma (10,11), and development of a xenogeneic tyrosinase DNA vaccine for melanoma (12-14). Such studies have helped to define clinical toxicities and safety of targeted therapeutics, establish pharmacokinetic/pharmacodynamic relationships, and identify dosing regimens most likely to demonstrate clinical activity. These efforts have laid the groundwork for enhanced integration of Dogs with naturally occurring tumors into the development path for new Cancer diagnostics and therapeutics. Such an approach has the potential not only to serve as an important bridge from rodent systems to humans, but to assist in the optimization of subsequent human clinical trials. References: 1. Khanna C et al. Nat Biotechnol. 2006;24:1065. 2. Khanna C, London C, Vail D, Mazcko C, Hirschfeld S. Clin Cancer Res. 2009;15:5671. 3. Fossey SL et al. BMC Cancer. 2009;9:81. 4. Kent MS, Collins CJ, Ye F. Am J Vet Res. 2009;70:263. 5. Kirpensteijn J, Kik M, Teske E, Rutteman GR. Vet Surg. 2008;37:454. 6. London CA et al. Exp Hematol. 1999;27:689. 7. London CA et al. Clin Cancer Res. 2003;9:2755. 8. Pryer NK et al. Clin Cancer Res. 2003;9:5729. 9. Paoloni MC et al. PLoS One. 2009;4:e4972. 10. Reiser H et al. Clin Cancer Res. 2008;14:2824. 11. Vail DM et al. Clin Cancer Res. 2009;15:3503. 12. Bergman PJ et al. Vaccine. 2006;24:4582. 13. Bergman PJ et al. Clin Cancer Res. 2003;9:1284. 14. Liao JC et al. Cancer Immun. 2006;6:8. Citation information: Clin Cancer Res 2010;16(14 Suppl):IA5-1.
Kirsten E Young - One of the best experts on this subject based on the ideXlab platform.
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urinary bladder Cancer in Dogs a naturally occurring model for Cancer biology and drug development
Ilar Journal, 2014Co-Authors: Deborah W Knapp, Jose A Ramosvara, George E Moore, Deepika Dhawan, Patty L Bonney, Kirsten E YoungAbstract:Each year more than 65,000 people are diagnosed with urinary bladder Cancer, and more than 14,000 people die from the disease in the United States. Studies in relevant animal models are essential to improve the management of bladder Cancer. Naturally occurring bladder Cancer in Dogs very closely mimics human invasive bladder Cancer, specifically high-grade invasive transitional cell carcinoma (TCC; also referred to as invasive urothelial carcinoma) in cellular and molecular features; biological behavior, including sites and frequency of metastasis; and response to therapy. Canine bladder Cancer complements experimentally induced rodent tumors in regard to animal models of bladder Cancer. Results of cellular and molecular studies and -omics analyses in Dogs are expected to lead to improved detection of TCC and preneoplastic lesions, earlier intervention, better prediction of patient outcome, and more effective TCC management overall. Studies in Dogs are being used to help define heritable risks (through very strong breed-associated risk) and environment risks and to evaluate prevention and treatment approaches that benefit humans as well as Dogs. Clinical treatment trials in pet Dogs with TCC are considered a win-win scenario by clinician scientists and pet owners. The individual dog benefits from effective treatment, the results are expected to help other Dogs, and the findings are expected to ultimately help humans with TCC. This article provides an overview of canine TCC, a summary of the similarities and differences between canine and human invasive TCC, and examples of the types of valuable translational research that can be done using Dogs with naturally occurring TCC.
Biasoli Deborah - One of the best experts on this subject based on the ideXlab platform.
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Data from: A synonymous germline variant in a gene encoding a cell adhesion molecule is associated with cutaneous mast cell tumour development in Labrador and Golden Retrievers
2019Co-Authors: Biasoli Deborah, Compston-garnett Lara, Ricketts Sally, Birand Zeynep, Courtay-cahen Celine, Fineberg Elena, Arendt Maja, Boerkamp Kim, Melin Malin, Koltookian MicheleAbstract:Mast cell tumours are the most common type of skin Cancer in Dogs, representing a significant concern in canine health. The molecular pathogenesis is largely unknown, but breed-predisposition for mast cell tumour development suggests the involvement of inherited genetic risk factors in some breeds. in this study, we aimed to identify germline risk factors associated with the development of mast cell tumours in Labrador Retrievers, a breed with an elevated risk of mast cell tumour development. Using a methodological approach that combined a genome-wide association study, targeted next generation sequencing, and TaqMan genotyping, we identified a synonymous variant in the DSCAM gene on canine chromosome 31 that is associated with mast cell tumours in Labrador Retrievers. DSCAM encodes a cell-adhesion molecule. We showed that the variant has no effect on the DSCAM mRNA level but is associated with a significant reduction in the level of the DSCAM protein, suggesting that the variant affects the dynamics of DSCAM mRNA translation. Furthermore, we showed that the variant is also associated with mast cell tumours in Golden Retrievers, a breed that is closely related to Labrador Retrievers and that also has a predilection for mast cell tumour development. The variant is common in both Labradors and Golden Retrievers and consequently is likely to be a significant genetic contributor to the increased susceptibility of both breeds to develop mast cell tumours. The results presented here not only represent an important contribution to the understanding of mast cell tumour development in Dogs, as they highlight the role of cell adhesion in mast cell tumour tumourigenesis, but they also emphasise the potential importance of the effects of synonymous variants in complex diseases such as Cancer
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A synonymous germline variant in a gene encoding a cell adhesion molecule is associated with cutaneous mast cell tumour development in Labrador and Golden Retrievers
'Public Library of Science (PLoS)', 2019Co-Authors: Biasoli Deborah, Compston-garnett Lara, Birand Zeynep, Courtay-cahen Celine, Fineberg Elena, Boerkamp Kim, Melin Malin, Ricketts, Sally L., Arendt, Maja Louise, Koltookian MicheleAbstract:Mast cell tumours are the most common type of skin Cancer in Dogs, representing a significant concern in canine health. The molecular pathogenesis is largely unknown, but breed-predisposition for mast cell tumour development suggests the involvement of inherited genetic risk factors in some breeds. in this study, we aimed to identify germline risk factors associated with the development of mast cell tumours in Labrador Retrievers, a breed with an elevated risk of mast cell tumour development. Using a methodological approach that combined a genome-wide association study, targeted next generation sequencing, and TaqMan genotyping, we identified a synonymous variant in the DSCAM gene on canine chromosome 31 that is associated with mast cell tumours in Labrador Retrievers. DSCAM encodes a cell-adhesion molecule. We showed that the variant has no effect on the DSCAM mRNA level but is associated with a significant reduction in the level of the DSCAM protein, suggesting that the variant affects the dynamics of DSCAM mRNA translation. Furthermore, we showed that the variant is also associated with mast cell tumours in Golden Retrievers, a breed that is closely related to Labrador Retrievers and that also has a predilection for mast cell tumour development. The variant is common in both Labradors and Golden Retrievers and consequently is likely to be a significant genetic contributor to the increased susceptibility of both breeds to develop mast cell tumours. The results presented here not only represent an important contribution to the understanding of mast cell tumour development in Dogs, as they highlight the role of cell adhesion in mast cell tumour tumourigenesis, but they also emphasise the potential importance of the effects of synonymous variants in complex diseases such as Cancer. Author summary The combination of various genetic and environmental risk factors makes the understanding of the molecular circuitry behind complex diseases, like Cancer, a major challenge. The homogeneous nature of pedigree dog breed genomes makes these Dogs ideal for the identification of both simple disease-causing genetic variants and genetic risk factors for complex diseases. Mast cell tumours are the most common type of canine skin Cancer, and one of the most common Cancers affecting Dogs of most breeds. Several breeds, including Labrador Retrievers (which represent one of the most popular dog breeds), have an elevated risk of mast cell tumour development. Here, by using a methodological approach that combined different techniques, we identified a common inherited synonymous variant, that predisposes Labrador Retrievers to mast cell tumour development. interestingly, we showed that this variant, despite its synonymous nature, appears to have an effect on translation dynamics as it is associated with reduced levels of DSCAM, a cell adhesion molecule. The results presented here reveal dysregulation of cell adhesion to be an important factor in mast cell tumour pathogenesis, and also highlight the important role that synonymous variants can play in complex diseases
Jong Hyuk Kim - One of the best experts on this subject based on the ideXlab platform.
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pik3ca mutations matter for Cancer in Dogs
Research in Veterinary Science, 2020Co-Authors: Jong Hyuk KimAbstract:Abstract Cancer is a genetic disease that arises from the accumulation of genetic mutations within a cell. Mutations in PIK3CA gene are frequently observed in human solid Cancers, and also appear to occur in canine tumors. Specifically, recurrent somatic PIK3CA variants identified in canine mammary tumors and hemangiosarcomas are comparable to human hotspot mutations such as H1047R. PIK3CA mutations found in canine tumors encode functional proteins that may alter downstream PI3K/Akt/mTOR signaling pathway. Therefore, PI3K inhibitors have potential in Cancer therapy for Dogs. This article concisely reviews the emerging evidence concerning the genetic and molecular properties of PIK3CA mutations to discuss future perspectives in veterinary and comparative oncology.
