ABSTRACT: Leveraging the conserved cancer genomes across mammals has the potential to transform driver gene discovery in orphan cancers. Here, we combine cross-species genomics with validation across human-dog-mouse systems to uncover a new osteosarcoma driver genes. This widely applicable cross-species approach serves as a platform to expedite search of cancer drivers in rare human malignancies offering new targets for cancer therapy.
Project description:Osteosarcomas (OS) have highly chaotic genomes, yet their cancer drivers are poorly defined. Given that cancer genes are conserved among mammals, cross-species genomics of naturally arising cancers opens a powerful approach to identifying oncogenic drivers to broaden the therapeutic opportunities for aggressive cancers. Here, we utilized a dog-to-human cross-species genomics combined with gain- and loss-of-function analysis to uncover novel OS driver genes.
Project description:Dogs develop osteosarcoma (OSA) and the disease process closely resembles that of human OSA. OSA has a poor prognosis in both species and disease free intervals and cure rates have not improved in recent years. Gene expression in canine OSAs was compared with non-tumor tissue utilising next generation RNA sequencing. The data provides novel insights into the molecular mechanisms of OSA in high risk breeds. This knowledge may inform development of prevention and treatment for OSA in dogs and supports the dog as a model of OSA in people.
Project description:Human colorectal cancer (CRC) is one of the better-understood systems for studying the genetics of cancer initiation and progression. To develop a cross-species comparison strategy for identifying CRC causative gene or genomic alterations, we performed array comparative genomic hybridization (aCGH) to investigate copy number abnormalities (CNAs), one of the most prominent lesion types reported for human CRCs, in 10 spontaneously occurring canine CRCs. The results revealed for the first time a strong degree of genetic homology between sporadic canine and human CRCs. First, we saw that between 5 and 22% of the canine genome was amplified/deleted in these tumors, and that, reminiscent of human CRCs, the total altered sequences directly correlated to the tumorâs progression stage, origin, and likely microsatellite instability status. Second, when mapping the identified CNAs onto syntenic regions of the human genome, we noted that the canine orthologs of genes participating in known human CRC pathways were recurrently disrupted, indicating that these pathways might be altered in the canine CRCs as well. Lastly, we observed a significant overlapping of CNAs between human and canine tumors, and tumors from the two species were clustered according to the tumor subtypes but not the species. Significantly, compared with the shared CNAs, we found that species-specific (especially human-specific) CNAs localize to evolutionarily unstable regions that harbor more segmental duplications and interspecies genomic rearrangement breakpoints. These findings indicate that CNAs recurrent between human and dog CRCs may have a higher probability of being cancer-causative, compared with CNAs found in one species only Comparison of human and dog colon cancer CNAs
Project description:Pulmonary metastasis continues to be the most common cause of death in osteosarcoma. Indeed, the 5-year survival for newly diagnosed osteosarcoma patients has not significantly changed in over 20 years. Further understanding of the mechanisms of metastasis and resistance for this aggressive pediatric cancer is necessary. Pet dogs naturally develop osteosarcoma providing a novel opportunity to model metastasis development and progression. Given the accelerated biology of canine osteosarcoma, we hypothesized that a direct comparison of canine and pediatric osteosarcoma expression profiles may help identify novel metastasis-associated tumor targets that have been missed through the study of the human cancer alone. Collectively, these data support the strong similarities between human and canine osteosarcoma and underline the opportunities provided by a comparative oncology approach as a means to improve our understanding of cancer biology and therapy. Profiles of dog osteosarcoma and several normal tissues, single channel design, tumor versus normal
Project description:Our understanding of disease is increasingly informed by changes in gene expression between normal and abnormal tissues. The release of the canine genome sequence in 2005 provided an opportunity to understand health and disease in the dog using investigative techniques including gene expression profiling. Accordingly, we now present a publicly accessible canine normal tissue gene expression database that will streamline the study of canine tissues and facilitate comparative genomic analysis with other mammals. The Affymetrix platform was utilized to catalogue the genetic signatures of normal canine tissues including: liver, kidney, heart, lung, cerebrum, lymph node, spleen, jejunum, pancreas and skeletal muscle. The quality of the database was assessed in several ways. Organ defining gene sets were identified for each tissue and functional enrichment analysis revealed themes consistent with known physio-anatomic functions for each organ. In addition, a comparison of orthologous gene expression between matched canine and human normal tissues uncovered remarkable similarity. Public access and use of this data, using infrastructure identical to that currently in use for human normal tissues, has been established and allows for additional cross-species comparisons. To demonstrate the utility of this dataset, novel canine gene annotations were established based on comparative analysis of dog and human tissue selective gene expression and manual curation of canine probeset mapping. It is expected that this dataset will contribute to more advanced study of disease in the dog and biologically robust biomedical studies that utilize the dog as a model for translational research. 39 pathologically normal organ samples were collected from four dogs, 10 organs from each dog. Organ samples included the pancreas, kidney, liver, lung, heart, skeletal muscle, jejunum, cerebrum, spleen and peripheral lymph node.
Project description:Our understanding of disease is increasingly informed by changes in gene expression between normal and abnormal tissues. The release of the canine genome sequence in 2005 provided an opportunity to understand health and disease in the dog using investigative techniques including gene expression profiling. Accordingly, we now present a publicly accessible canine normal tissue gene expression database that will streamline the study of canine tissues and facilitate comparative genomic analysis with other mammals. The Affymetrix platform was utilized to catalogue the genetic signatures of normal canine tissues including: liver, kidney, heart, lung, cerebrum, lymph node, spleen, jejunum, pancreas and skeletal muscle. The quality of the database was assessed in several ways. Organ defining gene sets were identified for each tissue and functional enrichment analysis revealed themes consistent with known physio-anatomic functions for each organ. In addition, a comparison of orthologous gene expression between matched canine and human normal tissues uncovered remarkable similarity. Public access and use of this data, using infrastructure identical to that currently in use for human normal tissues, has been established and allows for additional cross-species comparisons. To demonstrate the utility of this dataset, novel canine gene annotations were established based on comparative analysis of dog and human tissue selective gene expression and manual curation of canine probeset mapping. It is expected that this dataset will contribute to more advanced study of disease in the dog and biologically robust biomedical studies that utilize the dog as a model for translational research.
Project description:Human colorectal cancer (CRC) is one of the better-understood systems for studying the genetics of cancer initiation and progression. To develop a cross-species comparison strategy for identifying CRC causative gene or genomic alterations, we performed array comparative genomic hybridization (aCGH) to investigate copy number abnormalities (CNAs), one of the most prominent lesion types reported for human CRCs, in 10 spontaneously occurring canine CRCs. The results revealed for the first time a strong degree of genetic homology between sporadic canine and human CRCs. First, we saw that between 5 and 22% of the canine genome was amplified/deleted in these tumors, and that, reminiscent of human CRCs, the total altered sequences directly correlated to the tumor’s progression stage, origin, and likely microsatellite instability status. Second, when mapping the identified CNAs onto syntenic regions of the human genome, we noted that the canine orthologs of genes participating in known human CRC pathways were recurrently disrupted, indicating that these pathways might be altered in the canine CRCs as well. Lastly, we observed a significant overlapping of CNAs between human and canine tumors, and tumors from the two species were clustered according to the tumor subtypes but not the species. Significantly, compared with the shared CNAs, we found that species-specific (especially human-specific) CNAs localize to evolutionarily unstable regions that harbor more segmental duplications and interspecies genomic rearrangement breakpoints. These findings indicate that CNAs recurrent between human and dog CRCs may have a higher probability of being cancer-causative, compared with CNAs found in one species only
Project description:Histiocytic sarcoma (HS) is a highly aggressive malignancy characterized by excessive proliferation of histiocytes in dogs and humans. A subset of dog breeds, including the Bernese mountain dog (BMDs) show a remarkably high prevalence of HS, thus provide opportunities for insight into the molecular pathogenesis of the disease. Previous work by our lab and others has identified somatic driver mutations of HS in the PTPN11 and KRAS genes that activate the MAPK pathway in about 60% of canine HS cases. However, no somatic driver mutations have been identified in the remaining 40%. Here, we report our whole transcriptome analysis of eighteen well-characterized BMD HS tumor tissues, as well as three HS cell lines, allowing us to gain further insight into the molecular basis of HS tumorigenesis. Our analysis reveals significant upregulation of molecular pathways involving the FOXM1, AURKB, PLK1, and E2F genes, providing new information regarding pathways that may be targeted with inhibitors. In addition, we document the expression of multiple checkpoint genes, suggesting the option of treatment with small molecule inhibitors together with checkpoint inhibitors. Further, we show that the transcriptomes of three canine HS cell lines mirror those of canine patient tumors, further highlighting their potential use in drug efficacy studies. Finally, we demonstrate, for the first time, that aurora kinase inhibitors are effective in curtailing growth of HS cells in vitro and show synergism with MAPK inhibition. This study provides the most detailed analysis of the canine HS transcriptome to date, highlighting key pathways in its pathogenesis and suggesting new avenues for both single and combination treatment strategies which may be pertinent to treatment of human HS.
Project description:An integration of several studies normalized to enable consistent cross-study comparisons and enrichment of the less frequent breast cancer types, enabling detection of new potential cancer driver genes.