Authors Benoit Hédan (1), Mélanie Rault (1), Ronan Ulvé (1,2), Aline Primot (1), Edouard Cadieu (1), Clotilde de Brito (1), Nadine Botherel (1), Maud Rimbault (1), Jérôme Abadie (3), Anne-Sophie Guillory (1), Anais Prouteau (1), Amaury Vaysse (1), Patrick Devauchelle (4), Annabelle Garand (1), Celine Le Beguec (1), Laetitia Lagoutte(1), Valentin Wucher (1), David Gilot (1), Thomas Derrien (1), Christophe Hitte (1) and Catherine André (1)
Affiliations 1 Institut Génétique et Développement de Rennes, CNRS-UMR6290, University Rennes1, 35000 Rennes, France 2 BIOTRIAL Pharmacology, Unite de pharmacologie préclinique, 7-9 rue Jean-Louis Bertrand, 35000 Rennes, France. 3 ONIRIS, AMaROC, Ecole Nationale Vétérinaire, Agroalimentaire et de l’Alimentation Nantes Atlantique, 44307 Nantes, France. 4 Centre de Cancérologie Vétérinaire, MICEN Vet 58 rue Auguste Perret, 94000 Creteil, France.
Presentation Type Talk
Abstract
Through the French Cani-DNA biobank, developed in the team since 2005, we have collected over 3000 samples (blood and paired tumour/normal tissues) form many dogs affected by breed specific cancers, as well as controls of the same breeds, for which there are specific issues in the human corresponding cancers. Indeed, naturally occurring canine cancers are recently receiving attention in comparative oncology because of their high similarity to human cancers both in their clinical and histological presentations as well as in their response to treatments.
We have constituted large collections of cases and controls as well as large family pedigrees and through genome wide association studies (GWAS) and genetic linkage approaches, we have identified predisposition loci for Histiocytic Sarcoma (HS) and oral melanomas. In parallel, through the search of somatic genetic alterations in the tumour (whole exome sequence -WES-; capture/sequencing and RNAseq techniques), we have identified relevant genetic alterations in canine lymphomas, sarcomas, melanomas and gliomas. Either we found new genes implicated in dogs and we could identify the same genes in the corresponding human cancers, or we found already known genes, especially oncogenes with the same hotspots than in humans, as well as gene fusions with the same partners and the same over-expression mechanism than in humans, for lymphoma, sarcoma and glioma (Ulvé, Rault et al., 2017). We have identified such genes and their pathogenic somatic alterations for HS (TP53 and a MAPK oncogene), melanomas (over 50 genes, including PTEN, NRAS), lymphomas (26 genes, including cyclins) and gliomas (a BRAF-MBP fusion). For oral melanomas, we also have identified specific Copy Number alterations (CNA) that we showed to be significantly linked to survival.
Finally, we developed cell lines for these canine cancers (8 for HS, 10 for oral and uveal melanomas, 2 for gliomas and 1 for lymphoma), and were able to demonstrate the effect on proliferation, of drugs targeting genes coding for MAPK pathway oncogenes and cyclin genes, for HS and lymphomas respectively. We thus showed that canine cancers might be highly useful for clinical trials, as in vitro and in vivo models to screen drugs in dog/human homologous cancers, prior to test them in humans, in the frame of the treatment of the dogs and with the owner partnership and consent. Finally, to also benefit breeders, we also developed a genetic risk test for Histiocytic Sarcoma, made of 9 markers predictive of a “protective” or “at risk” haplotype and status, available for breeders to help their selection against HS in the Bernese Mountain Dog breed.
To conclude, these genetic findings bring a better understanding of the genetics and potential treatments for dog but also for human medicine. More widely, these results show the interest of the dog model to decipher the genetic bases and plan clinical trials in dogs for rare and/or aggressive-refractory human cancers.