Download lymphomas in dogs - spontaneous models to decipher the genetics

LYMPHOMAS IN DOGS: SPONTANEOUS MODELS TO DECIPHER
THE GENETICS OF LYMPHOMAGENESIS IN DOGS AND HUMANS
Ronan Ulvé1,2*, Benoit Hédan1,2*, Edouard Cadieu1,2, Clotilde De Brito1,2, Anne Sophie Guillory1,2, Patrick Devauchelle3, Jocelyn
Plassais1,2, Frédérique Nguyen4, Jérome Abadie4, Laëtitia Lagoutte1,2, Nadine Botherel1,2 and Catherine André1,2
1 CNRS, UMR 6290, Institut de Génétique et Développement de Rennes, 2 Avenue du Pr. Leon Bernard, 35000 Rennes, France. 2 Université Rennes 1, UEB, IFR140, Faculté de Médecine, 2 Avenue du Pr. Leon Bernard,
35000 Rennes, France. 3 Centre de Cancérologie Vétérinaire, MICEN Vet 58 rue Auguste Perret, 94000 Creteil, France 4 LUNAM University, ONIRIS, AMaROC, Ecole Nationale Vétérinaire, Agroalimentaire et de
l’Alimentation Nantes Atlantique, 44307 Nantes, France. * Both author equally contributed
The interest of the dog as a spontaneous genetic model:
- 350 breeds:
-  high inter-breed variability
Breed = Genetic isolate
-  high intra-breed genetic homogeneity
- Breeding practices: •  drastic selection
Founder
•  inbreeding
High breed predisposition
mutations
•  popular sire effect
- Most of dog’s cancers are: -  Animal species with best medical care 1. Spontaneous
-  Easy access to large kindred & numerous biological samples
2. With breed predisposition -  Physiology close to human
3. Homologous to human cancers
Powerful model for searching genes implicated in human cancers
Research of predisposing & tumor progression genes in cancers:
Human: Dog:
  Complex & multifactorial disease
(environment / genetics)
  Genetic heterogeneity
  Very rare familial cases
  Difficult access to samples
USE OF GENETIC MODEL
  Breed predisposition with high frequencies
  Breeds predisposed specifically to one type   Familial forms
  Easy recruitment & access to samples
Simplifed genetic studies
Complex genetic studies
2
Lymphoma project: 1 Sample collection : 3
Blood and tissue samples (tumor & healthy) of Bernese Mountain Dogs (BMD). 2153 blood and > 900 tissue samples.
Pedigree analysis : A portion of 241 dogs of the BMD family
segregating lymphoma.
4
Histological characterization : 25 µm
60 µm
⇒ Most of the tumors are B lymphoma type 60 µm
60 µm
Histological characteristics of (A) DLBCL (Hematoxylin-EosinSafran stain, (B) B-cell lymphoma (CD20+), (C) T-cell lymphoma
(CD3+) and (D) B-cell lymphoma proliferation (Ki-67)
pvalue Genome wide association Level of study (GWAS):
significance Chr23 Genotyping of BMD on 170 000 SNP
chips (Illumina) :
46 cases and 156 controls (old healthy
dogs)
Manhattan plot : each dot corresponds to one
SNP ordered from chr 1 to chr 38 and X.
Each color represents a chromosome.
⇒ 1% of collaterals are diagnosed with lymphomas
38 canine chromosomes + X Conclusion and Prospects: - Collection of many lymphoma types in many breeds : CaniDNA biobank http://dog-genetics.genouest.org
- Identification of familial transmission of lymphoma in BMD
- Genetic analysis (GWAS) and gene expression studies (RNAseq) are performed to decipher the genetics of dog lymphoma
- Identification of allelic combinations predisposing to specific lymphoma types
transfer to human homologous types
- Identification of prediction markers and therapeutic target preclinical trials on dogs
This work has been funded by the CNRS (Centre National de la Recherche Scientifique) and INCa (Institut National du Cancer).
Authors want to thank veterinary pathology labs (LAPVSO, Toulouse ; IDEXX, Paris ; LHA, Nantes and others), veterinarians, breeders and dog owners.