Clonal origin and evolution of a transmissible cancer.
The transmissible agent causing canine transmissible venereal tumor (CTVT) is thought to be the tumor cell itself. To test this hypothesis, we analyzed genetic markers including major histocompatibility (MHC) genes, microsatellites, and mitochondrial DNA (mtDNA) in naturally occurring tumors and matched blood samples. In each case, the tumor is genetically distinct from its host. Moreover, tumors collected from 40 dogs in 5 continents are derived from a single neoplastic clone that has diverged into two subclades. Phylogenetic analyses indicate that CTVT most likely originated from a wolf or an East Asian breed of dog between 200 and 2500 years ago. Although CTVT is highly aneuploid, it has a remarkably stable genotype. During progressive growth, CTVT downmodulates MHC antigen expression. Our findings have implications for understanding genome instability in cancer, natural transplantation of allografts, and the capacity of a somatic cell to evolve into a transmissible parasite.
Murgia
Claudio
C
MRC/UCL Centre for Medical Molecular Virology, Division of Infection and Immunity, University College London, 46 Cleveland Street, London W1T 4JF, UK.
Pritchard
Jonathan K
JK
Kim
Su Yeon
SY
Fassati
Ariberto
A
Weiss
Robin A
RA
D000782:Aneuploidy; D000818:Animals; D001483:Base Sequence; D046028:Canidae / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics*; D002999:Clone Cells / Q000166:cytology / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics; D004283:Dog Diseases / Q000235:genetics* / Q000635:transmission*; D004285:Dogs; D015536:Down-Regulation / Q000235:genetics; D019143:Evolution, Molecular; D005260:Female; D005819:Genetic Markers; D042822:Genomic Instability / Q000235:genetics; D005838:Genotype; D006649:Histocompatibility Antigens / Q000235:genetics; D007108:Immune Tolerance / Q000235:genetics; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008969:Molecular Sequence Data; D010802:Phylogeny; D012726:Sexual Behavior, Animal; D014685:Venereal Tumors, Veterinary / Q000235:genetics*
D004272:DNA, Mitochondrial; D005819:Genetic Markers; D006649:Histocompatibility Antigens