Sunday, January 26, 2014

Genomics and immune evasion in a transmissible dog cancer

Nature and several other news sources describe gene sequencing of Canine Transmissible Venereal Tumor (CTVT), a sexually transmitted neoplasm which has spread among dogs worldwide. Transmissible cancers are extremely rare;  usually, tumor cells transplanted from one individual to the other are quickly recognized by the immune system. The other well-known example of a transmissible tumor is the Tasmanian Devil facial tumor disease.
Evasion of the immune system by transmissible tumors.
Tasmanian Devil facial tumor (A) is not recognized as foreign
because the species has too little diversity in MCH I and II 
genes. CTVT temporarily succeeds in escaping detection
through lower MHC I expression and by secreting the
immune response suppressant TGFbeta .
Figure credit: E.P. Murchison, Oncogene 2007.
This tumor is indeed derived from one single dog, and has somehow managed to survive and propagate among all kinds of dogs. One clue to its possible evasion of the immune system is that it downregulates the major histocompatibility (MHC) genes, which are used by the immune system to distinguish self from non-self cells. It has been speculated that dogs and Tasmanian Devils both suffer increased risk of cancer-contagion via their reduced diversity of MHC genes, which makes immune surveillance much less efficient.  Similarly, human patients on immune suppressants can occasionally obtain cancer from organ transplants.

CTVT, like all cancers, accumulates genomic mutations as it divides and grows. To get more information about the population characteristics of the disease, the scientists sequenced the entire genomes of tumors obtained from widely separated dogs- one in Australia, and one in South America. These samples would give an idea of the range of genomic variation in the tumor worldwide, and give a clue about the origins of the cells. A surprise from the sequencing was the high degree of similarity of the two, widely separated tumor isolates. A molecular clock calculation suggested the cells were only separated by 460 or so years, putting the worldwide dispersal of the disease at around the same time as Christopher Columbus; and around the same time that intensive breeding of dogs for particular purposes took off.  Since the disease is sexually transmissible, the use of infected sires to breed for many litters may have amplified the disease's spread.

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