Researchers at the Veterinary Genetics Laboratory and the University of California, Davis School of Veterinary Medicine investigated ocular Squamous Cell Carcinoma (SCC) and determined that a recessive mode of inheritance explains some of the genetic components involved in the development of this cancer. They also discovered a DNA marker that identifies horses at higher risk for this cancer occurring on the limbus (junction of the cornea and the sclera) and/or third eyelid.
Squamous cell carcinoma (SCC) is the second most common type of tumor in the horse and the most frequent tumor of the horse’s eye. Factors thought to increase risk for SCC include UV exposure, pigmentation, and genetics. Among reported cases, Haflingers and Belgians have higher incidence of SCC of both the limbus and the third eyelid, which suggests that genetic factors play a role in these breeds. When originating at the limbus, SCC can spread into the cornea, and quickly lead to visual impairment and destruction of the eye.
Our research initially identified a variant in the UV damage DNA repair gene Damage-specific DNA Binding Protein 2 (DDB2) that was strongly associated with cancer risk. A single base pair change (DBB2 c.1013C>T) causes a missense mutation that changes the 338th amino acid of the gene’s protein product from threonine to methionine (T338M). Subsequently, functional evidence determined that the site of the amino acid change is a crucial DNA anchor point, and the mutated protein cannot bind DNA. Thus damage to DNA from the sun cannot be repaired, and the accumulation of DNA damage may lead to cancer.
Horses homozygous (R/R) for the risk variant factor are 5.6 times (Haflinger) or 4.0 times (Belgians) more likely to develop ocular SCC than those with one copy (R/N) or no copies (N/N) of the risk factor. This risk factor does not explain all cases of ocular SCC, but it appears to be a major contributor in Haflingers and Belgians.
Most recently, our research team identified a Rocky Mountain Horse with limbal SCC, two Connemara Ponies affected with ocular SCC, and a Holsteiner-Belgian Warmblood cross with limbal SCC, all also homozygous for this risk variant. Therefore, this DNA test may also be appropriate for these breeds.
The frequency of the risk allele is approximately 20% in Haflingers, Belgians, Rocky Mountain Horses, and Connemara Ponies, suggesting that these breeds may benefit most from genetic testing to assist in mate selection. Frequency in the warmblood breeds is much lower, specifically estimated to be 0.43% in the Holsteiner and 1.4% in the Belgian Warmblood. Therefore the probability of mating two carriers is low in these two warmblood breeds and additional work is needed to determine the relative risk and percentage of ocular SCC cases explained by the DDB2 variant in these and other warmblood breeds.
Testing for this SCC risk variant can help owners and breeders assisting in mate selection and identify horses at higher risk for developing ocular SCC. Homozygous horses (R/R) are advised to have routine eye exams performed by a veterinary ophthalmologist for early detection and better prognosis, and to wear a UV protecting fly mask when out during the daylight hours. Breeding homozygotes (R/R) and heterozygous (R/N) among or to each other should be avoided to reduce the chances of producing horses that have a high risk of developing this cancer. The ideal mate in either case (R/R or R/N) is a horse with no copies of the risk factor (N/N).
Reference: UC Davis