Created at the VGL Ocular Squamous Cell Carcinoma (SCC)

Quick Summary

Ocular squamous cell carcinoma (SCC) is a condition characterized by tumors of the limbus (junction of the cornea and sclera), third eyelid, and/or upper and lower eyelids.

Phenotype: Ocular Squamous Cell Carcinoma (SCC) is a condition characterized by tumors of the limbus (junction of the cornea and sclera), third eyelid, and/or upper and lower eyelids. If left untreated they may spread into the surrounding eye tissue and cause vision loss.

Mode of Inheritance: Autosomal recessive with incomplete penetrance

Alleles: N = Normal or non-risk, R = Risk for SCC

Breeds appropriate for testing: Belgian, Haflinger, Rocky Mountain Horse, Connemara Pony, Holsteiner, Belgian Warmblood

Explanation of Results:

  • Horses with N/N genotype do not carry this risk variant for SCC and cannot transmit this SCC risk variant to their offspring.
  • Horses with N/R genotype are not at elevated risk of developing SCC, but are carriers. They may transmit this SCC risk variant to 50% of their offspring. Matings between two carriers result in a 25% chance of producing a foal that will be at elevated risk of developing SCC.
  • Horses with R/R genotype are more likely to develop ocular SCC than horses that genotype as N/R and N/N. They will transmit this SCC risk variant to all of their offspring.
Price

$40 one test per individual animal

Additional Details

Researchers at the Veterinary Genetics Laboratory and the University of California, Davis School of Veterinary Medicine investigated ocular Squamous Cell Carcinoma (SCC) in the Haflinger and Belgian breeds 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 in both the Haflinger and Belgian breeds. A single base pair change (DDB2 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).

Turnaround Time
10-15 business days
Type of Sample

Species

Type of Test

Results Reported As
Test Result Ocular Squamous Cell Carcinoma (SCC)
N/N No copies of the SCC risk marker. Horse has a lower risk of developing limbal or third eye lid SCC.
N/R 1 copy of the SCC risk marker. Horse has a lower risk of developing ocular SCC but can pass on the risk factor to 50% of the offspring.
R/R 2 copies of the SCC risk marker. Horse is more likely to develop ocular SCC than horses that genotype as N/R and N/N. Routine ophthalmological exams and use of UV-protecting fly masks during sun exposure are advised.
References

Lassaline, M., Cranford, T. L., Latimer, C. A., & Bellone, R. (2015) Limbal squamous cell carcinoma in Haflinger horses. Veterinary Ophthalmology, 18(5), 404-408. doi: 10.1111/vop.12229

Bellone, R. R., Liu, J., Petersen, J. L., Mack, M., Singer-Berk, M., Drögemüller, C., Malvick, J., Wallner, B., Brem, G., Penedo, M. C., & Lassaline, M. (2017). A Missense Mutation in Damage-specific DNA Binding Protein 2 Is a Genetic Risk Factor for Limbal Squamous Cell Carcinoma in Horses. International Journal of Cancer, 141(2), 342-353. doi: 10.1002/ijc.30744

Singer‐Berk, M., Knickelbein, K. E., Vig, S., Liu, J., Bentley, E., Nunnery, C., Reilly, C., Dwyer, A., Drögemüller, C., Unger, L., Gerber, V., Lassaline, M., & Bellone, R.R. (2018). Genetic risk for squamous cell carcinoma of the nictitating membrane parallels that of the limbus in Haflinger horses. Animal Genetics, 49(5), 457-460. doi: 10.1111/age.12695

Knickelbein, K. E., Lassaline, M. E., & Bellone, R. R. (2018). Limbal squamous cell carcinoma in a Rocky Mountain Horse: Case report and investigation of genetic contribution. Veterinary Ophthalmology, 22(2), 1-5. doi: 10.1111/vop.12612

Knickelbein, K. E., Lassaline, M. E., Singer‐Berk, M., Reilly, C. M., Clode, A. B., Famula, T. R., Michau T.M., & Bellone, R. R. (2019). A missense mutation in damage‐specific DNA binding protein 2 is a genetic risk factor for ocular squamous cell carcinoma in Belgian horses. Equine Veterinary Journal, 52(1), 34-40. doi: 10.1111/evj.13116

Singer-Berk, M., Knickelbein, K.E., Lounsberry, Z.T., Crausaz, M., Vig, S., Joshi, N., Britton, M., Settles, M.L., Reilly, C.N., Bentley, E., Nunnery, C., Dwyer, A., Lassaline, M.E. & Bellone, R.R. (2019). Additional Evidence for DDB2 T338M as a genetic risk factor for ocular squamous cell carcinoma in horses. International Journal of Genomics, Vol. 2019, Article ID 3610965, 10 pages. doi: 10.1155/2019/3610965

Chen, L., Bellone, R.R., Wang, Y., Singer-Berk, M., Sugasawa, K., Ford, J.M., & Artandi, S.E. (2020). A novel DDB2 mutation causes defective recognition of UV-induced DNA damages and prevalent equine squamous cell carcinoma. DNA Repair97. doi: 10.1016/j.dnarep.2020.103022

Crausaz, M., Launois, T., Smith-Fleming, K., McCoy, A.M., Knickelbein, K.E., & Bellone, R.R. (2020). DDB2 Genetic Risk Factor for Ocular Squamous Cell Carcinoma Identified in Three Additional Horse Breeds. Genes, 11(12), 1460. doi: 10.3390/genes11121460