A Milestone Reached in Equine Eye Cancer Research
By Margaret Evans
For a prey animal that instinctively depends on sight for survival, a horse’s loss of vision or even the loss of an eye is devastating. Yet, squamous cell carcinoma (SCC) is the most common cancer found in equine eyes and the second most common tumour in horses.
Squamous cell carcinoma is the most common cancer of the equine eye and the second most common tumour in horses. Photo courtesy University of California, Davis
The disease originates in the junction between the cornea – the clear surface of the eyeball – and the conjunctiva that covers the white of the eye. In advanced cases, SCC can be locally invasive, spread to the orbit, and eat away at the bone and eventually the brain leading to loss of life.
But a recent genetic study led by scientists at the University of California, Davis, will help owners identify if their horses are at risk for SCC and make informed decisions on two levels. For horses with a known susceptibility to the disease, regular eye exams can lead to early diagnosis of a tumour, which can then be surgically removed and the eye saved. Secondly, knowledge of a horse’s susceptibility will allow owners to make critical decisions regarding breeding.
What researchers discovered was a genetic mutation that is thought to impact the ability of damage-specific DNA binding protein 2 (DDB2) to perform its role. DDB2 acts like a surveillance protein. It looks for UV damage in the eye and then “calls in” other proteins to help repair the harm. But changes in the DNA can interfere with this process.
“Changes in the DNA (stored informational molecules) can affect protein (functional informational molecules of the cell),” says Dr. Rebecca Bellone, equine geneticist at the Veterinary Genetics Laboratory and associate adjunct professor at UC Davis School of Veterinary Medicine. “If you have a change in the DNA sequence, that can ultimately lead to a change in the protein sequence. There are many ways that mutations in the DNA can occur. One way is during DNA replication. When this happens in the germ line cells, these changes can get passed on to the next generation. DNA is the biological material that is inherited and it contains stored information. This stored information can be translated into protein that has a job to perform in the cell. A change in the DNA sequence can therefore result in a change in the protein sequence, which can lead to altered protein function.”
Under normal conditions, Bellone says that DDB2 binds to DNA that has been damaged by ultraviolet light, and it then recruits other proteins to come to the damaged site and repair it.
But if the DDB2 protein does not have the right sequences then damaged DNA has lost its ability to call for help, so to speak.
“We hypothesize that methionine instead of threonine at position 338 of the protein will change the shape of the protein so that it is unable to bind to UV-damaged DNA,” says Bellone. “Amino acids in a protein interact with each other to form the three-dimensional shape. It is the precise shape of the protein that determines its function.”
She adds that it’s not the mutation itself that creates the cancer. It is the accumulation of damage to the DNA. If the DDB2 protein with methionine is less effective at detecting UV-damaged DNA, then the cell will continue to accumulate damage, which leads to uncontrollable cell division and, eventually, cancer. This change – mutation – is thought to alter the shape of the protein so it can’t recognize UV-damaged DNA. Without that recognition, cells cannot repair any damage and the risk factor grows as the mutated DNA leads to cancer.
Several breeds are at risk for this condition, in particular Haflingers. In a previous study, Bellone and one of her research partners, Dr. Mary Lassaline, found that about 26 percent of SCC-affected horses were Haflingers. But other breeds are also affected.
“There are lots of breeds in the literature described as being at a higher risk including Belgians, Paints, Quarter Horses, and Thoroughbreds, among others,” says Bellone. “It is possible that the DDB2 variant may help to identify genetic risk for some of these breeds and other inherited mutations (not yet known) may explain the increased risk in other breeds.”
As a preventative measure, Bellone recommends that horses identified with genotype R/R should wear a UV protective fly mask when they are in the sun and exposed to UV rays. She also recommends that these horses be routinely screened by a veterinary ophthalmologist for early detection of cancer, which could lead to a better prognosis.
Based on the study, the scientists were able to develop a genetic test for horses to determine their susceptibility to equine SCC. The test shows whether a horse carries the mutation or has two copies of the risk variant, putting it at high risk for cancer.
What makes this research all the more interesting is that the study also has implications for human health. The gene associated with equine SCC is also linked in humans to a disease characterized by sun sensitivity and increased risk of cutaneous SCC and melanoma.
“Mutations in the same gene that increase risk for limbal SCC in Haflingers (DDB2) have been shown to increase risk for SCC, basal cell carcinoma, and melanomas in humans,” says Bellone. “Several of the mutations identified in humans are in the same region of the gene as the horse mutation, illustrating the importance of this region in identifying UV damaged DNA.”
Emphasizing the importance of the parallel in humans with the mutation in this protein, she says that they now have the ability to understand why it’s affecting the eyes of horses as well as the skin of humans.
This research was supported in part by generous donors to the Center for Equine Health as well as the Morris Animal Foundation. The research was published in the International Journal of Cancer.
Dr. Rebecca Bellone is an equine geneticist at the Veterinary Genetics Laboratory and associate adjunct professor at UC Davis School of Veterinary Medicine. Photo courtesy University of California, Davis
Main photo: Canstock/Zuzule A study by Drs. Bellone and Lassaline found that 26 percent of horses affected with squamous cell carcinoma were Haflingers.