Additional Evidence for DDB2 T338M as a Genetic Risk Factor for Ocular Squamous Cell Carcinoma in Horses

Squamous cell carcinoma (SCC) is the most common periocular cancer in horses, and the second most common tumor of the horse overall. A missense mutation on ECA12 damage specific DNA binding protein 2 (DDB2, p.Thr338Met), was previously found to be strongly associated with ocular SCC in Haflinger and Belgian horses. To determine if this same variant in DDB2 contributes to risk for ocular SCC in the Arabian, Appaloosa, and Percheron breeds, and to determine if the variant contributes to risk for oral or urogenital SCC, histologically confirmed SCC cases were genotyped for the DDB2 variant and associations were investigated. Horses heterozygous for the DDB2 risk allele were identified in Appaloosas with urogenital SCC, but a significant association with SCC in this breed for any location was not detected. The risk allele was not identified in the Arabian or Percheron samples investigated. Furthermore, high throughput sequencing data from six Haflingers were analyzed to ascertain if another variant from the 483 kb associated locus on ECA12 locus was more concordant with the SCC phenotype, as 24% of ocular SCC cases for both Haflingers and Belgians were not explained by the DDB2 risk variant. Sixty polymorphisms were prioritized for evaluation and no other variant from this locus explained the genetic risk better than the DDB2 allele (P = 3.39 × 10^-17, n=118). These data provide further support of the DDB2 variant contributing to risk for ocular SCC specifically in the Haflinger and Belgian breeds.