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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 in  damage-specific DNA-binding protein 2  ( DDB2 , c.1012  C > T , p.Thr338Met) was previously found to be strongly associated with ocular SCC in Haflinger and Belgian horses, explaining 76% of cases across both breeds. 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 with urogenital SCC that were heterozygous for the  DDB2  risk allele were identified in the Appaloosa breed, but a significant association between the  DDB2  variant and SCC occurring at any location in this breed was not detected. The risk allele was not identified in Arabians, and no Percherons were homozygous for the risk allele. High-throughput sequencing data from six Haflingers were analyzed to ascertain if any other variant from the previously associated 483 kb locus on ECA12 was more concordant with the SCC phenotype than the  DDB2  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.

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