Additional Evidence forDDB2T338M as a Genetic Risk Factor for Ocular Squamous Cell Carcinoma in Horses

Abstract

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.

DDB2 Genetic Risk Factor for Ocular Squamous Cell Carcinoma Identified in Three Additional Horse Breeds

“…While risk for ocular SCC has been highly correlated with the DDB2 genotype, not all cases of ocular SCC were explained by homozygosity for this variant. Genetic heterogeneity is likely involved [18]. In our study, the mean age of diagnosis from two retrospective data sets was found to be 14.11 ± 5.39 years, consistent with what is reported in the literature [10].…”

“…The aim of this work was to determine if the known risk variant (DDB2 c.1013C>T) could have led to the development of SCC in the affected Holsteiner cross and the two affected Connemara Ponies and these data support this to be the case. Other potential risk factors for SCC development have been studied previously, including age, sex, coat color, and equine papilloma virus type 2 infection [18]. While risk for ocular SCC has been highly correlated with the DDB2 genotype, not all cases of ocular SCC were explained by homozygosity for this variant.…”

“…Previous research has also implicated hormones as a risk factor for ocular SCC with geldings being overrepresented compared to stallions and mares in retrospective studies [3,4,18,23,24,30]. It has been proposed that lack of circulating androgens and estrogens in castrated males predispose geldings to ocular SCC [8,18].…”

“…The DDB2 risk variant was also identified at a low frequency in the Percheron and Appaloosa breeds (0.07 and 0.02, respectively) [4,18]. Subsequent studies using 46 SCC-affected Appaloosas did not support genotyping for DDB2 in the Appaloosa as none of these cases were homozygous for this risk variant.…”

“…Subsequent studies using 46 SCC-affected Appaloosas did not support genotyping for DDB2 in the Appaloosa as none of these cases were homozygous for this risk variant. However, additional work is needed to evaluate if testing for the DDB2 risk allele is warranted in Percherons, as only two horses were identified to have SCC in that study and none were homozygous for the risk allele [18]. Retrospective studies have identified warmblood and pony breeds also as overrepresented for ocular SCC [4,[19][20][21][22][23], however, the role of the DDB2 variant in these breeds has not been determined [4,[15][16][17][18].…”