# Studying the Impact of the DDB2 T338M Missense Mutation on the Development of Equine Squamous Cell Carcinoma and Sarcoid

## TL;DR

A specific DDB2 gene mutation increases the risk of eye cancer in Haflinger and Noriker horses but not in other tumour types or breeds.

## Contribution

The study confirms the DDB2 T338M mutation's role in ocular SCC in Haflingers and identifies its presence in Noriker horses with the same condition.

## Key findings

- DDB2-TT Haflingers have a significantly higher risk of developing ocular SCC.
- The DDB2-T allele was found in Noriker horses with ocular SCC but not in Warmbloods.
- No significant link was found between the DDB2-T allele and SCC or ES at non-ocular sites.

## Abstract

Squamous cell carcinoma (SCC) and equine sarcoid (ES) are the most common tumours in horses. It has been shown previously that Haflinger horses with a homozygous genotype for a missense variant in the DDB2 (damage-specific DNA binding protein 2) gene have an increased risk of developing ocular SCC (OSCC). Genetic testing for this variant is commercially available. Here, we studied the DDB2 genotype in patients with SCC, OSCC, or ES at the Vetmeduni Vienna. Results confirmed the impact of the DDB2 risk variant on the development of OSCC in Haflingers. We found homozygous risk allele carriers in OSCC patients of the Noriker breed, but we did not detect the risk allele in Warmbloods with OSCC. No evidence of an influence of the DDB2 genotype on the development of ES and squamous cell carcinoma in sites other than the eye was found. Our results underline the impact of the DDB2 risk allele on animal health. In Haflingers, the DDB2 genotype should be considered in mating strategies and preventive management. Furthermore, regular veterinary eye examinations for early detection of OSCC are recommended in this breed.

A missense mutation in damage-specific DNA binding protein 2 (DDB2 c.1013 C>T; p.Thr338Met) has been described as a risk factor for ocular squamous cell carcinoma (OSCC) in the Haflinger breed. Here, we examined the impact of DDB2 C>T allele status on the development of OSCC, squamous cell carcinoma (SCC) at other localisations, or equine sarcoid (ES) in Haflingers and other breeds with a high incidence of these tumour types. We genotyped affected Haflinger, Noriker, Warmblood, and Icelandic horses. Results based on 56 Haflingers confirmed the significantly higher risk for OSCC in DDB2-TT Haflingers but also suggested an increased risk in heterozygous (DDB2-CT) Haflingers. We also found the DDB2-T allele in Norikers with OSCC but not in Warmbloods. Only one homozygous DDB2-T allele carrier was among the 23 Haflinger and 44 Noriker/Warmblood/Icelandic horses with an SCC at a localisation other than the eye or ES. Overall, our data underline the severity of the DDB2-T allele with regard to OSCC and provide no evidence for the impact of the DDB2 risk allele status on the development of ES and SCC at localisations other than the eye.