A missense mutation in damage-specific DNA binding protein 2 is a genetic risk factor for limbal squamous cell carcinoma in horses.

The research identifies a specific genetic missense mutation in horses that increases the risk of developing squamous cell carcinoma (SCC), a common equine eye cancer. It furthers the understanding of the genetic factors underlying SCC predisposition in certain horse breeds.

Context and Aim of the Research

• This research paper is situated within the field of veterinary genetics, specifically studying genetic factors related to equine eye cancers.
• The primary aim of the research was to identify potential genetic risk factors for limbal squamous cell carcinoma (SCC) — a common eye cancer in horses that starts in the limbus and can invade the cornea, impair vision, or cause loss of the eye.
• Given the high occurrence of limbal SCC in certain horse breeds, the researchers aimed to explore a genetic basis of susceptibility to this disease.

Methods

• A breed of horse, the Haflinger, with a high occurrence of limbal SCC, was analyzed genetically, revealing what the researchers describe as a simple recessive mode of inheritance.
• A genome-wide association study then identified a potential locus on a chromosome (ECA12) involved in this cancer’s occurrence.
• The researchers sequenced the most relevant gene from this identified locus, the Damage Specific DNA Binding Protein 2 (DDB2), and identified a missense mutation.
• The researchers used computer modeling to predict the mutation’s impact on recognising photolesion damages in DNA.

Findings

• The sequencing of DDB2 identified a missense mutation (c.1013 C > T p.Thr338Met) that showed a strong association with limbal SCC.
• Computational modeling predicted the mutation to be deleterious, likely altering the conformation of the β loop involved in photolesion recognition.
• The same DDB2 variant was found in two other horse breeds with reported cases of ocular SCC – Belgian and Percheron, suggesting their potential genetic predisposition to SCC.
• This finding aligns with existing knowledge about a human disease called xeroderma pigmentosum complementation group E, characterized by sun sensitivity and higher risk for skin SCC and melanomas, which also links to mutations in DDB2.

Implications

• The research demonstrates the SCC association with the identified DDB2 variant across multiple horse breeds which could aid in the development of future genetic testing strategies to detect at-risk animals.
• The findings also underline the importance of cross-species comparison in studying diseases and drawing parallels between human and animal disease mechanisms.