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Equine veterinary journal2019; 52(1); 34-40; doi: 10.1111/evj.13116

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

Abstract: Belgian horses are commonly affected with ocular squamous cell carcinoma (SCC), the most common cancer of the equine eye. A missense mutation in damage-specific DNA binding protein 2 (DDB2 c.1013C>T, p.Thr338Met) has been established as a recessive genetic risk factor for ocular SCC in the Haflinger breed. A sample of Belgian horses with unknown SCC phenotype was shown to possess this variant at a similar frequency to the Haflinger breed. Retrospective studies indicate that chestnut coat colour may predispose to the development of SCC. Objective: To determine if DDB2 c.1013C>T is a risk factor for ocular SCC in a strictly phenotyped sample of Belgian horses. To investigate associations between coat colour loci genotypes and ocular SCC. Methods: Retrospective and prospective case identification, genetic investigation. Methods: Genomic DNA was isolated from blood, hair or formalin-fixed paraffin-embedded tissue from 25 Belgian horses with histologically confirmed ocular SCC and 18 unaffected Belgian horses. Association testing of 34 single nucleotide variants from 11 genomic loci and genotyping for DDB2 c.1013C>T and coat colour alleles were performed. Exons of DDB2 were sequenced in four cases and two controls. Associations were analysed by Chi-square or Fisher's exact tests and relative risk was calculated. Results: Homozygosity for DDB2 c.1013C>T was significantly associated with ocular SCC (P = 7.4 × 10 ). Seventy-six per cent of affected horses were homozygous for the variant. Relative risk for homozygous horses developing SCC was 4.0 (P = 1.0 × 10 ). Sequencing DDB2 did not identify a variant more concordant with disease phenotype. An association between disease and coat colour loci was not identified. Conclusions: Phenotyping was determined at a single timepoint. Each included horse genotyped as chestnut, so association with this MC1R variant could not be investigated. Conclusions: A missense variant, DDB2 c.1013C>T, p.Thr338Met, is a risk factor for ocular SCC in Belgian horses. A genetic risk test is commercially available.
© 2019 EVJ Ltd.
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Publication Date: 2019-04-15 PubMed ID: 30903710DOI: 10.1111/evj.13116Google Scholar: Lookup
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  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research identifies a genetic mutation in Belgian horses that increases the risk of developing ocular squamous cell carcinoma (SCC), a common type of eye cancer. Exploration into the relationship between coat colour and the occurrence of SCC did not yield any significant associations.

Study Methodology

  • The study was conducted retrospectively and prospectively using genetic investigation.
  • The research involved extracting genomic DNA from various sources such as blood, hair or tissues embedded in paraffin extracted from 25 Belgian horses with confirmed ocular SCC and 18 unaffected horses.
  • The team then performed association testing of 34 single nucleotide variants from 11 genomic loci and genotyping on the extracted DNA for DDB2 c.1013C>T, a mutation known to increase the risk of SCC in the Haflinger breed, and various coat colour alleles.
  • Sequencing of the DDB2 exons was done in four cases and two controls.
  • Associations between disease presence and factors tested were analysed through Chi-square or Fisher’s exact tests, and relative risks were calculated.

Results

  • Homozygosity for DDB2 c.1013C>T was discovered to be significantly associated with ocular SCC. This mutation was present in 76% of the affected horses.
  • The relative risk for horses harbouring this mutation to develop SCC was estimated to be 4.0.
  • From sequencing DDB2, no variant that could be more associated with the disease phenotype was identified.
  • There was no association discovered between the disease and coat colour loci.

Conclusions

  • Phenotyping was conducted at a single timepoint, limiting the study’s scope.
  • All horses included in the study were genotyped as chestnut, preventing the researchers from investigating any potential association between the MC1R variant and the disease.
  • Despite these limitations, it was concluded that the DDB2 c.1013C>T, p.Thr338Met missense variant serves as a risk factor for ocular SCC in Belgian horses.
  • A genetic risk test based on this discovery is now commercially available for use.

Cite This Article

APA
Knickelbein KE, Lassaline ME, Singer-Berk M, Reilly CM, Clode AB, Famula TR, Michau TM, Bellone RR. (2019). A missense mutation in damage-specific DNA binding protein 2 is a genetic risk factor for ocular squamous cell carcinoma in Belgian horses. Equine Vet J, 52(1), 34-40. https://doi.org/10.1111/evj.13116

Publication

Equine veterinary journal
ISSN: 2042-3306
NlmUniqueID: 0173320
Country: United States
Language: English
Volume: 52
Issue: 1
Pages: 34-40

Researcher Affiliations

Knickelbein, K E
  • Veterinary Medical Teaching Hospital, University of California-Davis, Davis, California, USA.
  • Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
Lassaline, M E
  • Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
Singer-Berk, M
  • Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
Reilly, C M
  • Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
Clode, A B
  • New England Equine Medical & Surgical Center, PLLC, Dover, New Hampshire, USA.
Famula, T R
  • Department of Animal Science, University of California-Davis, Davis, California, USA.
Michau, T M
  • Blue Pearl Specialty and Emergency Pet Hospital, Tampa, Florida, USA.
Bellone, R R
  • Veterinary Medical Teaching Hospital, University of California-Davis, Davis, California, USA.
  • Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.

MeSH Terms

  • Animals
  • Carcinoma, Squamous Cell / veterinary
  • DNA-Binding Proteins / genetics
  • Eye Neoplasms / veterinary
  • Genetic Predisposition to Disease
  • Horse Diseases / genetics
  • Horses
  • Mutation, Missense

Grant Funding

  • UC Davis Veterinary Genetics Laboratory
  • UC Davis Center for Equine Health

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Citations

This article has been cited 8 times.
  1. Wotman KL, Chow L, Martabano B, Pezzanite LM, Dow S. Novel ocular immunotherapy induces tumor regression in an equine model of ocular surface squamous neoplasia. Cancer Immunol Immunother 2023 May;72(5):1185-1198.
    doi: 10.1007/s00262-022-03321-2pubmed: 36367558google scholar: lookup
  2. Crausaz M, Launois T, Smith-Fleming K, McCoy AM, Knickelbein KE, Bellone RR. DDB2 Genetic Risk Factor for Ocular Squamous Cell Carcinoma Identified in Three Additional Horse Breeds. Genes (Basel) 2020 Dec 5;11(12).
    doi: 10.3390/genes11121460pubmed: 33291392google scholar: lookup
  3. Chen L, Bellone RR, Wang Y, Singer-Berk M, Sugasawa K, Ford JM, Artandi SE. A novel DDB2 mutation causes defective recognition of UV-induced DNA damages and prevalent equine squamous cell carcinoma. DNA Repair (Amst) 2021 Jan;97:103022.
    doi: 10.1016/j.dnarep.2020.103022pubmed: 33276309google scholar: lookup
  4. Singer-Berk MH, Knickelbein KE, Lounsberry ZT, Crausaz M, Vig S, Joshi N, Britton M, Settles ML, Reilly CM, Bentley E, Nunnery C, Dwyer A, Lassaline ME, Bellone RR. Additional Evidence for DDB2 T338M as a Genetic Risk Factor for Ocular Squamous Cell Carcinoma in Horses. Int J Genomics 2019;2019:3610965.
    doi: 10.1155/2019/3610965pubmed: 31637255google scholar: lookup
  5. Quatember H, Nell B, Richter B, Rigler D, Dolezal M, Sykora S, Wallner B. Studying the Impact of the DDB2 T338M Missense Mutation on the Development of Equine Squamous Cell Carcinoma and Sarcoid. Animals (Basel) 2025 Mar 22;15(7).
    doi: 10.3390/ani15070911pubmed: 40218305google scholar: lookup
  6. Ing ST, Pinard CL, James-Jenks EM, Leis ML. A retrospective survey of equine ocular diseases evaluated at a referral hospital in Ontario (2011 to 2021). Can Vet J 2025 Mar;66(3):308-317.
    pubmed: 40070935
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    doi: 10.5455/OVJ.2024.v14.i11.35pubmed: 39737039google scholar: lookup
  8. Chow L, Flaherty E, Pezzanite L, Williams M, Dow S, Wotman K. Impact of Equine Ocular Surface Squamous Neoplasia on Interactions between Ocular Transcriptome and Microbiome. Vet Sci 2024 Apr 7;11(4).
    doi: 10.3390/vetsci11040167pubmed: 38668434google scholar: lookup
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