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Home / Equine Research Bank / Equine Vet J / A missense mutation in damage-specific DNA binding protein 2...
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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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

References

This article includes 38 references
  1. Strafuss AC. Squamous cell carcinoma in horses.. J. Am. Vet. Med. Ass. 168, 61-62.
  2. Schaffer PA, Wobeser B, Martin LE, Dennis MM, Duncan CG. Cutaneous neoplastic lesions of equids in the central United States and Canada: 3,351 biopsy specimens from 3,272 equids (2000-2010).. J. Am. Vet. Med. Ass. 242, 99-104.
  3. Dugan SJ, Roberts SM, Curtis CR, Severin GA. Prognostic factors and survival of horses with ocular/adnexal squamous cell carcinoma: 147 cases (1978-1988).. J. Am. Vet. Med. Ass. 198, 298-303.
  4. Scherrer NM, Lassaline-Utter M, Mckenna BC. Characterization and outcome following excision of masses in the nictitating membranes of horses: 50 cases (1998-2012).. J. Am. Vet. Med. Ass. 245, 812-815.
  5. Schwink K. Factors influencing morbidity and outcome of equine ocular squamous cell carcinoma.. Equine Vet. J. 19, 198-200.
  6. Dugan S, Curtis C, Roberts S, Severin G. Epidemiologic study of ocular/adnexal squamous cell carcinoma in horses.. J. Am. Vet. Med. Ass. 198, 251-256.
  7. Teifke JP, Löhr CV. Immunohistochemical detection of P53 overexpression in paraffin wax-embedded squamous cell carcinomas od cattle, horses, cats and dogs.. J. Comp. Pathol. 114, 205-210.
  8. Narayanan D, Saladi R, Fox J. Ultraviolet radiation and skin cancer.. Int. J. Dermatol. 49, 978-986.
  9. Emmett E, Epstein J. Ultraviolet radiation as a cause of skin tumors.. CRC Crit. Rev. Toxicol. 2, 211-255.
  10. Mosunic C, Moore P, Carmicheal K, Chandler MJ, Vidyashankar A, Zhao Y, Roberts RE, Dietrich UM. Effects of treatment with and without adjuvant radiation therapy on recurrence of ocular and adnexal squamous cell carcinoma in horses: 157 cases (1985-2002).. J. Am. Vet. Med. Ass. 225, 1733-1738.
  11. Plummer C, Smith S, Andrew S, Lassaline ME, Gelatt KN, Brooks DE, Kalberg ME, Ollivier FJ. Combined keratectomy, strontium-90 irradiation and permanent bulbar conjunctival grafts for corneolimbal squamous cell carcinomas in horses (1990-2002): 38 horses.. Vet. Ophthalmol. 10, 37-42.
  12. Michau T, Davidson M, Gilger B. Carbon dioxide laser photoablation adjunctive therapy following superficial lamellar keratectomy and bulbar conjunctivectomy for the treatment of corneolimbal squamous cell carcinoma in horses: a review of 24 cases.. Vet. Ophthalmol. 15, 245-253.
  13. Bellone RR, Liu J, Petersen JL, Mack M, Singer-Berk M, Drögemüller C, Malvick J, Wallner B, Brem G, Penedo MC, Lassaline M. A missense mutation in damage-specific DNA binding protein 2 is a genetic risk factor for limbal squamous cell carcinoma in horses.. Int. J. Cancer 141, 342-353.
  14. Lassaline M, Cranford TL, Latimer CA, Bellone RR. Limbal squamous cell carcinoma in Haflinger horses.. Vet. Ophthalmol. 18, 404-408.
  15. Singer-Berk M, Knickelbein KE, Vig S, Liu J, Bentley E, Nunnery C, Reilly C, Dwyer A, Drogemuller C, Unger L, Gerber V, Lassaline M, Bellone RR. Genetic risk for squamous cell carcinoma of the nictitating membrane parallels that of the limbus in Haflinger horses.. Anim. Genet. 49, 457-460.
  16. Knickelbein K, Lassaline M, Bellone R. Limbal squamous cell carcinoma in a Rocky Mountain Horse: case report and investigation of genetic contribution.. Vet. Ophthalmol. 22, 201-205.
  17. Rieder S, Taourit S, Mariat D, Langlois B, Guerin G. Mutations in the agouti (ASIP), the extension (MC1R), and the brown (TYRP1) loci and their association to coat color phenotypes in horses (Equus caballus).. Mamm. Genome 12, 450-455.
  18. Marklund L, Moller M, Sandberg K, Andersson L. A missense mutation in the gene for melanocyte-stimulating hormone receptor (MCR1) is associated with the chestnut coat color in horses.. Mamm. Genome 7, 895-899.
  19. Pielberg G, Golovko A, Sundstrom E, Curik I, Lennartsson J, Seltenhammer M, Druml T, Binns M, Fitzsimmons C, Lindgren G, Sandberg K, Baumung R, Vetterlein M, Stromber S, Grabherr M, Wade C, Lindblad-Toh K, Ponten F, Heldin C, Solkner J, Andersson L. A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse.. Nat. Genet. 40, 1004-1009.
  20. Mariat D, Taourit S, Guerin G. A mutation in the MATP gene causes the cream coat colour in the horse.. Genet. Sel. Evol. 35, 119.
  21. Cook D, Brooks S, Bellone R, Bailey E. Missense mutation in exon 2 of SLC36A1 responsible for champagne dilution in horses.. PLoS Genet. 4, e1000195.
  22. Brunberg E, Andersson L, Cothran G, Sandberg K, Mikko S, Lindgren G. A missense mutation in PMEL17 is associated with the Silver coat color in the horse.. BMC Genet. 7, 46.
  23. Imsland F, McGowan K, Rubin C, Henegar C, Sundstrom E, Berglund J, Schwochow D, Gustafson U, Imsland P, Lindblad-Toh K, Lindgren G, Mikko S, Millon L, Wade C, Schubert M, Orlando L, Penedo M, Barsh G, Andersson L. Regulatory mutations in TBX3 disrupt asymmetric hair pigmentation that underlies Dun camouflage color in horses.. Nat. Genet. 48, 152.
  24. Bellone R, Holl H, Setaluri V, Devi S, Maddodi N, Archer S, Sandmeyer L, Ludwig A, Foerster D, Pruvost M, Reissmann M, Bortfeldt R, Adelson D, Brooks S. Evidence for a retroviral insertion in TRPM1 as the cause of congenital stationary night blindness and leopard complex spotting in the horse.. PLoS ONE 8, e78280.
  25. Holl H, Brooks S, Archer S, Brown K, Malvick J, Penedo M, Bellone R. Variant in the RFWD3 gene associated with PATN1, a modifier of leopard complex spotting.. Anim. Genet. 47, 91-101.
  26. Metallinos D, Bowling A, Rine J. A missense mutation in the endothelin-B receptor gene is associated with Lethal White Foal Syndrome: an equine version of Hirschsprung disease.. Mamm. Genome 9, 426-431.
  27. Brooks S, Lear T, Adelson D, Bailey E. A chromosome inversion near the KIT gene and the Tobiano spotting pattern in horses.. Cytogenet. Genome Res. 119, 225-230.
  28. Brooks S, Bailey E. Exon skipping in the KIT gene causes a Sabino spotting pattern in horses.. Mamm. Genome 16, 893-902.
  29. Hasse B, Brooks S, Schlumbaum A, Azor P, Bailey E, Alaeddine F, Mevissen M, Burger D, Poncet P, Rieder S, Leeb T. Allelic heterogeneity at the equine KIT locus in domiant white (W) horses.. PLoS Genet. 3, e195.
  30. Hauswirth R, Haase B, Blatter M, Brooks S, Burger D, Drogemuller C, Gerber V, Henke D, Janda J, Jude R, Magdesian K, Matthews J, Poncet P, Svansson V, Tozaki T, Wilkinson-White L, Penedo M, Rieder S, Leeb T. Mutations in MITF and PAX3 cause “splashed white” and other white spotting phenotypes in horses.. PLoS Genet. 8, e1002653.
  31. Hauswirth R, Jude R, Haase B, Bellone R, Archer S, Holl H, Brooks S, Tozaki T, Penedo M, Rieder S, Leeb T. Novel variants in the KIT and PAX3 genes in horses with white-spotted coat colour phenotypes.. Anim. Genet. 44, 763-765.
  32. Sim N, Kumar P, Hu J, Henikoff S, Schneider G, Ng P. SIFT web server: predicting effects of amino acid substitutions in proteins.. Nucleic Acids Res. 40, W452-W457.
  33. Nasti T, Timares L. MC1R, eumelanin and pheomelanin: their role in determining the susceptibility to skin cancer.. Photochem. Photobiol. 81, 188-200.
  34. Healy E, Flannagan N, Ray A, Todd C, Jackson I, Matthews J, Birch-Machin M, Rees J. Melanocortin-1-receptor gene and sun sensitivity in individuals without red hair.. Lancet 355, 1072-1073.
  35. Sponenberg D, Bellone R. Dilutions of the basic dark colors.. In: Equine Color Genetics, 4th edn., John Wiley & Sons Inc, Hoboken, NJ. pp 122-123.
  36. Belgian Draft Horse Corporation of America. Colors and Markings.. Available at: http://www.belgiancorp.com/page.aspx?ID=431 (Accessed 5 May 2018).
  37. Lehmann U, Kreipe H. Real-time PCR analysis of DNA and RNA extracted from formalin-fixed and paraffin-embedded biopsies.. Methods 25, 409-418.
  38. Kainzbauer C, Rushton J, Tober R, Scase T, Nell B, Sykora S, Brandt S. Bovine papillomavirus type 1 and Equus caballus papillomavirus 2 in equine squamous cell carcinoma of the head and neck in a Connemara mare.. Equine Vet. J. 44, 112-115.

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
  7. Mather H, Stanley RG. Recurrence rate of corneal squamous cell carcinoma in dogs undergoing superficial keratectomy surgery. Open Vet J 2024 Nov;14(11):3063-3073.
    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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