A missense mutation in damage-specific DNA binding protein 2 is a genetic risk factor for limbal squamous cell carcinoma in horses.
Abstract: Squamous cell carcinoma (SCC) is the most common cancer of the equine eye, frequently originating at the limbus, with the potential to invade the cornea, cause visual impairment, and result in loss of the eye. Several breeds of horses have a high occurrence of limbal SCC implicating a genetic basis for limbal SCC predisposition. Pedigree analysis in the Haflinger breed supports a simple recessive mode of inheritance and a genome-wide association study (N = 23) identified a 1.5 Mb locus on ECA12 significantly associated with limbal SCC (Pcorrected = 0.04). Sequencing the most physiologically relevant gene from this locus, damage specific DNA binding protein 2 (DDB2), identified a missense mutation (c.1013 C > T p.Thr338Met) that was strongly associated with limbal SCC (P = 3.41 × 10-10 ). Genotyping 42 polymorphisms narrowed the ECA12 candidate interval to 483 kb but did not identify another variant that was more strongly associated. DDB2 binds to ultraviolet light damaged DNA and recruits other proteins to perform global genome nucleotide excision repair. Computational modeling predicts this mutation to be deleterious by altering conformation of the β loop involved in photolesion recognition. This DDB2 variant was also detected in two other closely related breeds with reported cases of ocular SCC, the Belgian and the Percheron, suggesting it may also be a SCC risk factor in these breeds. Furthermore, in humans xeroderma pigmentosum complementation group E, a disease characterized by sun sensitivity and increased risk of cutaneous SCC and melanomas, is explained by mutations in DDB2. Cross-species comparison remains to be further evaluated.
© 2017 UICC.
Publication Date: 2017-05-08 PubMed ID: 28425625DOI: 10.1002/ijc.30744Google Scholar: Lookup
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- Journal Article
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- Non-U.S. Gov't
Summary
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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.
Cite This Article
APA
Bellone RR, Liu J, Petersen JL, Mack M, Singer-Berk M, Drögemüller C, Malvick J, Wallner B, Brem G, Penedo MC, Lassaline M.
(2017).
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(2), 342-353.
https://doi.org/10.1002/ijc.30744 Publication
Researcher Affiliations
- Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California-Davis, Davis, CA.
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA.
- Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California-Davis, Davis, CA.
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA.
- Department of Animal Science, University of Nebraska - Lincoln, Lincoln, NE.
- Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California-Davis, Davis, CA.
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA.
- Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California-Davis, Davis, CA.
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA.
- Institute for Genetics University of Bern, Bern, Switzerland.
- Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California-Davis, Davis, CA.
- Department of Biomedical Sciences, University of Veterinary Medicine Vienna, Institute of Animal Breeding and Genetics, Vienna, Austria.
- Department of Biomedical Sciences, University of Veterinary Medicine Vienna, Institute of Animal Breeding and Genetics, Vienna, Austria.
- Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California-Davis, Davis, CA.
- Department of Surgical & Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA.
MeSH Terms
- Animals
- Carcinoma, Squamous Cell / genetics
- Carcinoma, Squamous Cell / veterinary
- Computational Biology
- DNA Damage
- DNA-Binding Proteins / chemistry
- DNA-Binding Proteins / genetics
- Eye Neoplasms / genetics
- Eye Neoplasms / veterinary
- Female
- Genetic Predisposition to Disease
- Genome-Wide Association Study / veterinary
- Horse Diseases / genetics
- Horses
- Limbus Corneae / pathology
- Male
- Mutation, Missense
- Pedigree
- Protein Structure, Secondary
- Sequence Analysis, DNA / veterinary
Citations
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