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Gewählte Publikation:

Publikationstyp: Zeitschriftenaufsatz
Dokumentart: Originalarbeit

Publikationsjahr: 2017

AutorInnen: Bellone, RR; Liu, J; Petersen, JL; Mack, M; Singer-Berk, M; Drögemüller, C; Malvick, J; Wallner, B; Brem, G; Penedo, MC; Lassaline, M

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

Quelle: Int J Cancer. 2017; 141(2):342-353

Autor/innen der Vetmeduni Vienna:

Brem Gottfried,
Wallner Barbara,

Beteiligte Vetmed-Organisationseinheiten
Abteilung für Molekulare Genetik,
Abteilung für Reproduktionsbiologie,

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.

Keywords Pubmed: 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*
Genetic Predisposition to Disease
Genome-Wide Association Study/veterinary
Horse Diseases/genetics*
Limbus Corneae/pathology*
Mutation, Missense*
Protein Structure, Secondary
Sequence Analysis, DNA/veterinary

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