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A missense mutation in damage‐specific DNA binding protein 2 is a genetic risk factor for ocular squamous cell carcinoma in Belgian horses
Author(s) -
Knickelbein K. E.,
Lassaline M. E.,
SingerBerk M.,
Reilly C. M.,
Clode A. B.,
Famula T. R.,
Michau T. M.,
Bellone R. R.
Publication year - 2020
Publication title -
equine veterinary journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.82
H-Index - 87
eISSN - 2042-3306
pISSN - 0425-1644
DOI - 10.1111/evj.13116
Subject(s) - missense mutation , allele , genotyping , biology , genotype , single nucleotide polymorphism , breed , genomic dna , genetics , exact test , medicine , mutation , gene
Summary Background 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 ( DDB 2 c.1013 C>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 . Objectives To determine if DDB 2 c.1013 C > 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 . Study design 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 DDB 2 c.1013 C > T and coat colour alleles were performed. Exons of DDB 2 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 DDB 2 c.1013 C > T was significantly associated with ocular SCC (P = 7.4 × 10 −7 ). 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 −4 ). Sequencing DDB 2 did not identify a variant more concordant with disease phenotype. An association between disease and coat colour loci was not identified. Main limitations Phenotyping was determined at a single timepoint. Each included horse genotyped as chestnut, so association with this MC 1R variant could not be investigated. Conclusions A missense variant, DDB 2 c.1013C>T, p.Thr338Met, is a risk factor for ocular SCC in Belgian horses. A genetic risk test is commercially available.