Limbal squamous cell carcinoma in a Rocky Mountain Horse: Case report and investigation of genetic contribution

Knickelbein, Kelly E.; Lassaline, Mary

doi:10.1111/vop.12612

Cited by 11 publications

(10 citation statements)

References 18 publications

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“…The median age at diagnosis of ocular SCC or carcinoma in situ in this sample was 11 years (range: 5-27 years). The median age at the time of examination of the control group was 15 years (range: [13][14][15][16][17][18][19][20][21][22][23][24][25]. The median age of the affected group was significantly younger than that of the control group (U = 101, P = 0.002).…”

Section: Resultsmentioning

confidence: 99%

“…The DDB2 c.1013C>T, p.Thr338Met variant was also confirmed as a risk factor for third eyelid SCC in the Haflinger breed, with 88% of Haflinger horses with SCC in this location determined to be homozygous for the variant [15]. The DDB2 c.1013C>T variant allele was most recently described to have a frequency of 0.20 in the Rocky Mountain Horse breed, and an initial ocular SCC-affected case was found to be homozygous T for the variant, suggesting the variant may also serve as a risk factor in Rocky Mountain Horses [16]. While the Belgian breed is commonly affected with ocular surface SCC and has been shown to possess the genetic risk variant confirmed to be strongly associated with the disease in the closely related Haflinger breed, the association between this variant and ocular surface SCC in Belgian horses had not been investigated.…”

Section: Introductionmentioning

confidence: 99%

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A missense mutation in damage‐specificDNAbinding protein 2 is a genetic risk factor for ocular squamous cell carcinoma in Belgian horses

Knickelbein

Lassaline

Singer-Berk

et al. 2019

Equine Veterinary Journal

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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 (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. Objectives 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. 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 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 × 10−7). 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 DDB2 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 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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A missense mutation in damage‐specificDNAbinding protein 2 is a genetic risk factor for ocular squamous cell carcinoma in Belgian horses

Knickelbein

Lassaline

Singer-Berk

et al. 2019

Equine Veterinary Journal

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“…This variant was strongly associated, but not perfectly concordant, with limbal and third eyelid SCC status in both the Haflinger and Belgian breeds, explaining 76% of the Haflinger and Belgian cases investigated [2–4]. A recent case report also implicated this DDB2 variant as a potential risk factor for ocular SCC in Rocky Mountain Horses [5]. The first aim of this study was to gain further insight into ocular SCC development in Haflinger and Belgian breeds by investigating other risk factors, including age.…”

Section: Introductionmentioning

confidence: 99%

Additional Evidence forDDB2T338M as a Genetic Risk Factor for Ocular Squamous Cell Carcinoma in Horses

Singer-Berk

Knickelbein

Lounsberry

et al. 2019

International Journal of Genomics

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Squamous cell carcinoma (SCC) is the most common periocular cancer in horses and the second most common tumor of the horse overall. A missense mutation in damage-specific DNA-binding protein 2 (DDB2, c.1012 C>T, p.Thr338Met) was previously found to be strongly associated with ocular SCC in Haflinger and Belgian horses, explaining 76% of cases across both breeds. To determine if this same variant in DDB2 contributes to risk for ocular SCC in the Arabian, Appaloosa, and Percheron breeds and to determine if the variant contributes to risk for oral or urogenital SCC, histologically confirmed SCC cases were genotyped for the DDB2 variant and associations were investigated. Horses with urogenital SCC that were heterozygous for the DDB2 risk allele were identified in the Appaloosa breed, but a significant association between the DDB2 variant and SCC occurring at any location in this breed was not detected. The risk allele was not identified in Arabians, and no Percherons were homozygous for the risk allele. High-throughput sequencing data from six Haflingers were analyzed to ascertain if any other variant from the previously associated 483 kb locus on ECA12 was more concordant with the SCC phenotype than the DDB2 variant. Sixty polymorphisms were prioritized for evaluation, and no other variant from this locus explained the genetic risk better than the DDB2 allele (P=3.39×10−17, n=118). These data provide further support of the DDB2 variant contributing to risk for ocular SCC, specifically in the Haflinger and Belgian breeds.

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“…Subsequent work identified the same risk factor in the Belgian Draft horse breed [16]. A case report of a Rocky Mountain Horse supported the DDB2 variant as an ocular SCC risk factor in this breed as well, as the horse afflicted with limbal SCC was homozygous for the risk allele [17], and the allele frequency in Rocky Mountain Horses was similar to that reported for the Haflinger and Belgian Draft horse breeds (0.20 compared to 0.25 and 0.21, respectively) [4,16,17].…”

Section: Introductionmentioning

confidence: 85%

“…However, additional work is needed to evaluate if testing for the DDB2 risk allele is warranted in Percherons, as only two horses were identified to have SCC in that study and none were homozygous for the risk allele [18]. Retrospective studies have identified warmblood and pony breeds also as overrepresented for ocular SCC [4,[19][20][21][22][23], however, the role of the DDB2 variant in these breeds has not been determined [4,[15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

DDB2 Genetic Risk Factor for Ocular Squamous Cell Carcinoma Identified in Three Additional Horse Breeds

Crausaz

Launois²,

Smith-Fleming

et al. 2020

Genes

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Squamous cell carcinoma (SCC) is the most common cancer affecting the equine eye. A missense variant within the gene damage-specific DNA binding protein 2 (DDB2 c.1013C>T, p.Thr338Met) was previously identified as a causal recessive genetic risk factor for the development of ocular SCC within Haflingers, Belgian Draft horses, and Rocky Mountain Horses, but not in the Appaloosa or Arabian breeds. This study aimed to evaluate three cases of ocular SCC in additional breeds and determine if DNA testing for the DDB2 variant in warmblood horses and Connemara ponies is warranted. Histopathology confirmed ocular SCC in all three cases and DNA testing confirmed each horse was homozygous for the DDB2 risk factor. The DDB2 risk allele frequency was estimated to be 0.0043 for Holsteiners (N = 115), 0.014 for Belgian Warmbloods (N = 71), and 0.22 for Connemara Ponies (N = 86). Taken together these data support using DNA testing for DDB2 in Connemara Ponies to assist in mate selection and clinical management. Given the low observed allele frequencies in both the Holsteiner and Belgian Warmblood breeds and that the case under investigation was a warmblood cross-bred, evaluating additional SCC affected warmbloods is warranted to fully determine the importance of DDB2 genotyping as a risk factor in warmblood breeds.

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Limbal squamous cell carcinoma in a Rocky Mountain Horse: Case report and investigation of genetic contribution

Cited by 11 publications

References 18 publications

A missense mutation in damage‐specificDNAbinding protein 2 is a genetic risk factor for ocular squamous cell carcinoma in Belgian horses

A missense mutation in damage‐specificDNAbinding protein 2 is a genetic risk factor for ocular squamous cell carcinoma in Belgian horses

Additional Evidence forDDB2T338M as a Genetic Risk Factor for Ocular Squamous Cell Carcinoma in Horses

DDB2 Genetic Risk Factor for Ocular Squamous Cell Carcinoma Identified in Three Additional Horse Breeds

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