In other species: domestic cat , taurine cattle , goat , sheep

Categories: Neoplasm

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 278740 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2017

Cross-species summary: Malignant new growth of squamous epithelial cells in the eye. Also called eye cancer.

Species-specific symbol: SCC

Species-specific description: “Squamous cell carcinoma (SCC) is the most common cancer of the equine eye, and is second to equine sarcoid as the most common tumor of the horse overall. . . . The Haflinger breed, developed in Austria and Northern Italy during the late 19th century, appears to be among those breeds overrepresented for this disease” (Bellone et al., 2017) {contributed by Meredith O’Connell, working under the guidance of Professor Ernie Bailey, 5 March 2019}

Inheritance: Bellone et al. (2017) reported pedigree data consistent with autosomal recessive inheritance, based on examination of the pedigrees for 43 affected and 24 unaffected horses. {revised version contributed by Meredith O’Connell, working under the guidance of Professor Ernie Bailey, 5 March 2019}

Mapping: A GWAS conducted by Bellone et al. (2017) on using 12 cases and 11 controls, each genotyped with the EquineSNP70 BeadChip yielding 41,743 informative SNPs, identified a 1.5Mb candidate region on chromosome EC12. {revised version based on a contribution by Meredith O’Connell, working under the guidance of Professor Ernie Bailey, 5 March 2019}

Markers: By "sequencing the most physiologically relevant gene from [the candidate region on EC12, namely] damage specific DNA binding protein 2 (DDB2)", Bellone et al. (2017) "identified a missense mutation (c.1013 C > T p.Thr338Met) that was strongly [but not completely] associated with limbal SCC". Singer-Berk et al. (2018) reported "that the genetic risk [for the above variant] is the same for the development of both limbal and nictitating membrane SCC in Haflinger horses". Knickelbein et al. (2019) reported the same variant homozygous in a Rocky Mountain Horse stallion. Knickelbein et al. (2020) reported that the same variant "is a risk factor for ocular SCC in Belgian horses". The extent to which this variant is an incomplete risk factor in this breed is indicated by the genotypic distribution of this variant among affected Belgian horses, namely 76% homozygous, 8% heterozygous, and 16% lacking the variant. Chen et al. (2020) "provide direct functional evidence indicating that the T338M mutant indeed is a loss-of-function allele that abolishes UV-DDB recognition of damaged DNA."

Clinical features: “Squamous cell carcinoma (SCC) is a slow-growing malignant neoplasia of the skin, mucous membranes and mucocutaneous junctions. It is the most common tumor of the eye and adnexa in the horse. Most commonly, the nictitating membrane, nasal canthus, limbus and eyelids are affected. Untreated ocular SCC may invade local soft tissues, the bony orbit, sinuses and brain and less commonly, it may metastasize to the regional lymph nodes, salivary glands and thorax. Limbal involvement can quickly lead to visual impairment and destruction of the globe” (Kaps et al., 2005). {contributed by Meredith O’Connell, working under the guidance of Professor Ernie Bailey, 5 March 2019}

Prevalence: For breeds in which SCC has been reported, the variant allele frequencies reported by Bellone et al. (2017) are 0.25 for Haflingers, 0.21 for Belgians, 0.20 for Rocky Mountain Horses, 0.07 for Percherons, 0.02 for Appaloosas, and zero for Arabian, Clydesdale, Dutch Warmblood, Hanoverian, Oldenburg, Paint Horse, Quarter Horse, Shire, and Thoroughbred. The breeds with zero variant frequency (but in which SCC has been reported) are indicative of the extent to which this variant is incompletely associated with SCC. Knickelbein et al. (2019) reported the frequency of the same variant in the Rocky Mountain breed to be 0.2. {much of the above information was contributed by Meredith O’Connell, working under the guidance of Professor Ernie Bailey, 5 March 2019}

Breeds: Appaloosa (Horse) (VBO_0000904), Belgian Draft (Horse) (VBO_0000915), Connemara Pony (Horse) (VBO_0000937), Haflinger (Horse) (VBO_0000978), Rocky Mountain, United States of America (Horse) (VBO_0011836), Welsh Pony (Horse) (VBO_0001091).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: