Scientists Decode the Genetic Secrets of Eye Cancer in Hereford Cattle

For the first time, researchers have mapped the complete gene expression landscape of bovine ocular squamous cell carcinoma (BOSCC), a devastating eye tumor that disproportionately strikes Hereford cattle. The pioneering study, published in the journal Veterinary Oncology, reveals a striking molecular portrait of a cancer long linked to the same breed-standard pale faces that make these animals so recognizable. The findings open a path toward molecular tests that could identify cattle with reduced cancer susceptibility, offering hope for both animal welfare and livestock productivity.

BOSCC is the primary epithelial neoplasm of the eye in cattle, arising in the conjunctiva, corneoscleral junction, nictitating membrane, cornea, and eyelids. It can develop from pre-existing papillomas or emerge independently as an invasive tumor capable of spreading to the ocular bone and adjacent structures through lymph nodes. Multiple environmental and genetic factors drive its development, including ultraviolet radiation, viral infections, diet, age, and above all, the lack of ocular pigmentation that characterizes Hereford cattle. Because melanin provides photoprotection against ultraviolet damage, animals with depigmented ocular areas are far more vulnerable, and approximately 30 percent of cases carry hereditary causes.

The research team, led by Nariné Balemian of the Universidad de la República in Uruguay, collected tumor samples from five adult purebred Hereford cattle during field surgeries conducted by qualified veterinarians, following animal welfare protocols. Control corneal tissues were obtained from three healthy animals of the same breed and similar age with non-pigmented ocular regions. Each sample was divided for histological analysis and whole transcriptome sequencing. The tissues were fixed, dehydrated through an ascending ethanol series, embedded in wax, and stained with Hematoxylin-Eosin before digital image analysis, while RNA was extracted and sequenced using DNBseq technology generating at least 45 million paired-end reads per sample.

Histopathological examination confirmed classic BOSCC features across all cases. The corneal epithelium is normally stratified but non-keratinizing, so the presence of extensive keratin pearls reflects squamous differentiation of tumor cells rather than native corneal biology. Eighty percent of tumors showed complete depigmentation of the upper eyelid, and the nictitating membrane was affected in 80 percent of cases. All samples exhibited lymphocytic infiltration, increased mitotic activity, and elevated vascularization, and 40 percent of samples also contained melanocytes interspersed within the tumoral process, a feature compatible with pigmented squamous cell carcinoma variants reported in veterinary and human pathology.

Whole transcriptome sequencing identified 836 genes underexpressed and 845 genes overexpressed in tumor tissue compared with healthy controls. Among the most significantly upregulated genes were TRPV3, KRT6A, KLK6, MMP13, PROKR2, IL31RA, DHRS9, and MMP9, with log2 fold-change values between 6 and 11. KRT6A is a stress-responsive cytokeratin essential for squamous differentiation and re-epithelialization, while KLK6 is a serine protease implicated in epithelial cell invasion. TRPV3, a calcium channel characteristic of stratified squamous epithelia, likely marks adoption of a keratinizing program by ocular surface tumor cells. MMP9 and MMP13 are classic mediators of basement membrane and stromal degradation that facilitate invasion and angiogenesis.

The downregulated set included GPHA2, TNN, EMILIN3, BGLAP, TGFB1, MATN4, CHAD, and CLEC3A, with log2 fold-change values between −12 and −6. Several of these genes maintain limbal stem cells, cell adhesion, and tumor suppression. The downregulation of GPHA2, a limbal stem-cell marker, is consistent with disturbance of ocular surface homeostasis, while reduced expression of adhesion and matrix regulators such as CHAD, EMILIN3, MATN4, TNN, and CLEC3A fits with altered stromal architecture during invasion. TGFB1, which can act as a tumor suppressor early in cancer but promote tumor growth at advanced stages, showed decreased expression in these samples.

Gene Ontology and KEGG pathway analyses revealed coordinated disruptions across immune response, transcriptional misregulation in cancer, and viral protein interactions with cytokines and cytokine receptors. Of the 72 altered genes in the cytokine–cytokine receptor interaction pathway, 67 were upregulated, and all 31 genes in the viral protein interaction pathway were upregulated, suggesting a strong cytokine-mediated inflammatory milieu within the tumor microenvironment. CXCL8, also known as IL-8, was upregulated, consistent with protumorigenic roles in invasion, angiogenesis, and matrix metalloproteinase activation, and with ultraviolet-induced IL-8 production in corneal epithelium. IL31RA was also elevated, aligning with reports that IL-31 signaling can promote tumor progression and metastasis.

The authors caution that the viral protein interaction signal likely reflects heightened immune activation rather than direct proof of viral causation, though papillomaviruses are known to act as cofactors with ultraviolet radiation in non-melanoma skin cancer, a possibility deserving further research. The study also carries limitations: the modest cohort size, anatomical heterogeneity among tumors, and bulk RNA sequencing without single-cell resolution may blur epithelial, stromal, and immune contributions. Future work should validate key proteins by immunohistochemistry, localize expression in situ, incorporate single-cell approaches, screen for viral sequences, and compare breeds with different pigmentation phenotypes.

Nevertheless, this first global expression profile of BOSCC provides a mechanistic framework uniting tumor-associated inflammation, epithelial keratinization, extracellular matrix remodeling, and disruption of limbal homeostasis. Because the samples were collected during routine field work under extensive management conditions, they reflect the pathological cases veterinarians face daily. The researchers hope the gene panel identified here will serve as a foundation for future genomic studies and, in the long term, enable molecular tests for selecting non-susceptible breeding animals, potentially reducing the burden of this cancer in Hereford cattle through informed selective breeding programs.

Subject of Research: Transcriptome analysis of bovine ocular squamous cell carcinoma in Hereford cattle

Article Title: Transcriptome analysis of bovine ocular squamous cell carcinoma (BOSCC) in Hereford cattle

Article References: Balemian, N., Pedrana, G., Fernández-Calero, T., Irabuena, O., & Armstrong, E. (2026). Transcriptome analysis of bovine ocular squamous cell carcinoma (BOSCC) in Hereford cattle. Veterinary Oncology, 3(1), Article 8. https://doi.org/10.1186/s44356-026-00058-3

Image Credits: AI Generated

DOI: 10.1186/s44356-026-00058-3

Keywords: bovine ocular squamous cell carcinoma, BOSCC, Hereford cattle, transcriptome analysis, RNA-seq, gene expression, cancer biology, veterinary oncology, ocular tumor, keratinization, tumor microenvironment, selective breeding