Biomarker discovery in ocular surface diseases through comprehensive omics investigations: a narrative review

Introduction

Background

In recent decades, our knowledge of the molecular underpinnings of ophthalmic disorders has grown substantially. Unraveling the complex interplay between genetic predisposition and environmental influences now demands high-throughput, systems-level approaches capable of hypothesis-free exploration across entire molecular networks (1).

Omics studies meet this need by enabling large-scale characterization and quantification of biological molecules. Examples of omics studies include genomics and epigenomics, transcriptomics, proteomics, metabolomics, and lipidomics, which correspond to global analyses of genes and methylated DNA, RNA, proteins, metabolites, and lipids, respectively (1). Multi-omics approaches, supported by the expanding integration of advanced bioinformatic tools, ranging from knowledge-based platforms and network-focused data-driven frameworks, together with artificial intelligence and curated molecular databases, further strengthens these applications by accelerating biomarker detection and supporting computer-assisted diagnostics (2). By capturing perturbations across the various ‘omes’, including the genome and epigenome, transcriptome, proteome, metabolome, and lipidome, these approaches provide insights into disease mechanisms, facilitate the discovery and validation of diagnostic, prognostic, and predictive biomarkers, and support the stratification of patients into biologically meaningful subgroups (3). In addition, they highlight potential therapeutic targets that can be explored in translational studies.

Rationale & knowledge gap

While omics has already delivered important advances in retinal diseases such as age-related macular degeneration (AMD), diabetic retinopathy (DR), retinal detachment (RD), and glaucoma, investigations targeting the anterior segment remain relatively limited and fragmented (4-7).

Objective

This review aims to provide an overview of omics approaches commonly applied in ophthalmology and to summarize the contribution of single- and multi-omics technologies to advancing our understanding of ocular surface diseases. The ocular surface comprises the cornea and conjunctiva and is affected by a broad spectrum of disorders with diverse etiologies and clinical behavior. Accordingly, we sought to present a representative narrative overview spanning the ocular surface disease continuum.

The conditions discussed were selected to reflect this biological and clinical diversity. Importantly, we focused on diseases that have already been the subject of tear-based proteomic, metabolomic, lipidomic, and transcriptomic investigations, enabling assessment of how omics technologies contribute to disease stratification, severity grading, and subtype differentiation. Common, highly prevalent disorders such as dry eye disease (DED) and meibomian gland dysfunction (MGD) are included as prototypical multifactorial inflammatory diseases with substantial public health impact. Non-inflammatory, non-neoplastic degenerative conditions, including epithelial basement membrane dystrophy (EBMD) and Salzmann’s nodular degeneration (SND), provide insight into epithelial adhesion abnormalities and stromal remodeling. Pterygium is examined as a paradigmatic example of an ultraviolet (UV) radiation-related ocular surface disease with proliferative and tumor-like features. Finally, ocular surface squamous neoplasia (OSSN) and conjunctival melanoma (CM) represent the malignant end of the ocular surface disease spectrum. We present this article in accordance with the Narrative Review reporting checklist (available at https://aes.amegroups.com/article/view/10.21037/aes-2025-1-64/rc).

Methods

For the present narrative, non-systematic review, the literature search was conducted on July 15, 2025. We explored the PubMed/MEDLINE, Scopus, and Cochrane Library databases. Additional sources, such as Google Scholar and the reference lists of included studies, were also screened. The search strategy combined both MeSH terms and free-text keywords. Controlled vocabulary included “Ocular Surface Squamous Neoplasia”, “Conjunctival Neoplasms”, “Conjunctival Melanoma”, “Dry Eye Syndrome”, “Meibomian Gland Dysfunction”, “Pterygium”, “Corneal Dystrophies”, “Genomics”, “Proteomics”, “Metabolomics”, and “Transcriptome”. Free-text terms encompassed “ocular surface squamous neoplasia”, “OSSN”, “conjunctival intraepithelial neoplasia”, “CIN”, “conjunctival melanoma”, “dry eye disease”, “meibomian gland dysfunction”, “Salzmann’s degeneration”, “pterygium”, “omics”, and “biomarkers”. Filters were applied to restrict the search to English-language publications (Table 1). A detailed PubMed search string is presented in Table S1.

The timeframe for the search was set from the 1^st of January 1990 to the 15^th of July 2025 to capture both early molecular investigations and more recent omics-based studies. Eligible publications included original research articles, systematic reviews, meta-analyses, and translational studies applying omics technologies, including genomics, transcriptomics, proteomics, metabolomics, or lipidomics, to ocular surface diseases or neoplasia. Studies published in languages other than English were excluded. The selection process was carried out independently by two reviewers (N.E.K. and S.P.), who screened titles and abstracts before retrieving eligible full texts. Any discrepancies were resolved through discussion.

Omics techniques

Genomics is the study of the entire genome, encompassing DNA sequencing and analysis of genetic variations. At the genomic level, much of the progress in understanding complex traits has come from genome-wide association studies (GWAS) (8). This approach seeks to link genetic variations with phenotypic differences by examining whether certain alleles occur more frequently in affected individuals compared to unaffected but ancestrally similar controls. Large case-control cohorts are typically analyzed using high-density single-nucleotide polymorphism (SNP) microarrays, which allow the simultaneous assessment of hundreds of thousands of variants distributed across the genome (9). Next-generation sequencing (NGS) approaches, including whole exome sequencing (WES) and whole-genome sequencing (WGS) studies are also particularly valuable in assessing large numbers of loci for the presence or absence of a genomic or epigenomic characteristic (10).

Epigenomic alterations are affecting gene regulation without altering DNA sequence and may occur through DNA methylation, histone modification, nucleosome remodeling and non-coding RNAs. Epigenetics or epigenomics is the field that studies these heritable changes, which due to their reversible nature are an appealing focus for targeted therapies (11). Several techniques have been developed to help identify epigenetic features, including array and sequence-based assays, with DNA methylation arrays and bisulfite sequencing being the ones most widely used in the field of ophthalmology (12,13).

Regulatory non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have attracted considerable attention for their ability to modulate gene expression at both the transcriptional and translational levels. The investigation of these molecules, along with other RNA species, falls within the scope of transcriptomic research. Transcriptomic technologies encompass both hybridization-based technologies and sequencing-based approaches, as well as RNA-sequencing. Transcriptomic studies provide valuable insights into the dynamic patterns of gene expression that underlie disease pathogenesis and have been consistently applied in ocular surface disease and neoplasia (14,15).

Proteomic studies have become a powerful complement to genomics and transcriptomics in ophthalmology, where direct tissue biopsies are limited by the eye’s nonregenerative cell populations (16). High-resolution mass spectrometry and protein chips, including stable isotope labeling by amino acids in cell culture (SILAC), isotopically coded affinity tags (iCAT), isobaric tags for relative and absolute quantitation (iTRAQ), and absolute quantification of proteins (AQUA), now allow detailed proteomic analysis of ocular fluids, such as aqueous humor (AH), vitreous, and tears, which serve as biologic fluids for liquid biopsies. By capturing protein-rich signatures, proteomic techniques can reveal disease mechanisms and support personalized therapeutic strategies (16). Unlike single- or multiplex-ELISAs that require preselected targets, unbiased proteomics surveys thousands of proteins from microvolume samples. Advances in AI-driven analytical pipelines, together with the expansion of publicly available databases, now enable more effective analysis of complex protein and metabolite mixtures, providing cell-level insights into disease processes (16).

Metabolomics and lipidomics studies are focused on the identification and quantification of molecular metabolites with a mass range between 50 and 1,500 Da, which are required for the maintenance of a specific cell or tissue function and are detectable within biofluids (17). Metabolomic studies use either an untargeted approach, which profiles as many metabolites as possible to drive hypothesis generation and biomarker discovery, or a targeted approach, which precisely quantifies a predefined panel of metabolites to test and validate specific hypotheses (17). The applications of metabolomic analysis in ophthalmology have shed light on various diagnostic and prognostic biomarkers in ocular diseases, including dry eye syndrome, keratoconus, pterygium and retinal diseases, among others (18).

In recent years, omics studies have been revolutionized by the broader availability and use of public omics resources. Large public repositories, including the Gene Expression Omnibus (GEO) and ProteomeXchange for nucleic acid and protein data, respectively, as well as metabolomics resources such as MetaboLights, Metabolomics Workbench, and Dryad, provide foundational infrastructure for data sharing. These platforms enable reuse and validation of bulk and single-cell transcriptomic datasets, while eye-focused platforms integrate disease-associated genes, variants, biomarkers, and drug information using standardized ontologies. By integrating multi-omics data with clinical and pharmacological annotations, these databases facilitate biomarker discovery, cross-disease comparisons, and translational analyses. To ensure reproducibility of ocular omics research, adherence to FAIR principles is essential, as it enhances data transparency, interoperability, and the robustness of downstream meta-analyses (19).

Ocular surface diseases and omics techniques

DED and MGD

DED is characterized by disruption of tear film homeostasis, which subsequently promotes ocular surface inflammation and discomfort (20,21). It is generally categorized into two major subtypes: aqueous-deficient dry eye (ADDE) and evaporative dry eye disease (EDED), with the latter being more frequently encountered in clinical practice (20,21). In EDED, instability of the tear film often arises from abnormalities in the lipid layer (20,21). Because the meibomian glands are the principal source of tear film lipids, dysfunction of these glands (MGD) represents a predominant cause of EDED. Although DED is a common ophthalmological condition (22), current treatments are mainly palliative, suggesting that its underlying pathogenesis is more complex than previously understood. In this context, the lack of robust and objective biomarkers has limited precise disease stratification and treatment monitoring. Recently, artificial intelligence-based approaches applied to ocular surface imaging have identified quantitative biomarkers that strongly correlate with disease severity, including meibomian gland dropout and density, tear film instability, tear meniscus height, and epithelial or corneal nerve alterations. These imaging-derived biomarkers provide an objective framework for assessing DED severity and highlight the multifactorial nature of the disease, particularly in EDED associated with MGD (23).

Across omic layers, DED emerges as an immune-metabolic disorder, where predisposing genetic factors together with ocular surface stressors lead to immune-inflammatory responses, tissue remodeling and osmotic pressure imbalances. Genomic screens of tear samples highlight candidate diagnostic biomarkers: a multiplex bead analysis in diabetic DED flagged increased EGF levels compared to the non-diabetic DED group (24), while a biobank-scale analysis identified independent risk loci: DNAJB6, MAML3, LINC02267, DCHS1, SIRPB3P, HULC, MUC16, GAS2L3, ZFPM2, whose polygenic score tracked prognosis (25). Moreover, genetic studies in blood samples have associated cytokine-gene variants including IL1B rs1143634 and IL6R rs8192284 with the susceptibility of developing non-Sjögren DED (26). Polymorphism in the TNFR1 gene, a key regulator of inflammation and innate immunity, has also been identified in DED samples, collectively reinforcing a genetic contribution to inflammatory signaling in the pathogenesis of the disease (27). At the epigenomic level, bisulfite sequencing in Sjögren-syndrome DED in NOD mice showed hypermethylation in the GTPase activation and Ras pathways, underscoring epigenetic control of inflammatory and stress responses and motivating human validation (28).

Transcriptomic studies converge on immune-stress modules across ocular surface tissues to analyze the complete set of RNA transcripts produced by a specific tissue. Integrated cornea and conjunctiva analyses report shared and compartment-specific transcripts, including Hdac4, Rhoa, Gnas, Mapk3/Map3k1, Mafg in cornea and Smad7, Nr3c1, Tcf4 in conjunctiva, which are implicated in inflammatory pathways (29). Similar findings have been reported in the study of Dong et al., where machine learning-guided gene selection with LASSO and SVM-RFE in a corneal injury mouse model identified JAK1, SKI, and ZBTB16 as key regulators in DED (30). Their upregulation paralleled increased expression of pro-inflammatory cytokines, suggesting a mechanistic link between innate immune activation and ocular surface stress responses (30). The search for potential biomarkers has highlighted HLA-DR as a potential biomarker for severity and prognosis of DED (29). Other studies, employing conjunctival imprint cytology and transcriptome sequencing, have reported aberrant expression of genes such as CCL22, C2, CFB, PSCA, FOS, TSC22D1, CAPN13, and CXCL6, suggesting their potential as novel diagnostic or therapeutic targets (31,32). It should be emphasized, however, that although omic studies have identified candidate genes, pathways, and molecular signatures associated with DED, their mechanistic roles and causal contributions to disease pathogenesis remain, to a significant extent, unresolved.

The hypothesis that DED pathogenesis is linked to an interplay between microorganisms and immune responses is supported by proteomic studies of tears and glands, which consistently map decreased concentrations of antimicrobial proteins, such as lysozyme, PRR3, and PRR4 in patients with DED (33), and increased inflammatory mediators, such as IL-17A (34), S100A6/A8/A9, thioredoxin and IgG-1 chain C region (35). Notably, the reduced expression of PRR4 appears to correlate with DED severity, making PRR4 an important biomarker (33,36). Single-cell RNA-sequence analyses have identified a persistently pro-inflammatory ocular surface microenvironment, marked by infiltration of macrophages, expansion of fibroblast-like epithelial subtypes with inflammatory phenotypes, and dominant CD4⁺ T-cell populations, including Th1 and Th17 cells, which together sustain chronic inflammation across disease stages (37). The clinically relevant distinction between ADDE and MGD-related EDED is also reflected at the proteomic level, where proteins such as annexin A1, clusterin (CLU), orosomucoid 1 (ORM1), and lactoperoxidase (LPO) are overexpressed in MGD, suggesting their potential as differentiating biomarkers (35). For MGD, Tong et al. have proposed S100A8 and A9 as biomarkers to track MGD severity (38). Another important distinction is Sjögren-related DED, which at the proteomic level shows pronounced immune-activation signatures (39), while proteomic signatures have also been reported in diabetes-related DED and smoking-linked PRR4/PRR1 changes in thyroid-related DED (40-42). Spatial transcriptomics of the lacrimal gland features in Sjögren-related DED implicate macrophage-driven inflammation through the TYROBP and Car6 signaling network with epithelial metabolic failure, highlighting both pathways as potential therapeutic targets (43). Therapeutic-response proteomics indicate immune-related shifts with cyclosporine A and diquafosol tetrasodium, which were distinct for each treatment type. While both improve disease symptoms, the two drugs activate different tear-specific biomarkers, with cyclosporine mainly influencing immune-related pathways and diquafosol inducing broader protein shifts (44).

Metabolomic profiling has further implicated several pathways in the pathogenesis of DED, including steroid hormone biosynthesis, glycolysis, gluconeogenesis, amino acid metabolism, glycerophosphocholine synthesis, and O-linked glycosylation of β-N-acetylglucosamine (45,46). Additionally, lipidomic surveys have catalogued 256 tear and meibum lipid species across 12 classes, with metabolites of arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) showing associations with clinical parameters such as tear break-up time (TBUT), Schirmer’s test, and ocular surface staining (47). Important advances have also been made in MGD, where lipidomic analyses reveal age-related reductions in polyunsaturated fatty acids (PUFAs) and their derivatives, with the exception of omega-3 docosapentaenoic acid (DPA), as well as correlations between very-long-chain (O-Acyl)-ω-hydroxy fatty acids (OAHFAs) and disease severity (48,49). The findings of omics studies concerning DED are summarized in Table 2.

EBMD and SND

EBMD and SND are two separate ocular surface diseases both characterized by changes in the corneal epithelium and Bowman’s layer (50,51). EBMD, also known as Cogan’s microcystic dystrophy, anterior basement membrane dystrophy, or map-dot-fingerprint dystrophy, occurs in 2 to 6% of the general population (52). In the updated classification of corneal dystrophies, EBMD is now regarded as a corneal degeneration rather than an inherited dystrophic disease, as no consistent inheritance pattern has been established (53). In rare familial cases of EBMD an autosomal dominant inheritance pattern with incomplete penetrance has been reported. In such cases, mutations in the TGFBI gene of chromosome 5q31 have been identified (54). These mutations are thought to alter integrin-binding regions or protein folding, thereby affecting epithelial adhesion and basement membrane integrity (53). In contrast, SND has not yet been linked to specific inherited mutations and is considered primarily degenerative rather than genetically determined (55).

To explore the transcriptomic landscape of EBMD and SND, impression cytology (IC) has been used in a recent study to assess mRNA expression of various transcription factors (56). Notably, TP63, a transcription factor responsible for the migration and proliferation of corneal epithelial cells, was found overexpressed in both EBMD and SND conjunctival samples (56). The same pattern has been observed in OSSN and particularly conjunctival intraepithelial neoplasia (CIN), which reflects that cell proliferation and inflammation is involved in the pathophysiology of both corneal epithelial diseases (57). Reduced expression of DSG1 and E-cadherin, two key adhesion molecules that improve cell adhesion and differentiation, was observed in corneal epithelia of both EBMD and SND, which can be associated with the increased susceptibility of affected patients to corneal erosions (56). In EBMD and SND, molecular alterations point toward disrupted epithelial identity and regulation. Specifically, an increased expression of the conjunctival keratin KRT13 and a corresponding imbalance between conjunctival and corneal keratins suggest that epithelial cells undergo a phenotypic shift away from corneal differentiation (56). miRNAs provide an additional regulatory layer in the pathogenesis of EBMD and SND. Notably, miR-138-5p and miR-204-5p, which normally act as negative regulators of cell proliferation and migration, are significantly reduced in the corneal epithelium of both diseases (56). Their downregulation may thus contribute to abnormal epithelial turnover, migratory activity, and possibly inflammation. Since PAX6 and miR-204-5p are known to be co-regulated during eye development, their joint deregulation in EBMD and SND suggests a developmental and regenerative pathway disturbance reminiscent of aniridia-related keratopathy (56). Although metabolomic studies in EBMD and SND remain limited, insights from related ocular surface diseases indicate a possible role of retinoic acid metabolism (56). Alterations in ADH7 and ADH1A1 expression were not observed in EBMD or SND, distinguishing them from pterygium (56). This suggests that EBMD and SND are less characterized by metabolic dysfunction and more by defects in adhesion, differentiation, and regulatory RNA networks (Table 3).

Pterygium

Pterygium is an ocular surface disorder characterized by hyperplastic growth and centripetal extension of altered limbal epithelial cells. This process is accompanied by dissolution of Bowman’s layer and activation of epithelial-mesenchymal transition (EMT) pathways (58). Clinically, this results in a wing-shaped fibrovascular tissue growth of the conjunctiva onto the cornea. Its pathogenesis is multifactorial, involving both genetic predisposition and environmental influences, with prolonged UV radiation exposure and the associated chronic inflammatory response regarded as the predominant drivers (58). Disease grading and progression are increasingly informed by omics-based studies, which have delineated molecular biomarkers, while artificial intelligence approaches have identified clinically relevant imaging biomarkers, including fibrovascular tissue extent and corneal encroachment (23).

From a genomic perspective, multiple mechanisms contribute to disease initiation and progression, including driver mutations, germline variants, and UV-responsive mitogens. Dysregulation of p53 represents a pivotal event in the pathogenesis of pterygium, with both abnormal expression and impaired function contributing to disease development (59,60). Somatic mutations in the TP53 gene, particularly within exons 4–8, have been detected in approximately 15.7% of lesions (60). In addition, UV-induced upregulation of survivin observed in pterygium tissue further suppresses p53 activity, thereby undermining normal mechanisms of cell-cycle control and DNA repair (59). One of the earliest molecular biomarkers implicated in pterygium is heparin-binding epidermal growth factor (HB-EGF), a potent epithelial mitogen whose activation in pterygium is induced by UV radiation (61). Additional molecular events implicated in pterygium pathogenesis include activating Ki-ras mutations. Codon 12 alterations in the Ki-ras gene were identified in a cohort of 50 pterygia and their matched blood samples, suggesting the potential utility of those mutations as biomarkers of diagnosis and recurrence risk (62). Differential expression of neutrophil gelatinase-associated lipocalin (NGAL), matrix metalloproteinase-9 (MMP9), and insulin-like growth factor-binding protein 3 (IGFBP3), highlights the contribution of extracellular matrix remodeling and proliferative signaling in disease progression (63,64). Finally, several germline variants have been linked to pterygium susceptibility. These include the ACE I/D polymorphism, with the DD genotype conferring an increased risk (65), and a familial missense variant in CRIM1 (H412P), which may facilitate aberrant cellular migration and angiogenesis, although larger studies are required to confirm its pathogenic significance (66).

Epigenomic studies in pterygium, particularly with respect to DNA methylation have highlighted aberrant methylation patterns in extracellular matrix-related genes, including TGM2, MMP2, CD24, E-cadherin, MDM2 promoter and p16 promoter (67-69). The UV-responsive DNA damage checkpoint genes LATS1/2 exhibit high levels of methylation, suggesting that continued UV exposure may lead to epigenetic silencing of these regulators and thus to higher risk of pterygium recurrence (70). Histone-level regulation in pterygium is suggested by experiments where butyrate/phenylbutyrate (HDAC inhibitors) reduce fibrosis-related proteins, such as α-SMA, collagen I/III, and MMP1 in pterygium models, nominating histone acetylation as a modifiable axis in treatment strategies for pterygium (71).

miRNA dysregulation in pterygium has emerged as a promising area of research, with potential implications both as prognostic biomarkers and as therapeutic targets. In particular, miR-221 upregulation and miR-215 downregulation have been shown to play a crucial role in promoting cell proliferation (72). The regulatory function of miR-215 in the G1/S and G2/M cell cycle transitions further highlights its potential as a therapeutic target (73). Similarly, miR-145, which is consistently downregulated in pterygium, has been implicated in the miR-145-MDM2-p53 axis, suggesting its therapeutic relevance (74). Moreover, the tumor-suppressive miR-122 is significantly decreased in pterygium, reinforcing its role as a candidate therapeutic target (75). Recent studies highlight the pivotal role of non-coding RNAs and protein dysregulation in pterygium pathogenesis. Upregulated miR-3175 promotes proliferation, migration, invasion, and EMT through inhibition of Smad7 (76), while aberrant EGFR signaling has been implicated in EMT and may represent a therapeutic target, particularly as miR-218-5p suppresses EGFR and its downstream PI3K/Akt/mTOR pathway (77). Other miRNAs, including miR-200a, miR-145, and several fibroblast-associated miRNAs, such as miR-143a-3p and miR-181a-2-3p, demonstrate diagnostic and prognostic value (13). In addition, multiple lncRNAs, such as linc-9432, and circRNAs, such as circ-LAPTM4B have been shown to regulate apoptosis, EMT, and stemness features, underscoring their therapeutic potential (73,78).

Proteomic analyses further reveal oxidative stress-related proteins, including PRDX2, ALDH3A1 and PDIA3, as well as MMP10 and CD34 as key factors in UV-induced damage, proliferation, invasion, and neovascularization, linking them to both disease progression and recurrence (79,80). Downregulation of ADH1A1 and FABP5 is further supported by IC studies, implicating the dysregulation of the retinoid acid pathway in pterygium pathogenesis (56). Lastly, tear metabolomics in pterygium have uncovered inflammatory lipid mediators which are relevant to disease pathophysiology, including PGE2, 5-HETE, and 12-HETE (81). In a separate study, increases in amino acid levels and particularly arginine, methionine, glycine and tyrosine differed significantly between pterygia and normal conjunctiva (82). The pterygium-related omics analyses are summarized in Table 4.

OSSN

OSSN encompasses a wide spectrum of dysplastic changes of the conjunctival and corneal epithelium, ranging from benign squamous dysplasia to conjunctival and corneal intraepithelial neoplasia (CIN), and ultimately to squamous cell carcinoma (SCC) (83). Much like pterygium, UV-radiation plays an important role in the pathogenesis of OSSN (83). In recent years, expanding research into the pathogenesis of OSSN has intensified efforts to identify diagnostic and therapeutic biomarkers and to explore the potential for targeted therapies (84).

Omics studies are identifying recurrent genomic alterations that highlight both environmental mutagenesis and intrinsic tumor suppressor pathway disruption. UV-signature TP53 mutations are among the most consistent findings, with CC→TT dimer transformations in exons 5–9 reported in nearly half to over 90% of cases (84-90). These rates mirror other SCCs (91,92), underscoring UV exposure as a dominant carcinogenic driver. Alterations in CDKN2A represent another hallmark of OSSN, with loss-of-function mutations, locus deletions, and UV-induced promoter hypermethylation frequently disrupting the p16-Rb axis (93-95). Functional loss of CDKN2A appears to act as a trigger event in malignant transformation, as opposed to TP53 mutations, which are also common in histologically normal sun-exposed epithelium (96). Prognostically, p16^INK4a expression appears to correlate with tumor progression, further supporting its role as a significant biomarker (97).

Whole-exome sequencing and integrative genomic studies have revealed additional recurrent events in chromatin modifiers (KMT2C/D, CREB, EP300), differentiation regulators (NOTCH1–3, FAT1/3), and proliferative pathways (EGFR, PI3K/AKT/mTOR, RAS/MAPK) (88,89,93,95,98). NOTCH and FAT mutations are thought to occur early in SCC pathogenesis, driving squamous differentiation programs and tumor initiation (99). On the other hand, alterations in KMT2 genes and other chromatin modifiers such as the cyclic-AMP response element-binding protein (CREB) gene and EP300 are considered later events and have been associated with poorer outcomes in cutaneous SCC (100,101). EGFR aberrations, including exon 19 deletions and exon 21 mutations, have been identified in up to 27% of conjunctival SCCs (102), potentially linking EGFR pathway dysregulation to malignant progression and therapy resistance (103,104). Other lesions include HGF/MET activation (88), UV-signature TERT promoter mutations (95,105), titin (TTN) alterations potentially linked to interferon resistance (106), and amplifications at 8p11.22 affecting ADAM family genes (107). Collectively, these genomic findings underscore a complex mutational landscape with both prognostic and therapeutic implications, including the potential for immunotherapy in high tumor mutational burden, HPV-negative OSSN (95).

Epigenetic mechanisms provide an additional layer of regulation in OSSN, modifying gene activity without altering DNA sequence. DNA methylation changes are frequently reported, with both hyper- and hypomethylation events implicated. Promoter demethylation of DNMT3L has been observed in OSSN compared to normal conjunctiva, resulting in its aberrant overexpression (108,109). Conversely, hypermethylation of tumor suppressor genes, such as p16^INK4a and Stratifin/14-3-3σ, has also been reported in conjunctival SCC, leading to decreased expression and tumor progression (97,110). Histone modifications, particularly upregulation of the histone deacetylase SIRT1, have been detected in OSSN (111). By deacetylating both histone and non-histone proteins, SIRT1 attenuates p53 activity and may worsen prognosis (112). However, contradictory evidence in other SCC types highlights the complexity of SIRT1’s role in disease progression (113,114). Small non-coding RNAs also appear to participate in OSSN pathogenesis. For instance, miR-196b-5p is upregulated in conjunctival SCC and may help distinguish OSSN from other ocular neoplasms (15). Interestingly, miRNAs such as miR-21 have been linked to chemotherapy resistance in other cancers (115), raising the possibility that specific miRNAs may serve as prognostic or predictive biomarkers in OSSN.

Recent transcriptomic studies demonstrate marked upregulation of keratinization and epidermal differentiation genes, including FLG2, LCE3D, and SPRR2G, in conjunctival SCC compared to healthy conjunctiva (116). Stratified epithelial keratins (KRT14, KRT16, KRT17, KRT6A-C) and S100 family proteins (S100A2, S100A7) also appear elevated, suggesting altered differentiation and stress response pathways (116). A 30-gene classifier derived from these transcriptomic data successfully distinguished conjunctival SCC from papilloma and normal conjunctiva with high accuracy, supporting transcriptome profiling as a diagnostic adjunct in challenging histological cases (116). Immune-related signatures in OSSN are equally prominent. Equine OSSN transcriptomics revealed upregulation of inflammatory mediators such as OSM, IL-1β, CXCL8, PTGS2, and TREM1, coupled with downregulation of ciliogenesis genes (117). Human OSSN samples show strong immune checkpoint activity, with PD-L1 expressed in up to 100% of conjunctival SCCs and correlating with invasiveness and T-stage in one study (118). Treg infiltration also increases with disease stage, with CXCR4⁺ FOXP3⁺ cells enriched in advanced tumors (119). Together, these findings position transcriptomic studies as a promising approach to refine diagnosis, predict recurrence, and identify immune-modulatory targets, including PD-1 blockade.

While proteomics is well-established in ocular oncology, where AH and vitreous analysis have transformed uveal melanoma and retinoblastoma management (120-122), applications in OSSN remain exploratory. Recent work demonstrates that tear-based miRNA assays can differentiate OSSN from pterygium with high accuracy (123). Metabolomic profiling represents a promising tool to capture tumor reprogramming at the biochemical level. Evidence from squamous neoplasms related to OSSN supports its relevance. In oral SCC, increased levels of glutamate and upregulation of glutaminase have been associated with tumor aggressiveness and poor prognosis (124,125). Similarly, elevated purine derivatives, such as hypoxanthine and guanosine, reflect the heightened nucleotide demand of rapidly proliferating squamous tumors (126). Dysregulation of amino acid and fatty acid metabolism, including enhanced glycine and omega-3 PUFA pathways, further correlates with invasive potential and immune suppression (127). Head and neck SCC metabolomics implicates aerobic glycolysis and broad metabolic downregulation in HPV-negative tumors, alongside T-cell exhaustion driven by kynurenine metabolism (128,129). These insights underscore metabolic reprogramming as both a hallmark of tumor biology and a source of therapeutic vulnerability (Table 5). Future studies are needed to validate whether such metabolic pathways distinguish OSSN from benign ocular surface disease or could help predict therapeutic outcomes.

CM

CM is a rare but aggressive ocular surface malignancy that arises from the melanocytes of the ocular surface. Melanocytic lesions of the conjunctiva, such as primary acquired melanosis (PAM) and conjunctival melanocytic intraepithelial neoplasia (C-MIN) are considered precursors of CM (130). This precursor spectrum helps explain the variable clinical behavior and underscores the role of chronic UV exposure on the bulbar surface (131). Given CM’s high recurrence rates and metastatic potential, a range of omics studies have been conducted to elucidate its molecular mechanisms and to identify biomarkers that support timely diagnosis and targeted therapy.

At the molecular level, whole-exome and genome studies consistently demonstrate a high tumor mutational burden with a dominant UV signature, C>T and CC>TT transitions, linking sunlight to tumorigenesis, similar to what is observed in OSSN (132). Pathway-centric analyses converge on constitutive MAPK and PI3K/AKT/mTOR cell proliferation pathway activation as the central drivers. Driver mutations in the BRAF, NRAS, c-KIT, and NF1 genes result in activation of these pathways and thereby to disease progression (95). BRAF mutations, predominantly including V600E but also V600K, V600R, D594G, and G469A single point mutations, lead to constitutive activation of the kinase domain of the BRAF protein and consequently to downstream activation of the MAPK pathway (133). CMs bearing BRAF mutations have been associated with greater invasion and metastatic potential (134,135). Other alterations leading to pervasive MAPK signaling include NRAS mutations, which are largely Q61 substitutions and mostly mutually exclusive with BRAF (135-137), NF1 loss-of-function mutations (137,138), and rarely c-KIT mutations (139). ACSS3 has recently been implicated in the pathogenesis of CM, with a recurrent missense mutation (c.1594C>T/p.P532S) being identified near the enzyme’s ATP-binding site in patient samples (140). ACSS3 encodes a mitochondrial acetyl-CoA synthetase, which facilitates acetyl-CoA production from acetate (141). This pathway is preferentially exploited by tumor cells under metabolic stress when glycolytic acetyl-CoA synthesis is diminished (141). Since acetyl-CoA supports both lipid synthesis and histone acetylation, ACSS3 activity directly contributes to tumor growth and gene regulation (140).

The development of CM is further influenced by epigenetic alterations. Telomerase reactivation through TERT promoter mutations, often carrying a UV-signature, occurs in approximately 5% of CM cases (136,142,143). In addition, chromosomal copy number alterations (CNAs) are frequently observed, particularly in BRAF/NRAS wild-type tumors, with 6p gain being the most common event detected by diverse molecular approaches, including whole-exome sequencing (132,142,144,145). More recently, dysregulated miRNA expression has been implicated in CM pathogenesis, with several miRNAs, including miR-30d, miR-506, miR-509, miR-146, and miR-20b, found to be upregulated. Notably, miR-20b has been linked to PTEN suppression, while miR-3916 overexpression is associated with local recurrence, suggesting that targeting miRNA pathways may offer novel therapeutic opportunities (134,146,147).

Beyond genomic studies, transcriptomic profiling in CM reveals distinctive molecular subtypes that closely mirror classifications described in cutaneous melanoma. In the study of Cisarova et al., patients in the cell cycle-driven class exhibited significantly greater tumor thickness, suggesting more aggressive disease (140). In the same study, integration of genomic and transcriptomic data showed frequent alterations in canonical cancer pathways, with universal involvement of RTK-RAS signaling and high prevalence of Hippo and Wnt pathway alterations. RNA-seq also identified 58 unique gene fusions, including recurrent events involving PMEL, the gene coding the promelanosome protein P100, implicating genes linked to pigmentation and cancer biology in CM pathogenesis (140). Aberrant expression of the chemokine receptors CXCL12, CXCR4, CCR10, and CCR7 has also been reported in previous studies (148,149). Interestingly, the expression of CXCR4, CCR10, and CCR7 has been associated with progression of nevi and PAM to CM, as well as with the metastatic potential of CM (148,149), underscoring the relevance of these receptors as potential biomarkers and therapeutic targets (Table 6).

Molecularly guided therapeutic strategies are already being applied in CM. In BRAF-mutant cases, case series have reported radiographic and clinical responses to BRAF inhibitors such as vemurafenib and dabrafenib, as well as to BRAF/MEK inhibitor combinations (dabrafenib/trametinib; vemurafenib/cobimetinib). These responses include near-complete regressions and effective neoadjuvant tumor downsizing, which can facilitate surgical resection (137,142,150-153). Similarly, immunotherapeutic approaches, including anti-PD-1 agents (nivolumab, pembrolizumab) and anti-CTLA-4 therapy (ipilimumab), administered either as monotherapy or in combination, have produced complete responses or durable partial remissions in locally advanced and metastatic CM (154-157). However, these benefits are often accompanied by substantial and sometimes severe adverse effects.

Limitations, clinical applicability, and future directions of omics studies in ocular surface diseases

Despite the advances enabled by omics technologies, their clinical translation in ocular surface diseases remains constrained by well-recognized methodological and translational limitations, with sample heterogeneity and source bias constituting major obstacles to reproducibility and validation. In ocular surface research, commonly used specimens, such as tears, IC, and conjunctival tissue, capture distinct biological compartments and disease stages, yet are often collected using non-standardized protocols. For example, tear-based analyses, although non-invasive and clinically attractive, are particularly vulnerable to variability related to collection technique, tear volume, and environmental exposure, limiting cross-study comparability.

Technological and analytical constraints further hinder biomarker robustness. Current mass spectrometry-based platforms face trade-offs between sensitivity, coverage, and reproducibility, with low-abundance metabolites, lipids, and regulatory molecules frequently underrepresented. Similar issues affect transcriptomic and proteomic studies, where batch effects, platform-specific biases, and heterogeneous bioinformatic pipelines contribute to inconsistent findings. Unfortunately, most reported biomarkers remain exploratory and are identified in small discovery cohorts without independent replication or longitudinal assessment. In ocular surface diseases, fluctuating disease activity, overlapping clinical phenotypes, and treatment-related effects further complicate validation.

Future progress will depend on methodological standardization and integrative study designs. Harmonized disease definitions, standardized sampling workflows, and multicenter longitudinal cohorts are essential to establish biomarker reliability and clinical relevance. Multi-omics integration, together with single-cell and spatial transcriptomics, offers promising strategies to overcome current limitations by resolving cell-type-specific and spatially localized molecular changes within the ocular surface. When combined with rigorously validated machine learning approaches, these technologies may enable more precise disease classification, objective severity assessment, and identification of biomarkers predictive of therapeutic response.

Conclusions

Omics technologies have profoundly expanded our understanding of the molecular basis of ocular surface diseases, revealing disease-specific signatures that extend beyond conventional histopathology. These approaches have uncovered key pathways involved in inflammation, epithelial integrity, tumorigenesis, and immune regulation, offering novel opportunities for biomarker discovery and targeted therapy.

However, meaningful clinical translation remains limited by methodological heterogeneity, insufficient validation, and fragmented analytical approaches. Future progress will depend on standardized study designs, robust multicenter validation, and the integration of multi-omics with advanced computational methods. Through these efforts, omics research has the potential to transition from exploratory discovery to clinically applicable precision medicine in ocular surface disease diagnosis and management.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Roy S. Chuck, Joann J. Kang and Viral V. Juthani) for the series “Inflammatory Disorders of the Cornea and Ocular Surface” published in Annals of Eye Science. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aes.amegroups.com/article/view/10.21037/aes-2025-1-64/rc

Peer Review File: Available at https://aes.amegroups.com/article/view/10.21037/aes-2025-1-64/prf

Funding: This study was supported by the Research to Prevent Blindness Unrestricted Award (GR004596) and the NIH Center Core Grant (P30EY014801).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aes.amegroups.com/article/view/10.21037/aes-2025-1-64/coif). The series “Inflammatory Disorders of the Cornea and Ocular Surface” was commissioned by the editorial office without any funding or sponsorship. S.P. serves as the consultant to Alcon S.A. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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