Uveal melanoma is a rare but aggressive intraocular malignancy with limited therapeutic options and a high risk of metastatic relapse. Although its mutational landscape is well defined, how genetic factors, uveal location, and disease progression shape cell states and the tumor ecosystem remains poorly understood. We integrate single-cell RNA sequencing and spatial transcriptomics across a cohort spanning healthy uveal tissue, primary tumors, and metastases. We uncover a continuous shift in melanoma cell states during disease progression, from differentiated, pigmentation-associated programs toward stress- and epithelial-to-mesenchymal transition-associated states. This trajectory is modulated by uveal tract location, with iris tumors exhibiting a more differentiated phenotype and choroidal tumors enriched for stemness-associated features that localize to melanoma-rich regions correlating with genomic instability. In parallel, genetic background defines distinct melanoma cell states and tumor–immune interactions. Together, these findings define clinically relevant cellular states and provide a framework for understanding metastatic progression and therapeutic vulnerability.

Uveal melanoma (UM) and nonacral cutaneous melanoma (CM) are distinct entities with varied genetic landscapes despite both arising from melanocytes. There are, however, similarities in that they most frequently affect people of European ancestry, and high penetrance germline variants in BAP1, POT1 and CDKN2A have been shown to predispose to both UM and CM. This study aims to further explore germline variants in patients affected by both UM and CM, shedding light on the underlying genetic mechanism causing these diseases. Using exome sequencing we analysed germline DNA samples from a cohort of 83 Australian patients diagnosed with both UM and CM. Eight (10%) patients were identified that carried pathogenic mutations in known melanoma predisposition genes POT1, MITF, OCA2, SLC45A2 and TYR. Three (4%) patients carried pathogenic variants in genes previously linked with other cancer syndromes (ATR, BRIP1 and MSH6) and another three cases carried monoallelic pathogenic variants in recessive cancer genes (xeroderma pigmentosum and Fanconi anaemia), indicating that reduced penetrance of phenotype in these individuals may contribute to the development of both UM and CM. These findings highlight the need for further studies characterising the role of these genes in melanoma susceptibility. Germline variants predisposing uveal and cutaneous melanoma are identified using exome sequencing. Created with .image

ObjectiveThe objective of this study was to determine whether combining verteporfin-based photodynamic therapy (PDT) and transpupillary thermotherapy (TTT) achieves adequate tumour control while maintaining visual acuity in individuals with small choroidal melanoma of amelanotic, melanotic, and variable pigmentation.DesignIndividuals with posterior choroidal melanomas up to 3 mm in height underwent verteporfin-based PDT followed by immediate TTT. Further combined laser therapy was performed if a poor response was noted at 12 weeks or beyond. Tumours that demonstrated significant further growth were treated with brachytherapy or enucleation. A total of 37 eyes of 37 patients from the Terrace Eye Centre in Brisbane, Australia were studied. Average age of participants was 59.62 ± 12.45 years, and 17 of 37 participants were female (46%).MethodsThis was a retrospective, noncomparative interventional study.ResultsSeven of the 37 participants (19%) had recurrence of their tumour requiring further brachytherapy or enucleation. There was no statistically significant difference in visual acuity before and after treatment. There were no baseline characteristics that predicted treatment outcome. Ten individuals developed complications including epiretinal membrane (16%), scotoma (8%), cataract (3%), and macular edema (3%). No individuals experienced extraocular extension or progressed to metastatic disease. The mean follow-up time was 49 months.ConclusionCombined PDT and TTT achieved 81% tumour control in this study while preserving visual acuity. However, higher rates of local recurrence compared with brachytherapy warrant close follow-up to identify recurrences early.

BACKGROUND:To report the clinicopathological features and epidemiology of iris melanoma in Queensland, Australia. METHODS:This was a retrospective study of 86 patients with iris melanoma treated between 2001 and 2022 at the Queensland Ocular Oncology Service, Brisbane, Australia. Main outcome measures included demographics, clinical and phenotypic features, age-adjusted incidence and relative survival. RESULTS:Eighty-six patients (63% female) were included. Mean age was 54 years (range 17-82 years). The majority of patients (97%) were Caucasian, with blue eyes, fair skin and Fitzpatrick Skin Type I or II. Demographic features and clinical history showed a tendency for high ultraviolet radiation (UVR) exposure in the cohort. Histopathology was available in 69 cases (82%), and of these, 77% tumours were of spindle cell origin, with low-risk genetic profiles. Patients were followed for a mean of 8 years (median 7, range 1-21 years) after diagnosis, and only one case of metastasis was documented. CONCLUSIONS:The association of iris freckles, history of UVR exposure and dermatologic findings supports the role of UVR in iris melanoma. Occupation and avocation history, as well as evaluation of iris freckles may offer an easily accessible way of stratifying the risk of an individual for development of UVR-related uveal melanoma.

Background To report a case of Fuchs’ adenoma occurring in an eye with a large choroidal melanoma. We have reviewed the literature to describe the clinical presentation, ultrasound characteristics and pathological features of these entities. Case presentation A 69-year-old Caucasian man presented with vision loss from a large choroidal melanoma. Enucleation showed an incidental Fuchs’ adenoma in the same eye. Whole-exome sequence analysis was also performed on the patient’s blood and melanoma, which showed a rarely-reported ATRX mutation. Conclusions Fuchs’ adenoma is an under-diagnosed benign age-related hyperplasia of the non-pigmented ciliary epithelium (NPCE). Given its location and characteristics, it can be mistaken for choroidal melanoma and clinicians are reminded how to differentiate between these pathologies and that they may co-exist.

Lymphoma of the conjunctiva is an ocular malignancy derived from clonal proliferation of lymphocytes. The majority of conjunctival lymphoma is extranodal marginal zone B-Cell lymphoma (EMZL), however diffuse large B-cell (DLBCL), follicular (FL), mantle cell (MCL) and T- cell subtypes are also seen. Clinical manifestations are non-specific, but include unilateral or bilateral painless salmon-pink conjunctival lesions. Approaches to treatment have centered around local immunomodulation, often with Interferon-α2b or Rituximab (anti-CD20 monoclonal antibody) with or without radiation. Although conjunctival lymphoma is generally considered an indolent disease, recent advances in next-generation sequencing have improved clinicians’ ability to predict future recurrence or systemic disease through assessment of cytogenic and molecular features. In this paper, we review the classification, clinical features, diagnostic techniques, and emerging strategies for management and prognostication of conjunctival lymphomas.

analyze the effectiveness of our approach to Operation

Pathogenic germline variants in protection of telomeres 1 ( POT1 ) result in a tumour predisposition syndrome (POT1-TPDS), which includes cutaneous melanoma (CM), glioma, chronic lymphocytic leukaemia (CLL), colorectal cancer, thyroid cancer and sarcoma.1 Through whole-genome sequencing (WGS) of 20 Australian individuals affected with both CM and uveal melanoma (UM), our study identified two truncating variants in POT1 . Functional analyses assessing telomere length indicated longer telomeres in variant carriers, compared with healthy age-matched controls, similar to observations in CM patients with loss-of-function POT1 variants.2 The risk for development of cancers such as CM and UM is influenced by genetics. In UM, this has mainly been attributed to loss-of-function variants in BAP1 .3 Predisposition in CM is largely due to multiple low-penetrance susceptibility alleles; however, 5%–12% of cases report first-degree or second-degree relatives with CM and in a proportion of these families disease segregates with high-penetrance single gene variants in CDKN2A , CDK4 and the telomere maintenance genes POT1 , ACD , TERF2IP and TERT (reviewed in ref 4). Pathogenic germline variants in POT1 result in an increase in telomere length and susceptibility to many cancer types including CM, glioma, CLL, thyroid cancer, colorectal cancer, angiosarcoma1 and osteosarcoma,5 now termed the POT1-TPDS. There is also recent evidence to suggest histological differences in melanomas of POT1 variant carriers versus non-carriers, highlighting the importance of telomere dysfunction on tumour biology.6 POT1 binds to telomeric single-stranded DNA (ssDNA) overhangs, preventing telomerase accessibility. Highly conserved oligonucleotide/oligosaccharide-binding (OB) folds in POT1 are essential for specific binding to ssDNA, and loss of function of these OB domains leads to increased telomere elongation due to an inability to inhibit telomerase. Certain germline missense variants occurring in these OB domains, and other protein truncating variants, have been reported to disrupt POT1 function, leading to …

Uveal melanoma (UM) is the most common intraocular tumour in adults and despite surgical or radiation treatment of primary tumours, ~50% of patients progress to metastatic disease. Therapeutic options for metastatic UM are limited, with clinical trials having little impact. Here we perform whole-genome sequencing (WGS) of 103 UM from all sites of the uveal tract (choroid, ciliary body, iris). While most UM have low tumour mutation burden (TMB), two subsets with high TMB are seen; one driven by germline MBD4 mutation, and another by ultraviolet radiation (UVR) exposure, which is restricted to iris UM. All but one tumour have a known UM driver gene mutation ( GNAQ, GNA11, BAP1, PLCB4, CYSLTR2, SF3B1, EIF1AX ). We identify three other significantly mutated genes ( TP53 , RPL5 and CENPE ).

INTRODUCTION:Conjunctival nevi are the most common tumor of the ocular surface. There are some rare reports of so-called 'giant' conjunctival nevi. We report a case of a 47-year-old female with a cutaneous and ocular surface giant congenital melanocytic nevus and describe her clinical course.CASE DESCRIPTION:This is a retrospective case report of a single patient. A 47-year-old female with a history of biopsy-proven periorbital congenital melanocytic nevus, with an associated giant conjunctival nevus presented for structural and functional rehabilitation. Serial surgeries were performed and excised tissue was sent for histopathological and genetic examination. The conjunctival nevus had a low tumor mutation burden, and of the 647 somatic mutations, only one occurred within a protein coding region, namely NRAS p.Gln61Arg.CONCLUSION:This is the first reported adult case including genomic analysis of an ocular surface giant congenital melanocytic nevus. The case shows a possible association between periorbital congenital melanocytic nevi and giant conjunctival nevi, and underscores the possible role that targeted drug therapies may have in malignant transformation of these conditions.

The authors regret that the online version of this article contains an error. The MBD4 mutation in sample MM138 was given an incorrect dbSNP ID. The correct ID is rs769076971.

PURPOSE:To determine if a circulating microRNA (miRNA) panel could be used to distinguish between uveal melanoma and uveal nevi.METHODS:We report on a multicenter, cross-sectional study conducted between June 2012 and September 2015. The follow-up time was approximately 3 to 5 years. Blood was drawn from participants presenting with a uveal nevus (n = 10), localized uveal melanoma (n = 50), or metastatic uveal melanoma (n = 5). Levels of 17 miRNAs were measured in blood samples of study participants using a sensitive real-time PCR system.RESULTS:A panel of six miRNAs (miR-16, miR-145, miR-146a, miR-204, miR-211, and miR-363-3p) showed significant differences between participants with uveal nevi compared with patients with localized and metastatic uveal melanoma. Importantly, miR-211 was able to accurately distinguish metastatic disease from localized uveal melanoma (P < 0.0001; area under the curve = 0.96). When the six-miRNA panel was evaluated as a group it had the ability to identify uveal melanoma when four or more miRNAs (93% sensitivity and 100% specificity) reached or exceeded their cut-point.CONCLUSIONS:This miRNA panel, in tandem with clinical findings, may be suited to confirm benign lesions. In addition, due to the panel's high precision in identifying malignancy, it has the potential to augment melanoma detection in subsequent clinical follow-up of lesions with atypical clinical features.TRANSLATIONAL RELEVANCE:Uveal nevi mimic the appearance of uveal melanoma and their transformation potential cannot be definitively determined without a biopsy. This panel is most relevant at the nevus stage and in lesions with uncertain malignant potential as a companion diagnostic tool to assist in clinical decision-making.

Germline mutations of BRCA1 and BRCA2 predispose individuals to a high risk of breast and ovarian cancer, and elevated risk of other cancers, including those of the pancreas and prostate. BRCA2 mutation carriers may have increased risk of uveal melanoma (UM) and cutaneous melanoma (CM), but associations with these cancers in BRCA1 mutation carriers have been mixed. Here, we further assessed whether UM and CM are associated with BRCA1 or BRCA2 by assessing the presence, segregation and reported/predicted pathogenicity of rare germline mutations (variant allele frequency < 0.01) in families with multiple members affected by these cancers. Whole-genome or exome sequencing was performed on 160 CM and/or UM families from Australia, the Netherlands, Denmark and Sweden. Between one and five cases were sequenced from each family, totalling 307 individuals. Sanger sequencing was performed to validate BRCA1 and BRCA2 germline variants and to assess carrier status in other available family members. A nonsense and a frameshift mutation were identified in BRCA1 , both resulting in premature truncation of the protein (the first at p.Q516 and the second at codon 91, after the introduction of seven amino acids due to a frameshift deletion). These variants co-segregated with CM in individuals who consented for testing and were present in individuals with pancreatic, prostate and breast cancer in the respective families. In addition, 33 rare missense mutations (variant allele frequency ranging from 0.00782 to 0.000001 in the aggregated ExAC data) were identified in 34 families. Examining the previously reported evidence of functional consequence of these variants revealed all had been classified as either benign or of unknown consequence. Seeking further evidence of an association between BRCA1 variants and melanoma, we examined two whole-genome/exome sequenced collections of sporadic CM patients (total N = 763). We identified one individual with a deleterious BRCA1 variant, however, this allele was lost (with the wild-type allele remaining) in the corresponding CM, indicating that defective BRCA1 was not a driver of tumorigenesis in this instance. Although this is the first time that deleterious BRCA1 mutations have been described in high-density CM families, we conclude that there is an insufficient burden of evidence to state that the increased familial CM or UM susceptibility is because of these variants. In addition, in conjunction with other studies, we conclude that the previously described association between BRCA2 mutations and UM susceptibility represents a rare source of increased risk.

Background:The BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome (BAP1-TPDS) is a hereditary tumor syndrome caused by germline pathogenic variants in BAP1 encoding a tumor suppressor associated with uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, and cutaneous BAP1-inactivated melanocytic tumors. However, the full spectrum of tumors associated with the syndrome is yet to be determined. Improved understanding of the BAP1-TPDS is crucial for appropriate clinical management of BAP1 germline variant carriers and their families, including genetic counseling and surveillance for new tumors.Methods:We collated germline variant status, tumor diagnoses, and information on BAP1 immunohistochemistry or loss of somatic heterozygosity on 106 published and 75 unpublished BAP1 germline variant-positive families worldwide to better characterize the genotypes and phenotypes associated with the BAP1-TPDS. Tumor spectrum and ages of onset were compared between missense and null variants. All statistical tests were two-sided.Results:The 181 families carried 140 unique BAP1 germline variants. The collated data confirmed the core tumor spectrum associated with the BAP1-TPDS and showed that some families carrying missense variants can exhibit this phenotype. A variety of noncore BAP1-TPDS -associated tumors were found in families of variant carriers. Median ages of onset of core tumor types were lower in null than missense variant carriers for all tumors combined (P < .001), mesothelioma (P < .001), cutaneous melanoma (P < .001), and nonmelanoma skin cancer (P < .001).Conclusions:This analysis substantially increases the number of pathogenic BAP1 germline variants and refines the phenotype. It highlights the need for a curated registry of germline variant carriers for proper assessment of the clinical phenotype of the BAP1-TPDS and pathogenicity of new variants, thus guiding management of patients and informing areas requiring further research.

e13534 Background: Germline mutations in the BRCA1-associated protein (BAP1) gene are linked to a large spectrum of cancers, defined as the BAP1 tumour predisposition syndrome (BAP1-TPDS). The cancers usually occurring in kindreds with BAP1-TPDS are uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, cholangiocarcinoma and meningioma. A 2017 review identified only 87 probands worldwide with germline BAP1 mutations. Methods: To better understand the frequency of BAP1-TPDS, we took a systematic BAP1 sequencing approach of a defined population. We screened Queensland uveal melanoma probands and their families for mutations in BAP1 (n = 64), identified variants from published studies from Australia and liaised with clinical genetics services Australia-wide to ascertain BAP1 germline variants. Only variants with a population frequency of < 0.0005 were considered. Results: We identified 2 truncating, 1 missense, 2 synonymous, 1 intronic and 1 promoter variant in the sequencing screen (7/64). Two truncating variants were referred by the clinical genetics services and finally, 13 published variants in Australian families were identified. The 4 truncating variants occur in kindreds with classical features of BAP1-TPDS and are disease causing. Of the total 11 missense variants, only 1 occurs in a family with BAP1-TPDS phenotype, which has been previously published (p.T173C) and is predicted to impair ubiquitin hydrolase activity. In silico prediction suggests 8/9 unique missense and 1 synonymous variants either alter splicing or damage protein structure, which requires functional confirmation. The intronic variant lies 8bp into intron 13 and is of unknown consequence. Finally, the promoter variant has been reported in an Italian family with the phenotype; however, in the Australian family, incomplete family history for the proband does not allow for a full assessment. Conclusions: The detection of six definite and two likely deleterious variants in this focused assessment of BAP1 in Australia suggests mutations may be more common than indicated by literature review. This study highlights a need for a comprehensive worldwide database of germline BAP1 variants and cancers present in carriers and development of a guide to clinical testing.

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Ophthalmology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Ophthalmology journal

Next generation sequencing of uveal melanoma (UM) samples has identified a number of recurrent oncogenic or loss-of-function mutations in key driver genes including: GNAQ, GNA11, EIF1AX, SF3B1 and BAP1. To search for additional driver mutations in this tumor type we carried out whole-genome or whole-exome sequencing of 28 tumors or primary cell lines. These samples have a low mutation burden, with a mean of 10.6 protein changing mutations per sample (range 0 to 53). As expected for these sun-shielded melanomas the mutation spectrum was not consistent with an ultraviolet radiation signature, instead, a BRCA mutation signature predominated. In addition to mutations in the known UM driver genes, we found a recurrent mutation in PLCB4 (c.G1888T, p.D630Y, NM_000933), which was validated using Sanger sequencing. The identical mutation was also found in published UM sequence data (1 of 56 tumors), supporting its role as a novel driver mutation in UM. PLCB4 p.D630Y mutations are mutually exclusive with mutations in GNA11 and GNAQ, consistent with PLCB4 being the canonical downstream target of the former gene products. Taken together these data suggest that the PLCB4 hotspot mutation is similarly a gain-of-function mutation leading to activation of the same signaling pathway, promoting UM tumorigenesis.

P>Purpose:To investigate the efficacy of intravitreal bevacizumab for the treatment of neovascular age-related macular degeneration (AMD) using an as required dosing regimen.Methods:A retrospective study of 210 patients (231 eyes) with choroidal neovascularization resulting from neovasacular AMD. Patients were treated with 1.25 mg intravitreal bevacizumab at a vitreoretinal practice in Adelaide, South Australia. Patients were followed up at 2-4 weeks and then at 1-month intervals; repeat injections were offered in the event of recurrence. Recurrence was defined as either a decrease of best-corrected visual acuity or an increase in macular oedema, subretinal fluid or intraretinal fluid on optical coherence tomography, after complete or partial resolution in previous follow-up visits. Patient data were collected for 12 months of follow up or until the patient's treatment was changed to ranibizumab.Results:Significant improvement in visual acuity and central retinal thickness was demonstrated at 1 month with an improvement of vision from logMAR equivalent 0.76 to 0.68 (P < 0.001) and a decrease of central retinal thickness from 306 mu m to 244 mu m (P < 0.001). This overall improvement was continued throughout the 12-month follow-up period; however, follow up was poor with 12-month data available for only a small number of patients (7.8%). Ocular and systemic side-effects were rare at 3.5% and 0.4%, respectively.Conclusion:Eyes with neovascular AMD treated with intravitreal bevacizumab for up to 12 months had significant functional and anatomical improvement. Further studies need to confirm the long-term safety and efficacy of this treatment.