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Advances in Molecular Understanding of Ocular Adnexal Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (15 March 2024) | Viewed by 8333

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Special Issue Editor

Dr. Robert M. Verdijk

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Guest Editor

1. Erasmus MC University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands
2. The Rotterdam Eye Hospital, 3000 CA Rotterdam, The Netherlands
3. Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

Interests: ocular oncology; neuro-oncology; autoimmune periorbital disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The ocular adnexal structures only make up a small volume when compared to other organs, with an orbital content of 30 cm³, a conjunctival surface area of 17 cm² and a corneal surface area of 120 mm². However, these structures, including the lacrimal gland, orbital tissues, cornea, conjunctiva, caruncle and eyelids, can yield a host of different neoplasms and disease processes. Due to the relative rarity of ocular adnexal tumors, in many cases, therapy is often guided in analogy to that for similar, more common, tumor types elsewhere in the body. It remains to be proven what is the optimum treatment for these particular patients. Other disease processes such as dry eye disease, pterygia/pinguecula and (auto-) immune diseases are responsible for a high burden of disease worldwide with vision loss as an ultimate consequence for many.

The full molecular characteristics of the diseases from this region are not fully known. Many advances have recently been made in the molecular understanding lymphoma, melanoma, squamous carcinoma and sebaceous carcinoma; however, whether there are special molecular–genetic or epigenetic features of tumors particular to this region is, as yet, insufficiently certain. Dry eye disease and degenerations like pterygia/pinguecula also have proven to be driven by different molecular processes that may show overlap with pathways described in neoplasms. Therefore, detailed information on chromosomal aberrations, gene fusions, mutations and epigenetics (such as microRNA, long-non-coding RNA and methylation profiling) may offer important new insights.

This Special Issue invites authors to submit comprehensive molecular biological work that aims to elucidate the molecular and epigenetic mechanisms operable in diseases of the ocular adnexa. As rare as these may be, a better understanding of their molecular genetic bases and epigenetics is essential for improving the diagnosis and treatment of patients.

Dr. Robert M. Verdijk
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

ocular adnexa
neoplasm
carcinoma
melanoma
lymphoma
degeneration
inflammation
immune disease

Published Papers (7 papers)

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Research

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16 pages, 1293 KiB

Open AccessArticle

The Genetic Profile of Large B-Cell Lymphomas Presenting in the Ocular Adnexa

by Stine Dahl Vest, Patrick Rene Gerhard Eriksen, Fleur A. de Groot, Ruben A. L. de Groen, Anne H. R. Kleij, Marina Knudsen Kirkegaard, Peter Kamper, Peter Kristian Rasmussen, Christian von Buchwald, Peter de Nully Brown, Jens Folke Kiilgaard, Joost S. P. Vermaat and Steffen Heegaard

Int. J. Mol. Sci. 2024, 25(6), 3094; https://doi.org/10.3390/ijms25063094 - 7 Mar 2024

Viewed by 735

Abstract

To provide insights into targetable oncogenic pathways, this retrospective cohort study investigated the genetic profile of 26 patients with diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS), and two patients with high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL) presenting in the ocular adnexa. Pathogenic variants and copy number variations in 128 B-cell lymphoma-relevant genes were analyzed by targeted next-generation sequencing. Genetic subtypes were determined with the LymphGen algorithm. Primary ocular adnexal DLBCL-NOS constituted 50% (n = 14) and was generally characterized by non-germinal center B-cell origin (non-GCB) (n = 8, 57%), and LymphGen MCD subtype (n = 5, 36%). Primary ocular adnexal DLBCL-NOS presented pathogenic variants in genes involved in NF-κB activation and genes which are recurrently mutated in other extranodal lymphomas of non-GCB origin, including MYD88 (n = 4, 29%), CD79B (n = 3, 21%), PIM1 (n = 3, 21%), and TBL1XR1 (n = 3, 21%). Relapsed DLBCL-NOS presenting in the ocular adnexa (n = 6) were all of non-GCB origin and frequently of MCD subtype (n = 3, 50%), presenting with a similar genetic profile as primary ocular adnexal DLBCL-NOS. These results provide valuable insights into genetic drivers in ocular adnexal DLBCL-NOS, offering potential applications in future precision medicine. Full article

(This article belongs to the Special Issue Advances in Molecular Understanding of Ocular Adnexal Disease)

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0 pages, 4097 KiB

Open AccessArticle

Machine Learning Methods for Gene Selection in Uveal Melanoma

by Francesco Reggiani, Zeinab El Rashed, Mariangela Petito, Max Pfeffer, Anna Morabito, Enrica Teresa Tanda, Francesco Spagnolo, Michela Croce, Ulrich Pfeffer and Adriana Amaro

Int. J. Mol. Sci. 2024, 25(3), 1796; https://doi.org/10.3390/ijms25031796 - 1 Feb 2024

Viewed by 896

Abstract

Uveal melanoma (UM) is the most common primary intraocular malignancy with a limited five-year survival for metastatic patients. Limited therapeutic treatments are currently available for metastatic disease, even if the genomics of this tumor has been deeply studied using next-generation sequencing (NGS) and functional experiments. The profound knowledge of the molecular features that characterize this tumor has not led to the development of efficacious therapies, and the survival of metastatic patients has not changed for decades. Several bioinformatics methods have been applied to mine NGS tumor data in order to unveil tumor biology and detect possible molecular targets for new therapies. Each application can be single domain based while others are more focused on data integration from multiple genomics domains (as gene expression and methylation data). Examples of single domain approaches include differentially expressed gene (DEG) analysis on gene expression data with statistical methods such as SAM (significance analysis of microarray) or gene prioritization with complex algorithms such as deep learning. Data fusion or integration methods merge multiple domains of information to define new clusters of patients or to detect relevant genes, according to multiple NGS data. In this work, we compare different strategies to detect relevant genes for metastatic disease prediction in the TCGA uveal melanoma (UVM) dataset. Detected targets are validated with multi-gene score analysis on a larger UM microarray dataset. Full article

(This article belongs to the Special Issue Advances in Molecular Understanding of Ocular Adnexal Disease)

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16 pages, 7978 KiB

Open AccessArticle

Interdependence of Molecular Lesions That Drive Uveal Melanoma Metastasis

by Francesco Reggiani, Marianna Ambrosio, Michela Croce, Enrica Teresa Tanda, Francesco Spagnolo, Edoardo Raposio, Mariangela Petito, Zeinab El Rashed, Alessandra Forlani, Ulrich Pfeffer and Adriana Agnese Amaro

Int. J. Mol. Sci. 2023, 24(21), 15602; https://doi.org/10.3390/ijms242115602 - 26 Oct 2023

Cited by 2 | Viewed by 1118

Abstract

The metastatic risk of uveal melanoma (UM) is defined by a limited number of molecular lesions, somatic mutations (SF3B1 and BAP1), and copy number alterations (CNA): monosomy of chromosome 3 (M3), chr8q gain (8q), chr6p gain (6p), yet the sequence of events is not clear. We analyzed data from three datasets (TCGA-UVM, GSE27831, GSE51880) with information regarding M3, 8q, 6p, SF3B1, and BAP1 status. We confirm that BAP1 mutations are always associated with M3 in high-risk patients. All other features (6p, 8q, M3, SF3B1 mutation) were present independently from each other. Chr8q gain was frequently associated with chr3 disomy. Hierarchical clustering of gene expression data of samples with different binary combinations of aggressivity factors shows that patients with 8q|M3, BAP1|M3 form one cluster enriched in samples that developed metastases. Patients with 6p combined with either 8q or SF3B1 are mainly represented in the other, low-risk cluster. Several gene expression events that show a non-significant association with outcome when considering single features become significant when analyzing combinations of risk features indicating additive action. The independence of risk factors is consistent with a random risk model of UM metastasis without an obligatory sequence. Full article

(This article belongs to the Special Issue Advances in Molecular Understanding of Ocular Adnexal Disease)

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15 pages, 3648 KiB

Open AccessArticle

Spatial Transcriptomic Analysis Reveals Regional Transcript Changes in Early and Late Stages of rd1 Model Mice with Retinitis Pigmentosa

by Ying Zhou, Yuqi Sheng, Min Pan, Jing Tu, Xiangwei Zhao, Qinyu Ge and Zuhong Lu

Int. J. Mol. Sci. 2023, 24(19), 14869; https://doi.org/10.3390/ijms241914869 - 3 Oct 2023

Viewed by 1000

Abstract

Retinitis pigmentosa (RP) is the leading cause of inherited blindness with a genetically heterogeneous disorder. Currently, there is no effective treatment that can protect vision for those with RP. In recent decades, the rd1 mouse has been used to study the pathological mechanisms of RP. Molecular biological studies using rd1 mice have clarified the mechanism of the apoptosis of photoreceptor cells in the early stage of RP. However, the pathological changes in RP over time remain unclear. The unknown pathology mechanism of RP over time and the difficulty of clinical treatment make it urgent to perform more refined and spatially informed molecular biology studies of RP. In this study, spatial transcriptomic analysis is used to study the changes in different retinal layers of rd1 mice at different ages. The results demonstrate the pattern of photoreceptor apoptosis between rd1 mice and the control group. Not only was oxidative stress enhanced in the late stage of RP, but it was accompanied by an up-regulation of the VEGF pathway. Analysis of temporal kinetic trends has further identified patterns of changes in the key pathways of the early and late stages, to help understand the important pathogenesis of RP. Overall, the application of spatial transcriptomics to rd1 mice can help to elucidate the important pathogenesis of RP involving photoreceptor apoptosis and retinal remodeling. Full article

(This article belongs to the Special Issue Advances in Molecular Understanding of Ocular Adnexal Disease)

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14 pages, 2566 KiB

Open AccessArticle

ATRX Loss in the Development and Prognosis of Conjunctival Melanoma

by Jolique A. van Ipenburg, Quincy C. C. van den Bosch, Dion Paridaens, Hendrikus J. Dubbink, Emine Kiliç, Nicole Naus and Robert M. Verdijk

Int. J. Mol. Sci. 2023, 24(16), 12988; https://doi.org/10.3390/ijms241612988 - 20 Aug 2023

Viewed by 833

Abstract

Metastatic disease is linked to TERT promoter mutations in conjunctival melanomas (CM). Both TERT promoter and ATRX mutations are associated with faulty telomere maintenance. This study aimed to determine the prognostic value of ATRX loss in conjunctival melanocytic lesions. Eighty-six conjunctival melanocytic lesions from the Rotterdam Ocular Melanoma Study group were collected. ATRX status and TERT promoter status were determined using immunohistochemical staining and molecular diagnostics, respectively. None of the nevi (n = 16) and primary acquired melanosis (PAM) without atypia (n = 6) showed ATRX loss. ATRX loss was found in 2/5 PAM with atypia without CM and in 8/59 CM. No cases with a TERT promoter mutation (n = 26) showed ATRX loss. Eight/eleven metastatic CM harbored a TERT promoter mutation, two other metastatic CM showed ATRX loss and one metastatic case showed no TERT promoter/ATRX alterations. In conclusion ATRX loss and TERT promoter mutations are only found in (pre)malignant conjunctival melanocytic lesions, with most metastatic cases harboring one of these alterations, suggesting that both alterations are associated with adverse behavior. Similar to TERT promoter mutations, ATRX loss may be used as a diagnostic tool in determining whether a conjunctival melanocytic lesion is prone to having an adverse course. Full article

(This article belongs to the Special Issue Advances in Molecular Understanding of Ocular Adnexal Disease)

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12 pages, 1587 KiB

Open AccessArticle

RNA-Seq Analysis Reveals an Essential Role of the cGMP-PKG-MAPK Pathways in Retinal Degeneration Caused by Cep250 Deficiency

by Chong Chen, Yu Rong, Youyuan Zhuang, Cheng Tang, Qian Liu, Peng Lin, Dandan Li, Xinyi Zhao, Fan Lu, Jia Qu and Xinting Liu

Int. J. Mol. Sci. 2023, 24(10), 8843; https://doi.org/10.3390/ijms24108843 - 16 May 2023

Viewed by 1367

Abstract

Usher syndrome (USH) is characterised by degenerative vision loss known as retinitis pigmentosa (RP), sensorineural hearing loss, and vestibular dysfunction. RP can cause degeneration and the loss of rod and cone photoreceptors, leading to structural and functional changes in the retina. Cep250 is a candidate gene for atypical Usher syndrome, and this study describes the development of a Cep250 KO mouse model to investigate its pathogenesis. OCT and ERG were applied in Cep250 and WT mice at P90 and P180 to access the general structure and function of the retina. After recording the ERG responses and OCT images at P90 and P180, the cone and rod photoreceptors were visualised using an immunofluorescent stain. TUNEL assays were applied to observe the apoptosis in Cep250 and WT mice retinas. The total RNA was extracted from the retinas and executed for RNA sequencing at P90. Compared with WT mice, the thickness of the ONL, IS/OS, and whole retina of Cep250 mice was significantly reduced. The a-wave and b-wave amplitude of Cep250 mice in scotopic and photopic ERG were lower, especially the a-wave. According to the immunostaining and TUNEL stain results, the photoreceptors in the Cep250 retinas were also reduced. An RNA-seq analysis showed that 149 genes were upregulated and another 149 genes were downregulated in Cep250 KO retinas compared with WT mice retinas. A KEGG enrichment analysis indicated that cGMP-PKG signalling pathways, MAPK signalling pathways, edn2-fgf2 axis pathways, and thyroid hormone synthesis were upregulated, whereas protein processing in the endoplasmic reticulum was downregulated in Cep250 KO eyes. Cep250 KO mice experience a late-stage retinal degeneration that manifests as the atypical USH phenotype. The dysregulation of the cGMP-PKG-MAPK pathways may contribute to the pathogenesis of cilia-related retinal degeneration. Full article

(This article belongs to the Special Issue Advances in Molecular Understanding of Ocular Adnexal Disease)

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Review

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16 pages, 29306 KiB

Open AccessReview

A Review of the Molecular Landscape of Adenoid Cystic Carcinoma of the Lacrimal Gland

by Sarah Kate Powell, Karina Kulakova and Susan Kennedy

Int. J. Mol. Sci. 2023, 24(18), 13755; https://doi.org/10.3390/ijms241813755 - 6 Sep 2023

Cited by 2 | Viewed by 1618

Abstract

Adenoid cystic carcinoma (ACC) has a worldwide incidence of three to four cases per million population. Although more cases occur in the minor and major salivary glands, it is the most common lacrimal gland malignancy. ACC has a low-grade, indolent histological appearance, but is relentlessly progressive over time and has a strong proclivity to recur and/or metastasise. Current treatment options are limited to complete surgical excision and adjuvant radiotherapy. Intra-arterial systemic therapy is a recent innovation. Recurrent/metastatic disease is common due to perineural invasion, and it is largely untreatable as it is refractory to conventional chemotherapeutic agents. Given the rarity of this tumour, the molecular mechanisms that govern disease pathogenesis are poorly understood. There is an unmet, critical need to develop effective, personalised targeted therapies for the treatment of ACC in order to reduce morbidity and mortality associated with the disease. This review details the evidence relating to the molecular underpinnings of ACC of the lacrimal gland, including the MYB–NFIB chromosomal translocations, Notch-signalling pathway aberrations, DNA damage repair gene mutations and epigenetic modifications. Full article

(This article belongs to the Special Issue Advances in Molecular Understanding of Ocular Adnexal Disease)

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