Dataset Information

Different Pigmentation Risk Loci for High-Risk Monosomy 3 and Low-Risk Disomy 3 Uveal Melanomas.

ABSTRACT:

Background

Uveal melanoma (UM), a rare malignant tumor of the eye, is predominantly observed in populations of European ancestry. UMs carrying a monosomy 3 (M3) frequently relapse mainly in the liver, whereas UMs with disomy 3 (D3) are associated with more favorable outcome. Here, we explored the UM genetic predisposition factors in a large genome-wide association study (GWAS) of 1142 European UM patients and 882 healthy controls .

Methods

We combined 2 independent datasets (Global Screening Array) with the dataset described in a previously published GWAS in UM (Omni5 array), which were imputed separately and subsequently merged. Patients were stratified according to their chromosome 3 status, and identified UM risk loci were tested for differential association with M3 or D3 subgroups. All statistical tests were 2-sided.

Results

We recapitulated the previously identified risk locus on chromosome 5 on CLPTM1L (rs421284: odds ratio [OR] =1.58, 95% confidence interval [CI] = 1.35 to 1.86; P = 1.98 × 10-8) and identified 2 additional risk loci involved in eye pigmentation: IRF4 locus on chromosome 6 (rs12203592: OR = 1.76, 95% CI = 1.44 to 2.16; P = 3.55 × 10-8) and HERC2 locus on chromosome 15 (rs12913832: OR= 0.57, 95% CI = 0.48 to 0.67; P = 1.88 × 10-11). The IRF4 rs12203592 single-nucleotide polymorphism was found to be exclusively associated with risk for the D3 UM subtype (ORD3 = 2.73, 95% CI = 1.87 to 3.97; P = 1.78 × 10-7), and the HERC2 rs12913832 single-nucleotide polymorphism was exclusively associated with risk for the M3 UM subtype (ORM3 = 2.43, 95% CI = 1.79 to 3.29; P = 1.13 × 10-8). However, the CLPTM1L risk locus was equally statistically significant in both subgroups.

Conclusions

This work identified 2 additional UM risk loci known for their role in pigmentation. Importantly, we demonstrate that UM tumor biology and metastatic potential are influenced by patients' genetic backgrounds.

SUBMITTER: Mobuchon L

PROVIDER: S-EPMC8826635 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Publications

Different Pigmentation Risk Loci for High-Risk Monosomy 3 and Low-Risk Disomy 3 Uveal Melanomas.

Mobuchon Lenha L Derrien Anne-Céline AC Houy Alexandre A Verrier Thibault T Pierron Gaëlle G Cassoux Nathalie N Milder Maud M Deleuze Jean-François JF Boland Anne A Scelo Ghislaine G Cancel-Tassin Géraldine G Cussenot Olivier O Rodrigues Manuel M Noirel Josselin J Machiela Mitchell J MJ Stern Marc-Henri MH

Journal of the National Cancer Institute 20220201 2

<h4>Background</h4>Uveal melanoma (UM), a rare malignant tumor of the eye, is predominantly observed in populations of European ancestry. UMs carrying a monosomy 3 (M3) frequently relapse mainly in the liver, whereas UMs with disomy 3 (D3) are associated with more favorable outcome. Here, we explored the UM genetic predisposition factors in a large genome-wide association study (GWAS) of 1142 European UM patients and 882 healthy controls .<h4>Methods</h4>We combined 2 independent datasets (Globa ...[more]

PMID: 34424336

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Project description:Uveal melanoma (UM) represents the most frequent primary tumor of the eye. Despite the development of new drugs and screening programs, the prognosis of patients with UM remains poor and no effective prognostic biomarkers are yet able to identify high‑risk patients. Therefore, in the present study, microRNA (miRNA or miR) expression data, contained in the TCGA UM (UVM) database, were analyzed in order to identify a set of miRNAs with prognostic significance to be used as biomarkers in clinical practice. Patients were stratified into 2 groups, including tumor stage (high‑grade vs. low‑grade) and status (deceased vs. alive); differential analyses of miRNA expression among these groups were performed. A total of 20 deregulated miRNAs for each group were identified. In total 7 miRNAs were common between the groups. The majority of common miRNAs belonged to the miR‑506‑514 cluster, known to be involved in UM development. The prognostic value of the 20 selected miRNAs related to tumor stage was assessed. The deregulation of 12 miRNAs (6 upregulated and 6 downregulated) was associated with a worse prognosis of patients with UM. Subsequently, miRCancerdb and microRNA Data Integration Portal bioinformatics tools were used to identify a set of genes associated with the 20 miRNAs and to establish their interaction levels. By this approach, 53 different negatively and positively associated genes were identified. Finally, DIANA‑mirPath prediction pathway and Gene Ontology enrichment analyses were performed on the lists of genes previously generated to establish their functional involvement in biological processes and molecular pathways. All the miRNAs and genes were involved in molecular pathways usually altered in cancer, including the mitogen‑activated protein kinase (MAPK) pathway. Overall, the findings of the presents study demonstrated that the miRNAs of the miR‑506‑514 cluster, hsa‑miR‑592 and hsa‑miR‑199a‑5p were the most deregulated miRNAs in patients with high‑grade disease compared to those with low‑grade disease and were strictly related to the overall survival (OS) of the patients. However, further in vitro and translational approaches are required to validate these preliminary findings.

Project description:BackgroundTo report on radiation-related side effects and complications after ruthenium-106 plaque brachytherapy of uveal melanomas.MethodsMedical records of 143 eyes with uveal melanoma, treated by ruthenium-106 brachytherapy between 1997 and 2012 at a single center, were analyzed. We evaluated the occurrence of radiation-related side effects on the anterior and posterior segment of the eye. The influence of patient, tumor and treatment parameters on outcome was analyzed by multivariate time to event analysis considering competing risks.ResultsThe median overall follow-up was 37.9 months. After treatment, the estimated risk at 12, 24 and 48 months for developing anterior segment complications was 25.3%, 37.5% and 50.3% for cataract formation and 5.4%, 6.4% and 8.1% for secondary glaucoma, respectively. The estimated risk for the occurrence of posterior segment complications 12, 24 and 48 months after treatment was 3.1%, 6.7% and 18.3% for radiation retinopathy, 18.3%, 27.1% and 42.6% for radiation maculopathy and 16.5%, 21.0% and 32.8% for radiation neuropathy, respectively. The risk of an increase in retinal detachment after treatment was 14.7%, 14.7% and 17.4% at 12, 24 and 48 months, respectively. The risk of vitreous hemorrhage occurring after treatment was 6.2%, 8.1% and 12.7%, and the risk of tumor vasculopathy was 15.4%, 17.4% and 19.0%. Scleral necrosis was observed in one patient.ConclusionRadiation-related side effects and complications are common among patients treated with ruthenium brachytherapy for uveal melanoma. However, the risk for those largely depends on individual tumor parameters. Before treatment, patients should be informed of their specific risks to develop various side effects. Patient information before treatment should cover not only general information about the treatment and possible complications and side effects but should also give details on the specific risks of the patient in her individual situation. This also includes elucidating the patient's individual resources and expectations and her willingness for long-term regular follow-up examinations and secondary adjunct treatments.

Dataset Information

Different Pigmentation Risk Loci for High-Risk Monosomy 3 and Low-Risk Disomy 3 Uveal Melanomas.

Background

Methods

Results

Conclusions

Publications

Different Pigmentation Risk Loci for High-Risk Monosomy 3 and Low-Risk Disomy 3 Uveal Melanomas.

Similar Datasets

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