Genomic Profiling and Identification of High-Risk Uveal Melanoma by Array CGH Analysis of Primary Tumors and Liver Metastases

Trolet, J.; Hupé, Philippe; Huon, Isabelle; Lebigot, Ingrid; Decraene, Charles; Delattre, Olivier; Sastre-Garau, Xavier; Saule, Simon; Thiéry, Jean‐Paul; Plancher, Corine; Asselain, Bernard; Desjardins, Laurence; Mariani, Pascale; Piperno‐Neumann, Sophie; Barillot, Emmanuel; Couturier, Jérôme

doi:10.1167/iovs.08-2296

Cited by 121 publications

(120 citation statements)

References 23 publications

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“…FISH was done on intact nuclei after dissociation of the tumor fragment using a labeled centromeric probe specific for chromosome 3 (Vysis, Abbott Molecular) according to the supplier's protocol. For array-CGH, DNA extraction, labeling, and hybridization were done as previously described (11).…”

Section: Translational Relevancementioning

confidence: 99%

Establishment and Characterization of a Panel of Human Uveal Melanoma Xenografts Derived from Primary and/or Metastatic Tumors

Némati

Sastre-Garau

Laurent

et al. 2010

Clinical Cancer Research

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136

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Purpose: Uveal melanoma is the most common primary intraocular malignant tumor in adults and is defined by a poor natural outcome, as 50% of patients die from metastases. The aim of this study was to develop and characterize a panel of human uveal melanoma xenografts transplanted into immunodeficient mice.Experimental Design: Ninety tumor specimens were grafted into severe combined immunodeficient mice, and 25 transplantable xenografts were then established (28%). Relationship between tumor graft and clinical, biological, and therapeutic features of the patients included were investigated. Characterization of 16 xenografts included histology, molecular analyses by immunohistochemistry, genetic alteration analysis (single-nucleotide polymorphism), and specific tumor antigen expression by quantitative reverse transcription-PCR. Pharmacologic characterization (chemosensitivity) was also done in four models using two drugs, temozolomide and fotemustine, currently used in the clinical management of uveal melanoma.Results: Take rate of human uveal melanoma was 28% (25 of 90). Tumor take was independent of size, histologic parameters, or chromosome 3 monosomy but was significantly higher in metastatic tumors. Interestingly, in vivo tumor growth was prognostic for a lower metastasis-free survival in patients with primary tumors. A high concordance between the patients' tumors and their corresponding xenografts was found for all parameters tested (histology, genetic profile, and tumor antigen expression). Finally, the four xenografts studied displayed different response profiles to chemotherapeutic agents.Conclusions: Based on these results, this panel of 16 uveal melanoma xenografts represents a useful preclinical tool for both pharmacologic and biological assessments. Clin Cancer Res; 16(8); 2352-62. ©2010 AACR.Uveal melanoma is the most common primary intraocular malignant tumor in adults. Despite the increased diagnostic accuracy and the development of conservative and effective treatments on primary tumor sites, such as plaque radiotherapy and photon beam therapy, the mortality remains stable and 50% of patients die from metastases that frequently involve the liver. Chemotherapy, such as oral temozolomide and intra-arterial fotemustine used at the metastatic stage, induces very low response rates, 14.3% and 36%, respectively, and a median survival time of 6.7 and 15 months (1-3). No postoperative adjuvant therapies are currently available to decrease the risk of metastases. Several prognostic factors of disseminated relapse after initial ophthalmologic treatment have been determined, including location with respect to the equator, monosomy 3, and retinal detachment (4). However, no effect of these prognostic markers on patient care can be envisaged in the absence of effective systemic therapies.The growing body of knowledge about molecular and genetics events involved in oncogenesis and tumor progression has led to the identification of new therapeutic targets and therapeutic agents. Preclinical investigatio...

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Section: Translational Relevancementioning

confidence: 99%

Establishment and Characterization of a Panel of Human Uveal Melanoma Xenografts Derived from Primary and/or Metastatic Tumors

Némati

Sastre-Garau

Laurent

et al. 2010

Clinical Cancer Research

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136

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“…Aberrant regions were determined by automatic breakpoint detection using the GLAD library 11 within the R Statistical Environment (http://www.r-project.org). All aberrations detected by two algorithms available in GLAD (smooth functions 'lawsglad' and 'haarseg'), covered by at least three oligonucleotides and with a minimum log2 ratio of ± 0.25, were mapped against the Database of Genomic Variants (http://projects.tcag.ca/variation) and UCSC (http://genome.ucsc.edu).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive array CGH of normal karyotype myelodysplastic syndromes reveals hidden recurrent and individual genomic copy number alterations with prognostic relevance

et al. 2011

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About 40% of patients with myelodysplastic syndromes (MDSs) present with a normal karyotype, and they are facing different courses of disease. To advance the biological understanding and to find molecular prognostic markers, we performed a highresolution oligonucleotide array study of 107 MDS patients (French American British) with a normal karyotype and clinical follow-up through the Duesseldorf MDS registry. Recurrent hidden deletions overlapping with known cytogenetic aberrations or sites of known tumor-associated genes were identified in 4q24 (TET2, 2x), 5q31.2 (2x), 7q22.1 (3x) and 21q22.12 (RUNX1, 2x). One patient with a 7q22.1 deletion had an additional 5q31.2 deletion of the acute myeloid leukemia/MDS region, the smallest deletion identified so far and including the putative tumor suppressor (ts) genes, EGR1 and CTNNA1. One TET2 deletion was homozygous and one heterozygous, with a missense mutation in the remaining allele, further supporting its role as a ts gene. Besides these recurrent alterations, additional individual imbalances were found in 34 cases; in total, 42/107 (39%) cases had genomic imbalances. These patients had an inferior survival as compared with the rest of the patients (P ¼ 0.002). This study emphasizes the heterogeneity of MDS, but points to interesting genes that may have diagnostic and prognostic impact.

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“…However, this might be an over-simplified explanation for the liver tropism as a certain fraction of metastatic UM retained their BAP1 expression and monosomy 3 is not always seen in hepatic metastasis. Polysomy 8q is rather a common feature of metastatic UM, and the role of this chromosomal abnormality on hepatic metastasis should be further explored [23,24] .…”

Section: Chromosomal and Genetic Abnormalitiesmentioning

confidence: 99%

Immunological aspect of the liver and metastatic uveal melanoma

Terai¹,

Mastrangleo²,

Sato³

2017

JCMT

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Uveal (eye) melanoma is the most common primary eye malignancy in adults. Despite optimal treatments for primary uveal melanoma, up to 50% of patients subsequently develop systemic metastasis, often in the liver. Once hepatic metastasis develops, the survival of patients is generally short and currently available treatments fail to show meaningful improvement of survival. Recent development of immune checkpoint blockades revolutionized immunotherapy for metastatic cutaneous (skin) melanoma. Unfortunately, metastatic uveal melanoma is unresponsive to this approach, thus there is an unmet need to improve the treatment of metastatic uveal melanoma. One unique characteristic of uveal melanoma is that the majority of metastases first develop in the liver. The liver is highly specialized in development of immune tolerance to food-derived antigens and consequently serves a unique function in the immune system. Understanding the mechanisms by which the liver orchestrates immune-related responses is important to the development of an effective immunotherapy for hepatic metastases such as metastatic uveal melanoma. In this review article, the authors overview the immunological aspects of the liver and discuss approaches to improve immunotherapy for metastatic uveal melanoma. Key words:Uveal melanoma, metastasis, liver, liver microenvironment, immunotherapy ABSTRACTArticle history:

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Genomic Profiling and Identification of High-Risk Uveal Melanoma by Array CGH Analysis of Primary Tumors and Liver Metastases

Abstract: The analysis of the status of these specific chromosome regions by genome profiling on SNP microarrays should be a reliable tool for identifying high-risk patients in future adjuvant therapy protocols.

Cited by 121 publications

References 23 publications

Establishment and Characterization of a Panel of Human Uveal Melanoma Xenografts Derived from Primary and/or Metastatic Tumors

Establishment and Characterization of a Panel of Human Uveal Melanoma Xenografts Derived from Primary and/or Metastatic Tumors

Comprehensive array CGH of normal karyotype myelodysplastic syndromes reveals hidden recurrent and individual genomic copy number alterations with prognostic relevance

Immunological aspect of the liver and metastatic uveal melanoma

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