Gene Expression Profiling in Uveal Melanoma Reveals Two Molecular Classes and Predicts Metastatic Death

Onken, Michael D.; Worley, Lori A.; Ehlers, Justis P.; Harbour, J. William

doi:10.1158/0008-5472.can-04-1750

Cited by 664 publications

(610 citation statements)

References 16 publications

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“…More recently, several genetic tests have been shown to aid prognostic prediction. Chromosome 3 loss, 19 BAP1 loss, 11 and RNA expression profiling 20,21 have high predictive values in terms of forecasting the course of disease and the risk of metastasis. SF3B1 codon 625 mutations also appear to be a genetic marker of good prognosis.…”

Section: Discussionmentioning

confidence: 99%

Genetic and clinico-pathologic analysis of metastatic uveal melanoma

et al. 2014

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Uveal melanoma is the most common malignant tumor of the adult eye. Fifty percent of tumors will eventually metastasize, and there are no effective treatments for them. Recent studies of uveal melanoma have identified activating mutations in GNAQ and GNA11, loss-of-function mutations in the tumor suppressor gene BAP1, and recurrent mutations in codon 625 of SF3B1. Previous studies have reported the existence of a higher frequency of GNA11 than GNAQ mutations, frequent BAP1 loss, and rare SF3B1 mutations in metastatic uveal melanoma. We analyzed a cohort of 30 uveal melanoma metastases for the occurrence of GNAQ, GNA11, and SF3B1 mutations, as well as BAP1 loss, and correlated these parameters with clinical and histopathologic features. Most (92%) tumors were composed of cells with an epithelioid or mixed (o100% spindle cells) morphology. Tumor samples composed exclusively of spindle cells were rare (n ¼ 2, 8%). Most tumors showed a moderate to marked degree of nuclear pleomorphism (n ¼ 24, 96%), and contained hyperchromatic, vesicular nuclei with variably conspicuous nucleoli. GNA11 mutations were considerably more frequent than GNAQ mutations (GNA11, GNAQ, and wild-type in 18 (60%), 6 (20%), and 6 (20%) cases, respectively). SF3B1 mutation was found in 1 of 26 tumors (4%), whereas loss of BAP1 expression was present in 13 of 16 tumors (81%). Patients with GNA11-mutant tumors had poorer disease-specific survival (60.0 vs 121.4 months, P ¼ 0.03) and overall survival (50.6 vs 121.4 months, P ¼ 0.03) than those with tumors lacking GNA11 mutations. The survival data, combined with the predominance of GNA11 mutations in metastases, raises the possibility that GNA11-mutant tumors may be associated with a higher risk of metastasis and poorer prognosis than GNAQ-mutant tumors. Further studies of uveal melanoma are required to investigate the functional and prognostic relevance of oncogenic mutations in GNA11 and GNAQ.

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Section: Discussionmentioning

confidence: 99%

Genetic and clinico-pathologic analysis of metastatic uveal melanoma

et al. 2014

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“…These advances include newer formalin-fixed paraffin-embedded tissue extraction protocols, cDNA-mediated annealing, selection, extension and ligation, the addition of random hexamer priming to oligo(dT) priming and newly developed array platforms with redesigned probes. [30][31][32][33][34]57,[67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82] Although sensitivity is low, high specificity and positive predictive value suggest that transcript detection is reliable from formalin-fixed paraffin-embedded tissue. 33 Although RNA isolation techniques from formalin-fixed paraffin-embedded tissues have improved, problems remain, largely because of the greater fragmented nature of RNA in formalin-fixed paraffin-embedded tissue.…”

Section: Discussionmentioning

confidence: 99%

Differential gene expression profiles of neurothekeomas and nerve sheath myxomas by microarray analysis

Sheth

Binder

et al. 2011

Modern Pathology

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“…Transcription profiling studies have provided evidence for distinct molecular subclasses of melanoma (Bittner et al 2000;Segal et al 2003;Tschentscher et al 2003;Onken et al 2004;Haqq et al 2005). At the genomic DNA level, the nonrandom nature of the chromosomal alterations characteristic of melanoma likely also dictates disease behavior; thus, patterns of alterations detectable at either the DNA or RNA level may segregate melanoma tumors into subtypes with distinct clinical behaviors and possibly therapeutic responses.…”

Section: Genomic Heterogeneity Of Melanomamentioning

confidence: 99%

Malignant melanoma: genetics and therapeutics in the genomic era

2006

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Cell for cell, probably no human cancer is as aggressive as melanoma. It is among a handful of cancers whose dimensions are reported in millimeters. Tumor thickness approaching 4 mm presents a high risk of metastasis, and a diagnosis of metastatic melanoma carries with it an abysmal median survival of 6-9 mo. What features of this malignancy account for such aggressive behavior? Is it the migratory history of its cell of origin or the programmed adaptation of its differentiated progeny to environmental stress, particularly ultraviolet radiation? While the answers to these questions are far from complete, major strides have been made in our understanding of the cellular, molecular, and genetic underpinnings of melanoma. More importantly, these discoveries carry profound implications for the development of therapies focused directly at the molecular engines driving melanoma, suggesting that we may have reached the brink of an unprecedented opportunity to translate basic science into clinical advances. In this review, we attempt to summarize our current understanding of the genetics and biology of this disease, drawing from expanding genomic information and lessons from development and genetically engineered mouse models. In addition, we look forward toward how these new insights will impact on therapeutic options for metastatic melanoma in the near future. The diseaseMelanomas most often arise within epidermal melanocytes of the skin, although they can also derive from noncutaneous melanocytes such as those lining the choroidal layer of the eye, GI and GU mucosal surfaces, or the meninges. Melanoma is also among the more common causes of "metastatic cancer of unknown primary," which may reflect either a propensity to arise in unexpected sites along the neural crest migratory route, or rapid growth of poorly differentiated lesions arising from indolent or unrecognized cutaneous primary lesions. Clinical staging for primary cutaneous melanoma employs measurements of thickness (in millimeters), presence of ulceration, penetration through cutaneous layers, mitotic rate, evidence of "in transit" metastasis, tumor spread to draining lymph nodes, and evidence of distant metastasis. Management issues in melanoma can be classified in terms of prevention, diagnosis, local disease management, and treatment of metastatic disease.In view of the epidemiological and emerging experimental evidence linking melanoma incidence to UV exposure and skin phototype, prevention and screening strategies represent key areas for reduction of disease incidence and severity. For most cutaneous melanomas in the so-called radial growth phase (e.g., thin melanomas), surgical removal affords curative treatment. In contrast, a significant fraction of patients diagnosed with intermediate-thickness (2-4 mm) cutaneous melanoma eventually succumb to recurrence at regional or distant sites.Critical biological questions facing the melanoma research community include: (1) What genetic and environmental factors contribute to and/or modulate risk of melanom...

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Gene Expression Profiling in Uveal Melanoma Reveals Two Molecular Classes and Predicts Metastatic Death

Cited by 664 publications

References 16 publications

Genetic and clinico-pathologic analysis of metastatic uveal melanoma

Genetic and clinico-pathologic analysis of metastatic uveal melanoma

Differential gene expression profiles of neurothekeomas and nerve sheath myxomas by microarray analysis

Malignant melanoma: genetics and therapeutics in the genomic era

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