Melanogenesis affects overall and disease-free survival in patients with stage III and IV melanoma

Brożyna, Anna A.; Jóźwicki, Wojciech; Carlson, J Andrew; Slominski, Andrzej

doi:10.1016/j.humpath.2013.02.022

Cited by 145 publications

(161 citation statements)

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“…Several prognostic factors have been identified including tumor thickness, clinical stage but also other factors like e.g. melanin content have been shown to influence treatment response and have been correlated with overall and disease free survival [28]–[29]. Thus – as expected - well established risk factors like tumor thickness and clinical stage correlate with disease free and overall survival also in our study population.…”

Section: Discussionsupporting

confidence: 69%

IL28B Polymorphism Cannot Predict Response to Interferon Alpha Treatment in Patients with Melanoma

et al. 2014

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BackgroundRecent genome-wide association studies revealed the rs12979860 single nucleotide polymorphism (SNP) of the IL28B gene (CC genotype) to be the strongest pre-therapeutic predictor of therapy response to interferon alpha in patients with chronic hepatitis C infection. The favorable CC genotype is associated with significantly higher rates of sustained virologic response. No data exist on the role of IL28B polymorphism in interferon therapy of diseases other than viral hepatitis.MethodsA retrospective study involving 106 patients with melanoma who received low- or high-dose interferon therapy was performed. The CC and non-CC genotype of IL28B rs12979860 SNP were correlated with progression-free and overall survival.Results44 (41.5%) patients were CC and 62 (58.5%) non-CC. There was no statistically significant difference in age at diagnosis, melanoma type or localization, Breslow level or AJCC stage between CC and non-CC patients. During the observation period (6.43±4.66 years) disease progression occurred in 36 (34%) patients after 5.5±4.3 years. 43.2% (19) of patients with CC and 27.4% (17) of patients with non-CC genotype were affected (p = 0.091). Disease progression was more frequent in patients on high dose interferon therapy and with a worse AJCC stage.ConclusionIn contrast to classical risk factors like tumor thickness and clinical stage, IL28B polymorphism was not associated with progression-free or overall survival in patients with melanoma treated with interferon alpha.

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Section: Discussionsupporting

confidence: 69%

IL28B Polymorphism Cannot Predict Response to Interferon Alpha Treatment in Patients with Melanoma

et al. 2014

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“…Previous data indicates that patients with pigmented melanomas experience worse outcomes compared to those with amelanotic melanomas (9, 10). MAPK pathway inhibitors enhance melanosomal gene expression (11) and our data confirm that melanoma cells respond to MAPK pathway inhibitors by exhibiting increased pigmentation and upregulating several melanosomal differentiation antigens.…”

Section: Discussionmentioning

confidence: 93%

“…While MITF is a master regulator of melanosomal pigmentation/function (6), it also promotes melanoma cell proliferation and is required for the maintenance of BRAF mutant melanoma (7, 8). Patients with pigment-producing metastatic melanomas have shorter disease-specific survival compared to those with non-pigmented melanoma (9, 10). Notably, treatment with BRAF and MEK inhibitors induces melanosomal antigen expression in patients with BRAF mutant melanoma (11).…”

Section: Introductionmentioning

confidence: 99%

MAPK Pathway Inhibitors Sensitize BRAF-Mutant Melanoma to an Antibody-Drug Conjugate Targeting GPNMB

Rose

Annis

Frederick

et al. 2016

Clinical Cancer Research

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Purpose: To determine if BRAF and/or MEK inhibitor-induced GPNMB expression renders melanomas sensitive to CDX-011, an antibody-drug conjugate targeting GPNMB. Experimental Design: The TCGA melanoma dataset was interrogated for a panel of MITF-regulated melanosomal differentiation antigens, including GPNMB. BRAF mutant melanoma cell lines treated with BRAF or MEK inhibitors were assessed for GPNMB expression by RT-qPCR, immunoblot and FACs analyses. Transient siRNA-mediated knockdown approaches were used to determine if MITF is requirement for treatment-induced GPNMB upregulation. GPNMB expression was analyzed in serial biopsies and serum samples from melanoma patients taken before, during and after disease progression on MAPK inhibitor treatment. Sub-cutaneous injections were performed to test the efficacy of MAPK inhibitors alone, CDX-011 alone, or their combination in suppressing melanoma growth. Results: A MITF-dependent melanosomal differentiation signature is associated with poor prognosis in patients with this disease. MITF is increased following BRAF and MEK inhibitor treatment and induces the expression of melanosomal differentiation genes, including GPNMB. GPNMB is expressed at the cell surface in MAPK inhibitor-treated melanoma cells and is also elevated in on-treatment versus pre-treatment biopsies from melanoma patients receiving MAPK pathway inhibitors. Combining BRAF and/or MEK inhibitors with CDX-011, an antibody-drug-conjugate targeting GPNMB, is effective in causing melanoma regression in pre-clinical animal models and delays the recurrent melanoma growth observed with MEK or BRAF/MEK inhibitor treatment alone. Conclusions: The combination of MAPK pathway inhibitors with an antibody-drug-conjugate targeting GPNMB is an effective therapeutic option for patients with melanoma.

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“…The relationship between miR-451a (but not its isomiR, mi-R451a.1) and melanogenesis may provide a novel molecular basis for the observed relationship between strongly pigmented melanoma phenotype and patient overall and disease-free survival [34].…”

Section: Discussionmentioning

confidence: 99%

A Novel miR-451a isomiR, Associated with Amelanotypic Phenotype, Acts as a Tumor Suppressor in Melanoma by Retarding Cell Migration and Invasion

Babapoor

Fleming

et al. 2014

PLoS ONE

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miRNAs are key regulatory small non-coding RNAs involved in critical steps of melanoma tumorigenesis; however, the relationship between sequence specific variations at the 5′ or 3′ termini (isomiR) of a miRNA and cancer phenotype remains unclear. Deep-sequencing and qRT-PCR showed reduced expression of miR-144/451a cluster and most abundant isomiR (miR451a.1) in dysplastic nevi, in-situ and invasive melanomas compared to common nevi and normal skin (n = 101). miRNA in situ hybridization reproducibly confirmed lost miR-451a.1 in melanoma compared to nevus cells or adjacent keratinocytes. Significantly higher expression of miR-451a.1 was associated with amelanotic phenotype in melanomas (n = 47). In contrast, miR-451a was associated with melanotic phenotype, absent pagetoid scatter of intraepidermal melanocytes, superficial spreading histological subtype and tumor inflammation. Sequencing miRNAs from cultured melanocytes with cytoplasmic melanin gradient (light, medium to dark) showed absent miR-451a while revealing other melanin-associated miRNAs, e.g. miR-30b, miR-100 and miR-590 in darkly and let-7a, let-7i and let-7f in lightly to moderately pigmented cultured melanocytes. Ectopic expression of miR-144/451a in melanoma cell lines resulted in markedly higher levels of mature miR-451a.1 than miR451a or miR-144; and significantly retarded cell migration and inhibited invasion in a glucose-sensitive manner. Surprisingly, these effects were not mediated by calcium binding protein 39 (CAB39), a proven miR451a gene target. miR-144/miR-451a cluster is a novel miRNA locus with tumor suppressive activity in melanoma.

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Melanogenesis affects overall and disease-free survival in patients with stage III and IV melanoma

Cited by 145 publications

References 13 publications

IL28B Polymorphism Cannot Predict Response to Interferon Alpha Treatment in Patients with Melanoma

IL28B Polymorphism Cannot Predict Response to Interferon Alpha Treatment in Patients with Melanoma

MAPK Pathway Inhibitors Sensitize BRAF-Mutant Melanoma to an Antibody-Drug Conjugate Targeting GPNMB

A Novel miR-451a isomiR, Associated with Amelanotypic Phenotype, Acts as a Tumor Suppressor in Melanoma by Retarding Cell Migration and Invasion

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