The role of CCND1 alterations during the progression of cutaneous malignant melanoma

Vízkeleti, Laura; Ecsedi, Szilvia; Rákosy, Zsuzsa; Orosz, Adrienn; Lázár, Viktória; Emri, Gabriella; Koroknai, Viktória; Kiss, Tímea; Ádány, Róza; Balázs, Margit

doi:10.1007/s13277-012-0480-6

Cited by 47 publications

(34 citation statements)

References 38 publications

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“…Recently, it has become widely accepted that Knudson's two-hit hypothesis is often confirmed through a combination of differing types of genomic alterations [17], [18], which prompted us to investigate whether methylation patterns are associated with other types of somatic alterations, such as the most frequent mutations (BRAF and NRAS) and DNA copy number (CN) alterations. Notable previous investigations demonstrated the prognostic relevance of CN aberrations [19], [20], [21], [22]. Therefore, we also highlighted the cis-and trans-acting CN alterations of gene expression in malignant melanoma [23].…”

Section: Introductionsupporting

confidence: 55%

DNA Methylation Characteristics of Primary Melanomas with Distinct Biological Behaviour

et al. 2014

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In melanoma, the presence of promoter related hypermethylation has previously been reported, however, no methylation-based distinction has been drawn among the diverse melanoma subtypes. Here, we investigated DNA methylation changes associated with melanoma progression and links between methylation patterns and other types of somatic alterations, including the most frequent mutations and DNA copy number changes. Our results revealed that the methylome, presenting in early stage samples and associated with the BRAFV600E mutation, gradually decreased in the medium and late stages of the disease. An inverse relationship among the other predefined groups and promoter methylation was also revealed except for histologic subtype, whereas the more aggressive, nodular subtype melanomas exhibited hypermethylation as well. The Breslow thickness, which is a continuous variable, allowed for the most precise insight into how promoter methylation decreases from stage to stage. Integrating our methylation results with a high-throughput copy number alteration dataset, local correlations were detected in the MYB and EYA4 genes. With regard to the effects of DNA hypermethylation on melanoma patients' survival, correcting for clinical cofounders, only the KIT gene was associated with a lower overall survival rate. In this study, we demonstrate the strong influence of promoter localized DNA methylation changes on melanoma initiation and show how hypermethylation decreases in melanomas associated with less favourable clinical outcomes. Furthermore, we establish the methylation pattern as part of an integrated apparatus of somatic DNA alterations.

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Section: Introductionsupporting

confidence: 55%

DNA Methylation Characteristics of Primary Melanomas with Distinct Biological Behaviour

et al. 2014

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“…Our BRD4 analysis further revealed that melanoma-associated genes such as LIF , CCND1 , and BRD2 (Kuphal et al, 2013; Vardabasso et al, 2015; Vízkeleti et al, 2012) have putative SEs (Figure 5A). AMIGO2 was associated with two SEs, and three other genes from the proliferation mini-screen ( HMGA2 , ZBTB38 , and PDGFC ) (Figure 1E) were also associated with SEs (Figures 5A, S5B, and S5F).…”

Section: Resultsmentioning

confidence: 78%

Harnessing BET Inhibitor Sensitivity Reveals AMIGO2 as a Melanoma Survival Gene

et al. 2017

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SUMMARY Bromodomain and extraterminal domain inhibitors (BETi) represent promising therapeutic agents for metastatic melanoma, yet their mechanism of action remains unclear. Here we interrogated the transcriptional effects of BETi and identified AMIGO2, a trans-membrane molecule, as a BET target gene essential for melanoma cell survival. AMIGO2 is upregulated in melanoma cells and tissues compared to human melanocytes and nevi, and AMIGO2 silencing in melanoma cells induces G1/S arrest followed by apoptosis. We identified the pseudokinase PTK7 as an AMIGO2 interactor whose function is regulated by AMIGO2. Epigenomic profiling and genome editing revealed that AMIGO2 is regulated by a melanoma-specific BRD2/4-bound promoter and super-enhancer configuration. Upon BETi treatment, BETs are evicted from these regulatory elements, resulting in AMIGO2 silencing and changes in PTK7 proteolytic processing. Collectively, this study uncovers mechanisms underlying the therapeutic effects of BETi in melanoma and reveals the AMIGO2-PTK7 axis as a targetable pathway for metastatic melanoma.

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“…In melanoma, MITF, CCND1, BRAF, CDKN2A, and PTEN are some of the validated oncogenes and tumor suppressors targeted by such focal copy number-changing aberrations (3–5). However, there are also many recurrent large regional or arm-level losses and gains that affect multiple resident genes (6, 7).…”

Section: Introductionmentioning

confidence: 99%

Chromosome 10, Frequently Lost in Human Melanoma, Encodes Multiple Tumor-Suppressive Functions

Kwong

Chin

2014

Cancer Research

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Although many DNA aberrations in melanoma have been well characterized, including focal amplification and deletions of oncogenes and tumor suppressors, broad regions of chromosomal gain and loss are less well understood. One possibility is that these broad events are a consequence of collateral damage from targeting single loci. Another possibility is that the loss of large regions permits simultaneous inactivation of multiple tumor suppressors, by broadly decreasing the resident gene dosage and expression. Here, we test this hypothesis in a targeted fashion using RNA interference to suppress multiple candidates resident in broad regions of loss. We find that loss of chromosome regions 6q, 10, and 11q21-ter are correlated with broadly decreased expression of most resident genes, and that multiple resident genes impacted by broad regional loss of chromosome 10 are bona fide tumor suppressors capable of affecting tumor growth and/or invasion. We also provide functional support for Ablim1 as a novel tumor suppressor. Our results support the hypothesis that multiple cancer genes are targeted by regional chromosome copy number aberrations.

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The role of CCND1 alterations during the progression of cutaneous malignant melanoma

Cited by 47 publications

References 38 publications

DNA Methylation Characteristics of Primary Melanomas with Distinct Biological Behaviour

DNA Methylation Characteristics of Primary Melanomas with Distinct Biological Behaviour

Harnessing BET Inhibitor Sensitivity Reveals AMIGO2 as a Melanoma Survival Gene

Chromosome 10, Frequently Lost in Human Melanoma, Encodes Multiple Tumor-Suppressive Functions

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