Somatic Copy Number Amplification and Hyperactivating Somatic Mutations of EZH2 Correlate With DNA Methylation and Drive Epigenetic Silencing of Genes Involved in Tumor Suppression and Immune Responses in Melanoma

Tiffen, Jessamy; Wilson, Stephen; Gallagher, Stuart J.; Hersey, Peter; Filipp, Fabian V.

doi:10.1016/j.neo.2016.01.003

Cited by 46 publications

(52 citation statements)

References 33 publications

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“…Melanoma is the most frequently EZH2-mutated solid neoplasm [37]. Melanoma cells harbor the Y641 activating mutation within the catalytic SET domain that was first described in Diffuse large B-cell (DLBC) lymphoma.…”

Section: Discussionmentioning

confidence: 99%

EZH2 Single Nucleotide Variants (SNVs): Diagnostic and Prognostic Role in 10 Solid Tumor Types

et al. 2017

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Abstract:The enhancer of zeste homolog 2 (EZH2) gene encodes a histone methyltransferase that is a catalytic subunit of the Polycomb repressive complex 2 (PRC2) group of proteins that act to repress gene expression. The EZH2 locus is rarely mutated in solid tumors and there is no comprehensive study of EZH2 single nucleotide variants (SNVs) associated with cancer susceptibility, prognosis and response to therapy. Here, for the first time, we review the functional roles of EZH2 DNA variants and propose a putative etiological role in 10 various solid tumors including: esophageal, hepatocellular, oral, urothelial, colorectal, lung and gastric cancers. In particular, we found that the C allele of the EZH2 variant rs3757441 is associated with increased EZH2 RNA expression and poorer prognosis (advanced stage) in at least two malignancies such as colorectal and hepatocellular carcinoma. This suggests that the C allele may be a functional risk variant in multiple malignant tumors. We therefore propose that the rs3757441 single nucleotide variant (SNV) be genotyped and real-time PCR assays be performed in large cohort studies in order to confirm this preliminary finding that could be useful for clinical practice.

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Section: Discussionmentioning

confidence: 99%

EZH2 Single Nucleotide Variants (SNVs): Diagnostic and Prognostic Role in 10 Solid Tumor Types

et al. 2017

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“…In cancer care, phenotype-driven gene target definition is typical and clinical genome-wide sequencing data interpretation is still accompanied by a large-scale research effort [84]. Here, we illustrate a complete precision medicine profile of a malignant melanoma patient [85] (Figs. 3 and 4).…”

Section: Precision Medicine Profile Of Malignant Melanoma Patient Witmentioning

confidence: 99%

“…The study on efficient detection of genomic drivers in malignant melanoma identified co-occurrence of a mutational and copy number hotspot on chromosome 7 including the known BRAF locus [13]. Interestingly, the activating somatic BRAF(V600E) mutation is accompanied by somatic mutation and/or somatic copy number amplification of prominent epigenetic regulators such as enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2, KMT6A, Gene ID: 2146), lysine demethylase 7A (KDM7A, JHDM1D, Gene ID: 80853), and euchromatic histone lysine methyltransferase 2 (EHMT2, KMT1C, Gene ID: 10919) [13, 85]. The detailed analysis of the mutational landscape of BRAF revealed missense mutations in the ATP-binding site of G466, S467, and G489 as well as in the activator loop of D594, L597, and K601 in the proximity of residue V600 [13].…”

Section: Precision Medicine Profile Of Malignant Melanoma Patient Witmentioning

confidence: 99%

“…EZH2 contains the catalytic histone lysine methyl transferase subunit of the polycomb repressive complex 2 (PRC2), which plays a role in maintenance of the stem cell-like state of cancer cells and in the progression of malignant melanoma [93]. Hyperactivation of EZH2 by somatic mutations or copy number gain occurs in 20% of melanoma patients and negatively impacts overall survival [85].

Fig.…”

Section: Precision Medicine Profile Of Malignant Melanoma Patient Witmentioning

confidence: 99%

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Precision medicine driven by cancer systems biology

Filipp

2017

Cancer Metastasis Rev

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Molecular insights from genome and systems biology are influencing how cancer is diagnosed and treated. We critically evaluate big data challenges in precision medicine. The melanoma research community has identified distinct subtypes involving chronic sun-induced damage and the mitogen-activated protein kinase driver pathway. In addition, despite low mutation burden, non-genomic mitogen-activated protein kinase melanoma drivers are found in membrane receptors, metabolism, or epigenetic signaling with the ability to bypass central mitogen-activated protein kinase molecules and activating a similar program of mitogenic effectors. Mutation hotspots, structural modeling, UV signature, and genomic as well as non-genomic mechanisms of disease initiation and progression are taken into consideration to identify resistance mutations and novel drug targets. A comprehensive precision medicine profile of a malignant melanoma patient illustrates future rational drug targeting strategies. Network analysis emphasizes an important role of epigenetic and metabolic master regulators in oncogenesis. Co-occurrence of driver mutations in signaling, metabolic, and epigenetic factors highlights how cumulative alterations of our genomes and epigenomes progressively lead to uncontrolled cell proliferation. Precision insights have the ability to identify independent molecular pathways suitable for drug targeting. Synergistic treatment combinations of orthogonal modalities including immunotherapy, mitogen-activated protein kinase inhibitors, epigenetic inhibitors, and metabolic inhibitors have the potential to overcome immune evasion, side effects, and drug resistance.

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“…Выявлены также эпигенетические предикторы. Амплификации и активирующие соматические мутации в гене EZH2 кор-релируют с уровнем метилирования ДНК, обеспечивая эпигенетическую инактивацию ряда генов, вовлеченных в опухолевую супрессию, и иммунный ответ при меланоме (Tiffen et al, 2016).…”

Section: системная биология и биомедицинаunclassified

Differences in expression profiles in malingant melanoma patients according to immunotherapy response

Lukyanova¹,

Fedorova²,

Pudova³

et al. 2017

Vestn. VOGiS

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One of the most important branch of modern mole cular genetics and biomedicine is the search for pre dictive markers that help choose the most effective way of treatment, drug and also determine its indi vidual dosage. Among the markers, those that can pro vide the possibility of using a noninvasive, socalled "liquid biopsy" are considered particularly promising. This method allows the condition of the tumor to be assessed by analyzing the body's natural fluids, such as blood, urine or saliva. Such studies are most conve nient in those cases when it is necessary to monitor the effectiveness of therapy in order to record the time of the onset of resistance of tumor cells, the onset of relapse and to move on to the next line of therapy. In the treatment of aggressive and rapidly became metastatic malignant tumors, such as melanoma, the presence of reliable markers that allow quick and ac curate determination of treatment tactics is especially important. Nowadays, there is an increasing number of studies devoted to the search for predictive markers of the effectiveness of immunotherapy. Melanoma is one of the most immunogenic tumors and, as a result, has become a model object for research into and introduction of new approaches to immunotherapy. In this study, we compared two groups of patients with metastatic skin melanoma, with different responses to immunotherapy with blockers of immune control points, to identify new predictive expression biomark ers among microRNAs and mRNAs, and to identify the Одним из важнейших направлений современной молекулярной генетики и биомедицины является поиск предиктивных маркеров, помогающих выбрать наиболее эффективный способ лечения и препарат, а также индивидуально подобрать его дозировку. Осо бенно перспективными считаются те маркеры, которые могут обе спечить возможность применения неинвазивной, так называемой жидкостной биопсии. Этот метод позволяет оценить состояние опухоли по анализу естественных жидкостей организма, таких как кровь, моча или слюна. Подобные исследования наиболее удобны в случаях, когда необходимо проводить мониторинг эффектив ности терапии, чтобы вовремя зафиксировать момент возникно ве ния резистентности опухолевых клеток, начало рецидива и перей ти на следующую линию терапии. При лечении агрессивных и быстро метастазирующих злокачественных новообразований, таких как меланома, наличие достоверных маркеров, позволя ющих быстро и точно определить тактику лечения, особенно важно. В последнее время появляется все больше исследований, посвя щенных поиску предиктивных маркеров эффективности иммуно терапии. Меланома характеризуется высокой иммуногенностью, в связи с чем она стала модельным объектом для исследования и внедрения новых подходов иммунотерапии. В настоящей работе проведено сравнение двух групп больных метастатической мела номой кожи с различным ответом на иммунотерапию блокаторами иммунных контрольных точек с целью идентифицировать новые предиктивные экспрессионные биомаркеры среди микро и мат ричных РНК, а также определить гены, ответственные за во...

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Somatic Copy Number Amplification and Hyperactivating Somatic Mutations of EZH2 Correlate With DNA Methylation and Drive Epigenetic Silencing of Genes Involved in Tumor Suppression and Immune Responses in Melanoma

Cited by 46 publications

References 33 publications

EZH2 Single Nucleotide Variants (SNVs): Diagnostic and Prognostic Role in 10 Solid Tumor Types

EZH2 Single Nucleotide Variants (SNVs): Diagnostic and Prognostic Role in 10 Solid Tumor Types

Precision medicine driven by cancer systems biology

Differences in expression profiles in malingant melanoma patients according to immunotherapy response

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