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Melanoma DNA methylation

Yuqing Yang, Renyi Wu, Davit Sargsyan, Ran Yin, Hsiao-Chen Kuo, Irene Yang, Lujing Wang, David Cheng, Chao Wang, Shanyi Li, Rasika Hudlikar, Yaoping Lu, Ah-Ng Kong
Exposure to ultraviolet B (UVB) irradiation results in multitude of cellular responses including generation of reactive oxygen species and DNA damage and is responsible for non-melanoma skin cancers (NMSCs). Although genetic mutation is well documented, the epi-mutation, the alteration in epigenetics, remains elusive. In this study, we utilized CpG Methyl-seq to identify a genome-wide DNA CpG methylation, to profile the DNA methylation in UVB-irradiated SKH-1 mouse skin epidermis and non-melanoma skin papillomas at various stages...
February 13, 2019: Cancer Letters
Cécile Desjobert, Arnaud Carrier, Audrey Delmas, Diego M Marzese, Antoine Daunay, Florence Busato, Arnaud Pillon, Jörg Tost, Joëlle Riond, Gilles Favre, Chantal Etievant, Paola B Arimondo
BACKGROUND: Efficient treatments against metastatic melanoma dissemination are still lacking. Here, we report that low-cytotoxic concentrations of 5-aza-2'-deoxycytidine, a DNA demethylating agent, prevent in vitro 3D invasiveness of metastatic melanoma cells and reduce lung metastasis formation in vivo. RESULTS: We unravelled that this beneficial effect is in part due to MIR-199A2 re-expression by promoter demethylation. Alone, this miR showed an anti-invasive and anti-metastatic effect...
January 16, 2019: Clinical Epigenetics
Kerstin Kapp, Barbara Volz, Michael A Curran, Detlef Oswald, Burghardt Wittig, Manuel Schmidt
BACKGROUND: Toll-like receptor 9 agonists are potent activators of the immune system. Their clinical potential in immunotherapy against metastatic cancers is being evaluated across a number of clinical trials. TLR9 agonists are DNA-based molecules that contain several non-methylated CG-motifs for TLR9 recognition. Chemical modifications of DNA backbones are usually employed to prevent degradation by nucleases. These, however, can promote undesirable off-target effects and therapeutic restrictions...
January 8, 2019: Journal for Immunotherapy of Cancer
Yang Li, Xuan Yang, Jingyan Yang, Heng Wang, Wenbin Wei
Uveal melanoma (UM) is the most common intraocular tumor worldwide. We proposed to identify a vital gene signature that has prognostic value for UM metastasis. For this purpose, we obtained a published DNA methylation and gene expression data set associated with UM from the Gene Expression Omnibus. The genes whose aberrant expression significantly associated with UM patients' metastasis-free survival (MFS) were identified by applying a univariate Cox proportional hazards model to the gene expression data set followed by a robust likelihood-based survival analysis to screen the optimal prognostic gene signatures (PGS)...
December 16, 2018: Journal of Cellular Biochemistry
Kathleen Conway, Sharon N Edmiston, Joel S Parker, Pei Fen Kuan, Yi-Hsuan Tsai, Pamela A Groben, Daniel C Zedek, Glynis A Scott, Eloise A Parrish, Honglin Hao, Michelle V Pearlstein, Jill S Frank, Craig C Carson, Matthew D Wilkerson, Xiaobei Zhao, Nathaniel A Slater, Stergios J Moschos, David W Ollila, Nancy E Thomas
Early diagnosis improves melanoma survival, yet the histopathological diagnosis of cutaneous primary melanoma can be challenging even for expert dermatopathologists. Analysis of epigenetic alterations, such as DNA methylation, that occur in melanoma can aid in its early diagnosis. Using a genome-wide methylation screen, we assessed CpG methylation in a diverse set of 89 primary invasive melanomas, 73 nevi, and 41 melanocytic proliferations of uncertain malignant potential, classified based on interobserver review by dermatopathologists...
December 6, 2018: Journal of Investigative Dermatology
Alvin Ho-Kwan Cheung, Chit Chow, Mei-Yung Yu, Wendy Wai-Tak Law, Peggy Pui-Ying Law, Paul Cheung-Lung Choi, Wei Kang, Ka-Fai To
Malignant transformation of benign mature ovarian teratoma can result in a wide spectrum of cancer, including a variety of carcinoma, sarcoma, or melanoma. The role of mismatch repair defects in such malignant transformation is still elusive. In view of current immunotherapy, the role of mismatch repair deficiency can have significant implications on therapeutic strategy. Thus, we aimed to investigate the possible involvement of mismatch repair deficiency in somatic-type carcinoma arising from teratoma. We examined seven cases of malignant transformation of ovarian teratoma to carcinoma from the years 2000-2017...
November 27, 2018: Pathology
Alexander Renziehausen, Hexiao Wang, Bhavya Rao, Lynda Weir, Cristiana Lo Nigro, Laura Lattanzio, Marco Merlano, Antonio Vega-Rioja, Maria Del Carmen Fernandez-Carranco, Nabil Hajji, Rubeta Matin, Catherine Harwood, Su Li, Van Ren Sim, Kevin O'Neill, Alan Evans, Alastair Thompson, Peter Szlosarek, Colin Fleming, Justin Stebbing, Charlotte Proby, Andreas G Tzakos, Nelofer Syed, Tim Crook
Despite emergence of new systemic therapies, metastatic melanoma remains a challenging and often fatal form of skin cancer. The renin-angiotensin system (RAS) is a major physiological regulatory pathway controlling salt-water equilibrium, intravascular volume and blood pressure. Biological effects of the RAS are mediated by the vasoactive hormone angiotensin II (AngII) via two receptor subtypes, AT1R (encoded by AGTR1) and AT2R (encoded by AGTR2). We report decreasing expression and increasing CpG island methylation of AGTR1 in metastatic versus primary melanoma and detection in serum of methylated genomic DNA from the AGTR1 CpG island in metastatic melanoma implying that AGTR1 encodes a tumour suppressor function in melanoma...
November 26, 2018: Oncogene
Rosa F Brissos, Pau Clavero, Albert Gallen, Arnald Grabulosa, Leoní A Barrios, Ana B Caballero, Luís Korrodi-Gregório, Ricardo Pérez-Tomás, Guillermo Muller, Vanessa Soto-Cerrato, Patrick Gamez
In the present study, the potential anti-neoplastic properties of a series of ruthenium half-sandwich complexes of formula [Ru(η6 -arene)Cl2 (PR1 R2 (1-pyrenyl))] (η6 -arene = p-cymene and R1 = R2 = methyl for 1; η6 -arene = methylbenzoate and R1 = R2 = methyl for 2; η6 -arene = p-cymene and R1 = R2 = phenyl for 3; η6 -arene = methylbenzoate and R1 = R2 = phenyl for 4; η6 -arene = p-cymene, R1 = methyl and R2 = phenyl for 5; η6 -arene = methylbenzoate, R1 = methyl and R2 = phenyl for 6) have been investigated...
November 16, 2018: Inorganic Chemistry
Javier I J Orozco, Theo A Knijnenburg, Ayla O Manughian-Peter, Matthew P Salomon, Garni Barkhoudarian, John R Jalas, James S Wilmott, Parvinder Hothi, Xiaowen Wang, Yuki Takasumi, Michael E Buckland, John F Thompson, Georgina V Long, Charles S Cobbs, Ilya Shmulevich, Daniel F Kelly, Richard A Scolyer, Dave S B Hoon, Diego M Marzese
Optimal treatment of brain metastases is often hindered by limitations in diagnostic capabilities. To meet this challenge, here we profile DNA methylomes of the three most frequent types of brain metastases: melanoma, breast, and lung cancers (n = 96). Using supervised machine learning and integration of DNA methylomes from normal, primary, and metastatic tumor specimens (n = 1860), we unravel epigenetic signatures specific to each type of metastatic brain tumor and constructed a three-step DNA methylation-based classifier (BrainMETH) that categorizes brain metastases according to the tissue of origin and therapeutically relevant subtypes...
November 6, 2018: Nature Communications
Fengju Chen, Yiqun Zhang, Sooryanarayana Varambally, Chad J Creighton
Tumor metastasis is a major contributor to cancer patient mortality, but the process remains poorly understood. Molecular comparisons between primary tumors and metastases can provide insights into the pathways and processes involved. Here, we systematically analyzed and cataloged molecular correlates of metastasis using The Cancer Genome Atlas (TCGA) datasets across 11 different cancer types, these data involving 4,473 primary tumor samples and 395 tumor metastasis samples (including 369 from melanoma). For each cancer type, widespread differences in gene transcription between primary and metastasis samples were observed...
November 6, 2018: Molecular Cancer Research: MCR
Yichen Chen, Da Ma, Xi Wang, Juan Fang, Xiangqi Liu, Jingjing Song, Xinye Li, Xianyue Ren, Qiusheng Li, Qunxing Li, Shuqiong Wen, Liqun Luo, Juan Xia, Jun Cui, Gucheng Zeng, Lieping Chen, Bin Cheng, Zhi Wang
Elucidation of the mechanisms of T cell-mediated antitumor responses will provide information for the rational design and development of cancer immunotherapies. Here, we found that calnexin, an endoplasmic reticulum (ER) chaperone protein, is significantly upregulated in oral squamous cell carcinoma (OSCC). Upregulation of its membranous expression on OSCC cells is associated with inhibited T-cell infiltration in tumor tissues and correlates with poor survival of OSCC patients. We found that calnexin inhibits the proliferation of CD4+ and CD8+ T cells isolated from the whole blood of healthy donors and OSCC patients and inhibits the secretion of IFNγ, TNFα, and IL2 from these cells...
November 6, 2018: Cancer Immunology Research
Matthew P Salomon, Javier I J Orozco, James S Wilmott, Parvinder Hothi, Ayla O Manughian-Peter, Charles S Cobbs, Richard A Scolyer, Dave S B Hoon, Diego M Marzese
Brain metastases (BM) are one the most lethal and poorly managed clinical complications in cancer patients. These secondary tumors represent the most common intracranial neoplasm in adults, most frequently originating from lung cancer, breast cancer, and cutaneous melanoma. In primary brain tumors, such as gliomas, recent advances in DNA methylation profiling have allowed for a comprehensive molecular classification. Such data provide prognostic information, in addition to helping predict patient response to specific systemic therapies...
November 6, 2018: Scientific Data
Yu Guo, Jianhong Long, Shaorong Lei
Melanoma is one of the most common skin cancer that is characterized by rapid growth, early metastasis, high malignant, and mortality. Accumulating evidence demonstrated that promoter methylation of tumor-suppressor genes is implicated in the pathogenesis of melanoma. In the current study, we performed a meta-analysis to identify promising methylation biomarkers in the diagnosis of melanoma. We carried out a systematic literature search using Pubmed, Embase, and ISI web knowledge database and found that gene promoter methylation of 50 genes was reported to be associated with the risk of melanoma...
October 28, 2018: Journal of Cellular Physiology
Jared Nesvet, Giovanni Rizzi, Shan X Wang
Aberrant hypermethylation of CpG islands in the promoter region of tumor suppressor genes is a promising biomarker for early cancer detection. This methylation status is reflected in the methylation pattern of ctDNA shed from the primary tumor; however, to realize the full clinical utility of ctDNA methylation detection via liquid biopsy for early cancer diagnosis, improvements in the sensitivity and multiplexability of existing technologies must be improved. Additionally, the assay must be cheap and easy to perform in a clinical setting...
January 15, 2019: Biosensors & Bioelectronics
Sadegh Saghafinia, Marco Mina, Nicolo Riggi, Douglas Hanahan, Giovanni Ciriello
The discovery of cancer-associated alterations has primarily focused on genetic variants. Nonetheless, altered epigenomes contribute to deregulate transcription and promote oncogenic pathways. Here, we designed an algorithmic approach (RESET) to identify aberrant DNA methylation and associated cis-transcriptional changes across >6,000 human tumors. Tumors exhibiting mutations of chromatin remodeling factors and Wnt signaling displayed DNA methylation instability, characterized by numerous hyper- and hypo-methylated loci...
October 23, 2018: Cell Reports
Goran Micevic, Durga Thakral, Meaghan McGeary, Marcus Bosenberg
The aim of this study is to determine the significance of programmed death-ligand 1 (PD-L1 or CD274) methylation in relation to PD-L1 expression and survival in melanoma. Despite the clinical importance of therapies targeting the PD-1/PD-L1 immune checkpoint in melanoma, factors regulating PD-L1 expression, including epigenetic mechanisms, are not completely understood. In this study, we examined PD-L1 promoter methylation in relation to PD-L1 expression and overall survival in melanoma patients. Our results suggest that DNA methylation regulates PD-L1 expression in melanoma, and we identify the key methylated CpG loci in the PD-L1 promoter, establish PD-L1 methylation as an independent survival prognostic factor, provide proof-of-concept for altering PD-L1 expression by hypomethylating agents, and uncover that PD-L1 methylation is associated with an interferon-signaling transcriptional phenotype...
October 21, 2018: Pigment Cell & Melanoma Research
George Jour, Varshini Vasudevaraja, Victor G Prieto, Matija Snuderl, Carlos A Torres-Cabala, Rami Al-Rohil, Erik P Sulman, Leomar Y Ballester, Phyu P Aung
Superficial/cutaneous malignant peripheral nerve sheath tumor is a rare soft tissue neoplasm that shares morphological, immunohistochemical, and molecular features with spindle/desmoplastic melanoma. We aimed to identify a methylome signature to distinguish these two entities. We analyzed 15 cases of spindle/desmoplastic melanoma and 15 cases of cutaneous malignant peripheral nerve sheath tumor in 23 men and 7 women. DNA from formalin-fixed, paraffin-embedded tissues was extracted and processed using the Illumina Infinium Methylation EPIC array interrogating 866,562 CpG sites...
October 11, 2018: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
Thomas C Chen, Nymph Chan, Radu O Minea, Hannah Hartman, Florence M Hofman, Axel H Schönthal
The chemotherapeutic agent temozolomide (TMZ) kills tumor cells preferentially via alkylation of the O6-position of guanine. However, cells that express the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT), or harbor deficient DNA mismatch repair (MMR) function, are profoundly resistant to this drug. TMZ is in clinical use for melanoma, but objective response rates are low, even when TMZ is combined with O6-benzylguanine (O6BG), a potent MGMT inhibitor. We used in vitro and in vivo models of melanoma to characterize the early events leading to cellular TMZ resistance...
September 28, 2018: Cancers
Anna-Maria Barciszewska
Brain metastases are the most common intracranial tumors in adults. They usually originate from: lung, breast, renal cell and gastrointestinal cancers, as well as melanoma. Prognosis for brain metastases is still poor and classical treatment combining surgery and radiation therapy should be strongly supported with molecular approaches. However, their successful application depends on a deep understanding of not only genetic, but also epigenetic background of the disease. That will result in an earlier and more precise diagnosis, successful treatment, as well as individualized estimation of clinical outcomes and prognosis...
October 31, 2018: Bioscience Reports
Aniruddha Chatterjee, Euan J Rodger, Antonio Ahn, Peter A Stockwell, Matthew Parry, Jyoti Motwani, Stuart J Gallagher, Elena Shklovskaya, Jessamy Tiffen, Michael R Eccles, Peter Hersey
Constitutive expression of the immune checkpoint, PD-L1, inhibits anti-tumor immune responses in cancer, although the factors involved in PD-L1 regulation are poorly understood. Here we show that loss of global DNA methylation, particularly in intergenic regions and repeat elements, is associated with constitutive (PD-L1CON ), versus inducible (PD-L1IND ), PD-L1 expression in melanoma cell lines. We further show this is accompanied by transcriptomic up-regulation. De novo epigenetic regulators (e.g., DNMT3A) are strongly correlated with PD-L1 expression and methylome status...
June 29, 2018: iScience
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