Melanoma epigenetics: novel mechanisms, markers, and medicines

Lee, Jonathan J.; Murphy, Gëorge F.; Lian, Christine G.

doi:10.1038/labinvest.2014.87

Cited by 76 publications

(86 citation statements)

References 185 publications

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“…Alternatively, the observed functional complexity and patient heterogeneity might refl ect multiple layers of adaptation of individual tumors to the continuously changing tumor environment or genomic context, with consequent activation of multiple and nonredundant signaling pathways and high frailty of the transformed phenotype. Notably, the identifi ed melanoma hits do not appear to be activated by somatic mutations in our patients, despite the fact that epigenetic genes are frequently mutated in cancer, including melanomas ( 34,35 ). The frequency of SNVs in the identifi ed hits, in fact, was slightly lower than in the nonhits ( Supplementary Figs.…”

Section: Discussionmentioning

confidence: 73%

In Vivo Genetic Screens of Patient-Derived Tumors Revealed Unexpected Frailty of the Transformed Phenotype

et al. 2016

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The identifi cation of genes maintaining cancer growth is critical to our understanding of tumorigenesis. We report the fi rst in vivo genetic screen of patient-derived tumors, using metastatic melanomas and targeting 236 chromatin genes by expression of specifi c shRNA libraries. Our screens revealed unprecedented numerosity of genes indispensable for tumor growth ( ∼ 50% of tested genes) and unexpected functional heterogeneity among patients (<15% in common). Notably, these genes were not activated by somatic mutations in the same patients and are therefore distinguished from mutated cancer driver genes. We analyzed underlying molecular mechanisms of one of the identifi ed genes, the Histone-lysine N-methyltransferase KMT2D , and showed that it promotes tumorigenesis by dysregulating a subset of transcriptional enhancers and target genes involved in cell migration. The assembly of enhancer genomic patterns by activated KMT2D was highly patient-specifi c, regardless of the identity of transcriptional targets, suggesting that KMT2D might be activated by distinct upstream signaling pathways. SIGNIFICANCE:Drug targeting of biologically relevant cancer-associated mutations is considered a critical strategy to control cancer growth. Our functional in vivo genetic screens of patient-derived tumors showed unprecedented numerosity and interpatient heterogeneity of genes that are essential for tumor growth, but not mutated, suggesting that multiple, patient-specifi c signaling pathways are activated in tumors. Cancer Discov;6(6);

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Section: Discussionmentioning

confidence: 73%

In Vivo Genetic Screens of Patient-Derived Tumors Revealed Unexpected Frailty of the Transformed Phenotype

et al. 2016

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“…Several studies have focused on genetic alterations beside BRAF mutations, which can be involved in target therapy response; however, still little is known on the possible epigenetic regulation of the melanoma pathways [11][12][13].…”

Section: Discussionmentioning

confidence: 99%

“…However the molecular mechanisms underlying this very short response duration are still unknown, and although several studies on genetic alterations have been conducted to uncover predictive biomarkers, very few data are present on epigenetic regulation in melanoma [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA expression in BRAF-mutated and wild-type metastatic melanoma and its correlation with response duration to BRAF inhibitors

Pinto

Strippoli

Summa

et al. 2015

Expert Opinion on Therapeutic Targets

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Objective: Currently, the treatment of BRAF V600-mutated metastatic melanoma with BRAF inhibitors gives a response rate of ~ 50% with a progression-free survival of ~ 6 -- 7 months. In order to identify predictive biomarkers capable of stratifying BRAF-mutated patients at high risk of shorter response duration to anti-BRAF therapy, the authors analyzed the expression of 15 microRNAs (miRNAs) targeting crucial genes involved in melanoma biology and drug response.Research design and methods: A total of 15 miRNAs and target gene expression were investigated in 43 patients (30 BRAF-mutated, and 13 BRAF wild-type). Moreover, 20 BRAF-mutated patients treated with vemurafenib were analyzed for miRNA expression in respect to time-to-progression.Results: All miRNAs except miR-192 showed low expression in BRAF-mutated as compared with BRAF wild-type patients. In particular, miR-101, miR-221,miR-21, miR-338-3p and miR-191 resulted in significant downregulation inBRAF-mutated patients. Moreover, high expression of miR-192 and miR-193b* and low expression of miR-132 resulted in significant association with shorter progression.Conclusion: Three miRNAs were significantly associated with clinical outcome in metastatic melanoma patients. An increased understanding of the molecular assessment of BRAF-mutated melanomas could allow development of specific molecular tests able to predict response duration.

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“…The epigenetic events involved in initiation and progression of melanoma may be aberrant methylation of the promoter regions, histone modification, chromatin remodeling, and the positioning of nucleosomes. 8 Additional epigenetic phenomena described more recently involve regulation of gene expression by non-coding RNAs (ncRNAs). 9 ncRNAs (small and long) are a new class of regulatory molecules, the differential expression of which is associated with normal physiological and diseased conditions, including cancer.…”

Section: Introductionmentioning

confidence: 99%