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Biomarkers as key contributors in treating malignant melanoma metastases.

ABSTRACT: Melanoma is a human neurocristopathy associated with developmental defects in the neural crest-derived epidermal melanocytes. At the present time, at least three hypotheses were identified that may explain melanoma aetiology, as follows: (1) a model of linear progression from differentiated melanocytes to metastatic cancer cells (2) a model involving the appearance of melanoma stem-like cells, and (3) an epigenetic progenitor model of cancer. Treating metastatic melanoma is one of the most serious challenges in the 21st century. This is justified because of a subpopulation of cells presenting a remarkable molecular heterogeneity, which is able to explain the drug resistance and the growing mortality rates worldwide. Fortunately, there are now evidences sustaining the importance of genetic, epigenetic, and metabolomic alterations as biomarkers for classification, staging, and better management of melanoma patients. To illustrate some fascinating insights in this field, the genes BRAF(V600E) and CTLA4 have been recognized as bona fide targets to benefit melanoma patients. Our research attempts to carefully evaluate data from the literature in order to highlight the link between a molecular disease model and the key contribution of biomarkers in treating malignant melanoma metastases.

SUBMITTER: de Souza CF

PROVIDER: S-EPMC3216378 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Biomarkers as key contributors in treating malignant melanoma metastases.

de Souza Camila Ferreira CF Morais Alice Santana AS Jasiulionis Miriam Galvonas MG

Dermatology research and practice 20111031

Melanoma is a human neurocristopathy associated with developmental defects in the neural crest-derived epidermal melanocytes. At the present time, at least three hypotheses were identified that may explain melanoma aetiology, as follows: (1) a model of linear progression from differentiated melanocytes to metastatic cancer cells (2) a model involving the appearance of melanoma stem-like cells, and (3) an epigenetic progenitor model of cancer. Treating metastatic melanoma is one of the most serio ...[more]

PMID: 22110486

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Project description:BackgroundCutaneous melanoma has a rapidly increasing incidence in Sweden, and it has more than doubled in the last two decades. In recent years, new systemic treatments for patients with metastatic disease have increased overall survival. The role of surgery in the metastatic setting has been unclear, and no randomized data exist. Many surgeons still perform metastasectomies; however, the exact role probably has to be redefined. The aim of this single-institution study was to retrospectively examine the safety and efficacy of surgery in abdominal melanoma metastases and to identify prognostic and predictive factors.MethodsRetrospective analysis of a consecutive series of all patients with stage IV melanoma with gastrointestinal metastases that underwent abdominal surgery at a single center between January 2010 and December 2018. Fifteen patients who underwent in total 18 abdominal procedures, both acute and elective, were identified and included in the study.ResultsOut of 18 laparotomies, six (33%) were emergency procedures due to ileus (n = 4), small bowel perforation (n = 1), and abdominal abscess (n = 1). Twelve procedures (66%) were elective with the most common indication being persistent anemia (58%, n = 7), abdominal pain and anemia (33%, n = 4), and abdominal pain (8%, n = 1). All procedures were performed by laparotomy. There were 19 small bowel resections, 3 partial colon resections, and 2 omental resections. Radical resection was possible in 56% (n = 10) of cases and 67% (n = 8) when only considering elective procedures. In 17 of 18 procedures (94%), there were mild or no surgical complications (Clavien-Dindo grades 0-I). The median overall survival was 14 months with a 5-year survival of 23%.ConclusionsPatients with abdominal melanoma metastases can safely undergo resection with a high grade of radical procedures when performed in the elective setting.Trial registrationClinicalTrials.gov , NCT03879395 . Registered 15 March 2019.

Project description:Perturbations in microRNA (miRNA) expression profiles has been reported for cutaneous malignant melanoma (CMM). With regards to a rapidly growing number of newly discovered miRNA sequences, the availability of up-to-date miRNA expression profiles for primary cutaneous malignant melanoma (PCMM), cutaneous malignant melanoma metastases (CMMM) and benign melanocytic naevi (BMN) is limited. Patients with PCMM (n=9), CMMM (n=4) and BMN (n=8) were included in the study. Specimens were obtained during surgery from the center of the tumors (lesional). An exploratory microarray analysis was performed by miRNA expression profiling based on miRBase V.16. Additionally, the expression levels of selected miRNA candidates were confirmed by TaqMan real-time quantitative polymerase chain reaction (RT-PCR). New miRNA candidates previously not described to be associated with CMM were found to be potentially dysregulated in CMM. Nine patients with PCMM (PCMM1-PCMM9), four patients with CMMM (CMMM1-CMMM4) and eight patients with BMN (BMN1-BMN8) were enrolled in the present study. All cutaneous specimens were harvested in the operating room, immediately stored in RNAlater (Quiagen, Hilden, Germany) and kept at - 80 °C until RNA isolation. Total RNA including miRNAs was isolated using the miRNeasy Mini Kit (Quiagen, Hilden, Germany) according to the manufacturer’s protocol. RNA concentration and purity was determined by NanoDrop ND-1000 spectral photometer (Peqlab, Erlangen, Germany). RNA integrity control (RIN) was determined by means of capillary electrophoresis with the 2100 Bioanalyzer and the RNA 6000 NanoLabCHip Kits (both Agilent Technologies, Santa Clara, USA). To be further considered for Microarray analysis a RIN ≥ 7.0 indicating medium to good RNA quality was defined as inclusion criteria. For assessment of labeling and hybridization efficiencies total RNA samples were spiked with in-vitro synthesized oligonucleotides by using the MicroRNA Spike-In Kit (Agilent Technologies, Santa Clara, USA). A total of 100 ng total RNA per sample were introduced into a labeling reaction. The spiked total RNA was treated with alkaline calf intestine phosphatase (CIP). The dephosphorylated RNA was labeled with the miRNA Complete Labeling and Hyb Kit (Agilent Technologies, Santa Clara, USA) according to the manufacturer´s instructions using T4 RNA ligase, incorporating Cyanine 3-Cytidine biphosphate (pCp). The Cyanine-3-labeled miRNA samples were prepared for One-Color based hybridization with Complete miRNA Labeling and Hyb Kit (Agilent Technologies, Santa Clara, USA) according to the manufacturer´s instructions. Labeled miRNA samples were hybridized at 55°C for 20 hrs on separate Human miRNA Microarrays Release 16.0 (8x60K format, (Agilent Technologies, Santa Clara, USA). Afterwards, microarrays were washed with increasing stringency using Gene Expression Wash Buffers (Agilent Technologies, Santa Clara, USA) followed by drying with acetonitrile (Sigma-Aldich, St.Louis, USA). Fluorescent signal intensities were detected with Scan Control A.8.4.1 Software (Agilent Technologies, Santa Clara, USA) on the Agilent DNA Microarray Scanner and extracted from the images using Feature Extraction 10.7.3.1 Software (Agilent Technologies, Santa Clara, USA). All the steps described were carried out according to the manufacturer´s instructions.

Project description:Evaluating the genetic contribution of individuals to population structure is essential to select informative individuals for genome sequencing, genotype imputation and to ascertain complex population structures. Existing methods for the selection of informative individuals for genomic imputation solely focus on the identification of key ancestors, which can lead to a loss of phasing accuracy of the reference population. Currently many methods are independently applied to investigate complex population structures. Based on the Eigenvalue Decomposition (EVD) of a genomic relationship matrix we describe a novel approach to evaluate the genetic contribution of individuals to population structure. We combined the identification of key contributors with model-based clustering and population network visualization into an integrated three-step approach, which allows identification of high-resolution population structures and substructures around such key contributors. The approach was applied and validated in four disparate datasets including a simulated population (5,100 individuals and 10,000 SNPs), a highly structured experimental sheep population (1,421 individuals and 44,693 SNPs) and two large complex pedigree populations namely horse (1,077 individuals and 38,124 SNPs) and cattle (2,457 individuals and 45,765 SNPs). In the simulated and experimental sheep dataset, our method, which is unsupervised, successfully identified all known key contributors. Applying our three-step approach to the horse and cattle populations, we observed high-resolution population substructures including the absence of obvious important key contributors. Furthermore, we show that compared to commonly applied strategies to select informative individuals for genotype imputation including the computation of marginal gene contributions (Pedig) and the optimization of genetic relatedness (Rel), the selection of key contributors provided the highest phasing accuracies within the selected reference populations. The presented approach opens new perspectives in the characterization and informed management of populations in general, and in areas such as conservation genetics and selective animal breeding in particular, where assessing the genetic contribution of influential and admixed individuals is crucial for research and management applications. As such, this method provides a valuable complement to common applied tools to visualize complex population structures and to select individuals for re-sequencing.

Project description:Perturbations in microRNA (miRNA) expression profiles has been reported for cutaneous malignant melanoma (CMM). With regards to a rapidly growing number of newly discovered miRNA sequences, the availability of up-to-date miRNA expression profiles for primary cutaneous malignant melanoma (PCMM), cutaneous malignant melanoma metastases (CMMM) and benign melanocytic naevi (BMN) is limited. Patients with PCMM (n=9), CMMM (n=4) and BMN (n=8) were included in the study. Specimens were obtained during surgery from the center of the tumors (lesional). An exploratory microarray analysis was performed by miRNA expression profiling based on miRBase V.16. Additionally, the expression levels of selected miRNA candidates were confirmed by TaqMan real-time quantitative polymerase chain reaction (RT-PCR). New miRNA candidates previously not described to be associated with CMM were found to be potentially dysregulated in CMM. Nine patients with PCMM (PCMM1-PCMM9), four patients with CMMM (CMMM1-CMMM4) and eight patients with BMN (BMN1-BMN8) were enrolled in the present study. All cutaneous specimens were harvested in the operating room, immediately stored in RNAlater (Quiagen, Hilden, Germany) and kept at - 80 M-BM-0C until RNA isolation. Total RNA including miRNAs was isolated using the miRNeasy Mini Kit (Quiagen, Hilden, Germany) according to the manufacturerM-bM-^@M-^Ys protocol. RNA concentration and purity was determined by NanoDrop ND-1000 spectral photometer (Peqlab, Erlangen, Germany). RNA integrity control (RIN) was determined by means of capillary electrophoresis with the 2100 Bioanalyzer and the RNA 6000 NanoLabCHip Kits (both Agilent Technologies, Santa Clara, USA). To be further considered for Microarray analysis a RIN M-bM-^IM-% 7.0 indicating medium to good RNA quality was defined as inclusion criteria. For assessment of labeling and hybridization efficiencies total RNA samples were spiked with in-vitro synthesized oligonucleotides by using the MicroRNA Spike-In Kit (Agilent Technologies, Santa Clara, USA). A total of 100 ng total RNA per sample were introduced into a labeling reaction. The spiked total RNA was treated with alkaline calf intestine phosphatase (CIP). The dephosphorylated RNA was labeled with the miRNA Complete Labeling and Hyb Kit (Agilent Technologies, Santa Clara, USA) according to the manufacturerM-BM-4s instructions using T4 RNA ligase, incorporating Cyanine 3-Cytidine biphosphate (pCp). The Cyanine-3-labeled miRNA samples were prepared for One-Color based hybridization with Complete miRNA Labeling and Hyb Kit (Agilent Technologies, Santa Clara, USA) according to the manufacturerM-BM-4s instructions. Labeled miRNA samples were hybridized at 55M-BM-0C for 20 hrs on separate Human miRNA Microarrays Release 16.0 (8x60K format, (Agilent Technologies, Santa Clara, USA). Afterwards, microarrays were washed with increasing stringency using Gene Expression Wash Buffers (Agilent Technologies, Santa Clara, USA) followed by drying with acetonitrile (Sigma-Aldich, St.Louis, USA). Fluorescent signal intensities were detected with Scan Control A.8.4.1 Software (Agilent Technologies, Santa Clara, USA) on the Agilent DNA Microarray Scanner and extracted from the images using Feature Extraction 10.7.3.1 Software (Agilent Technologies, Santa Clara, USA). All the steps described were carried out according to the manufacturerM-BM-4s instructions.

Dataset Information

Biomarkers as key contributors in treating malignant melanoma metastases.

Publications

Biomarkers as key contributors in treating malignant melanoma metastases.

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