Large-giant congenital melanocytic nevi have been well characterized clinically, yet questions remain about the heterogenous phenotypes observed. Martins da Silva et al. (2018) highlight the ...genotypic diversity between “classic” and “spilus-like” congenital melanocytic nevi by analyzing multiple biopsy sites and matching satellite nevi. This study provides evidence for alternative modes of development beyond the well-established NRAS mutation paradigm.
MicroRNAs (miRNAs) are 18-23 nucleotide non-coding RNAs that regulate gene expression in a sequence specific manner. Little is known about the repertoire and function of miRNAs in melanoma or the ...melanocytic lineage. We therefore undertook a comprehensive analysis of the miRNAome in a diverse range of pigment cells including: melanoblasts, melanocytes, congenital nevocytes, acral, mucosal, cutaneous and uveal melanoma cells.
We sequenced 12 small RNA libraries using Illumina's Genome Analyzer II platform. This massively parallel sequencing approach of a diverse set of melanoma and pigment cell libraries revealed a total of 539 known mature and mature-star sequences, along with the prediction of 279 novel miRNA candidates, of which 109 were common to 2 or more libraries and 3 were present in all libraries.
Some of the novel candidate miRNAs may be specific to the melanocytic lineage and as such could be used as biomarkers to assist in the early detection of distant metastases by measuring the circulating levels in blood. Follow up studies of the functional roles of these pigment cell miRNAs and the identification of the targets should shed further light on the development and progression of melanoma.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases, and rare variants in CDK4, BRCA2, BAP1 and the promoter of TERT have also been linked to the disease. Here ...we set out to identify new high-penetrance susceptibility genes by sequencing 184 melanoma cases from 105 pedigrees recruited in the UK, The Netherlands and Australia that were negative for variants in known predisposition genes. We identified families where melanoma cosegregates with loss-of-function variants in the protection of telomeres 1 gene (POT1), with a proportion of family members presenting with an early age of onset and multiple primary tumors. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding and leading to increased telomere length. These findings suggest that POT1 variants predispose to melanoma formation via a direct effect on telomeres.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Early detection of melanoma is critical to good patient outcomes, but we still know little about the mechanisms of early melanoma development. Normal epidermis has many of the sequence variants and ...genetic architecture disruptions found in both benign nevi, melanomas, and other skin cancers, yet continues to behave more or less normally. One hypothesis is that many melanocytes in this context are “tumor competent” but are regulated by the microenvironment provided by the surrounding keratinocytes to inhibit progress to nevi or melanoma. There is evidence of accumulating disorder in several measures of the genomic and epigenomic landscape from normal skin through nevi to melanoma that may be key to promoting nevogenesis and melanomagenesis.
Precise detection of early melanomas is essential as the stage of disease guides treatment options. One growing field that may facilitate the advancement of early melanoma detection, is achieved ...through profiling serum extracellular vesicles (EVs) using sensitive nanotechnology. As a proof of principle, using a detection platform that combines a microfluidic device and surface‐enhanced Raman spectroscopy (SERS), the expression profiles of 4 protein biomarkers in serum EVs (termed as “EV SERS signatures”) derived from 20 early stage melanoma patients (including in situ melanoma) and 21 healthy participants are multiplexed. Significantly higher signal intensities of selected protein biomarkers are observed in serum EVs from melanoma patients compared with healthy participants, with mean fold‐changes ranging from 3.7 to 4.2. It is demonstrated that the EV SERS signatures can accurately separate melanoma patients and healthy individuals, with an area under the curve of 0.95. Thus, with further development, this ultra‐sensitive detection platform, combined with the panel of melanoma‐associated biomarkers, has the ability to differentiate early stage melanoma patients from healthy participants.
A detection platform that integrates a circulating nanomixing‐microchip and a multiplexing surface‐enhanced Raman spectroscopy barcoding system for sensitive phenotypic characterization of serum extracellular vesicles, without extensive sample pre‐enrichment is developed. This platform, combined with the panel of melanoma‐associated biomarkers, has the ability to differentiate early stage melanoma patients from healthy participants.
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