The Development and Evaluation of a Convolutional Neural Network for Cutaneous Melanoma Detection in Whole Slide Images.

Context.—: The current melanoma staging system does not account for 26% of the variance seen in melanoma-specific survival, therefore our ability to predict patient outcome is not fully elucidated. Morphology may be of greater significance than in other solid tumors, with Breslow thickness remaining the strongest prognostic indicator despite being subject to high levels of interobserver variation.

Peroxiredoxin-2 represses NRAS-mutated melanoma cells invasion by modulating EMT markers.

The second most common mutation in melanoma occurs in NRAS oncogene, being a more aggressive disease that has no effective approved treatment. Besides, cellular plasticity limits better outcomes of the advanced and therapy-resistant patients. Peroxiredoxins (PRDXs) control cellular processes through direct hydrogen peroxide oxidation or by redox-relaying processes.

Image analysis of cutaneous melanoma histology: a systematic review and meta-analysis.

The current subjective histopathological assessment of cutaneous melanoma is challenging. The application of image analysis algorithms to histological images may facilitate improvements in workflow and prognostication. To date, several individual algorithms applied to melanoma histological images have been reported with variations in approach and reported accuracies.

Association of germline variants in telomere maintenance genes ( and ) with spitzoid morphology in familial melanoma: A multi-center case series.

Background: Spitzoid morphology in familial melanoma has been associated with germline variants in , a telomere maintenance gene (TMG), suggesting a link between telomere biology and spitzoid differentiation.

Objective: To assess if familial melanoma cases associated with germline variants in TMG (, , , and ) commonly exhibit spitzoid morphology.

Methods: In this case series, melanomas were classified as having spitzoid morphology if at least 3 of 4 dermatopathologists reported this finding in ≥25% of tumor cells.

Total serum N-glycans associate with response to immune checkpoint inhibition therapy and survival in patients with advanced melanoma.

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of melanoma and other cancers. However, no reliable biomarker of survival or response has entered the clinic to identify those patients with melanoma who are most likely to benefit from ICIs. Glycosylation affects proteins and lipids' structure and functions.

PTPN11 Mosaicism Causes a Spectrum of Pigmentary and Vascular Neurocutaneous Disorders and Predisposes to Melanoma.

Phakomatosis pigmentovascularis is a diagnosis that denotes the coexistence of pigmentary and vascular birthmarks of specific types, accompanied by variable multisystem involvement, including CNS disease, asymmetrical growth, and a predisposition to malignancy. Using a tight phenotypic group and high-depth next-generation sequencing of affected tissues, we discover here clonal mosaic variants in gene PTPN11 encoding SHP2 phosphatase as a cause of phakomatosis pigmentovascularis type III or spilorosea. Within an individual, the same variant is found in distinct pigmentary and vascular birthmarks and is undetectable in blood.

Population-based analysis of variants in a cutaneous melanoma case-control cohort.

Pathogenic germline variants in the protection of telomeres 1 gene () have been associated with predisposition to a range of tumour types, including melanoma, glioma, leukaemia and cardiac angiosarcoma. We sequenced all coding exons of the gene in 2928 European-descent melanoma cases and 3298 controls, identifying 43 protein-changing genetic variants. We performed POT1-telomere binding assays for all missense and stop-gained variants, finding nine variants that impair or disrupt protein-telomere complex formation, and we further define the role of variants in the regulation of telomere length and complex formation through molecular dynamics simulations.

Identifying the Transcriptional Drivers of Metastasis Embedded within Localized Melanoma.

Unlabelled: In melanoma, predicting which tumors will ultimately metastasize guides treatment decisions. Transcriptional signatures of primary tumors have been utilized to predict metastasis, but which among these are driver or passenger events remains unclear. We used data from the adjuvant AVAST-M trial to identify a predictive gene signature in localized tumors that ultimately metastasized.

Mutually exclusive genetic interactions and gene essentiality shape the genomic landscape of primary melanoma.

Melanoma is a heterogenous malignancy with an unpredictable clinical course. Most patients who present in the clinic are diagnosed with primary melanoma, yet large-scale sequencing efforts have focused primarily on metastatic disease. In this study we sequence-profiled 524 American Joint Committee on Cancer Stage I-III primary tumours.

Higher polygenic risk for melanoma is associated with improved survival in a high ultraviolet radiation setting.

Background: The role of germline genetic factors in determining survival from cutaneous melanoma (CM) is not well understood.

Objective: To perform a genome-wide association study (GWAS) meta-analysis of melanoma-specific survival (MSS), and test whether a CM-susceptibility polygenic risk score (PRS) is associated with MSS.

Methods: We conducted two Cox proportional-hazard GWAS of MSS using data from the Melanoma Institute Australia, a high ultraviolet (UV) radiation setting (MIA; 5,762 patients with melanoma; 800 melanoma deaths) and UK Biobank (UKB: 5,220 patients with melanoma; 241 melanoma deaths), and combined them in a fixed-effects meta-analysis.

Circulating inflammatory proteins associate with response to immune checkpoint inhibition therapy in patients with advanced melanoma.

Background: Inflammation can modulate tumour growth and progression, and influence clinical response to treatment. We investigated the potential of circulating inflammatory proteins for response stratification of immune checkpoint inhibitor (ICI) therapy for advanced melanoma.

Methods: Study subjects were 87 patients with unresectable stage III or IV cutaneous melanoma from the multiple centres across the United Kingdom (UK) and the Netherlands (NL) who received ipilimumab, nivolumab, or pembrolizumab, or a combination of ipilimumab and nivolumab.

ROR2 promotes epithelial-mesenchymal transition by hyperactivating ERK in melanoma.

Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a protein with important functions during embryogenesis that is dysregulated in human cancer. An intriguing feature of this receptor is that it plays opposite roles in different tumor types either promoting or inhibiting tumor progression. Understanding the complex role of this receptor requires a more profound exploration of both the altered biological and molecular mechanisms.

Defining novel causal SNPs and linked phenotypes at melanoma-associated loci.

A number of genomic regions have been associated with melanoma risk through genome-wide association studies; however, the causal variants underlying the majority of these associations remain unknown. Here, we sequenced either the full locus or the functional regions including exons of 19 melanoma-associated loci in 1959 British melanoma cases and 737 controls. Variant filtering followed by Fisher's exact test analyses identified 66 variants associated with melanoma risk.

Ulcerated melanoma: Systems biology evidence of inflammatory imbalance towards pro-tumourigenicity.

Microscopic ulceration is an independent predictor of melanoma death. Here, we used systems biology to query the role of host and tumour-specific processes in defining the phenotype. Albumin level as a measure of systemic inflammation was predictive of fewer tumour-infiltrating lymphocytes and poorer survival in the Leeds Melanoma Cohort.

ROR2 has a protective role in melanoma by inhibiting Akt activity, cell-cycle progression, and proliferation.

Background: Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a Wnt5a receptor aberrantly expressed in cancer that was shown to either suppress or promote carcinogenesis in different tumor types. Our goal was to study the role of ROR2 in melanoma.

Methods: Gain and loss-of-function strategies were applied to study the biological function of ROR2 in melanoma.

Road to Metastasis: The TWEAK Pathway as a Discriminant between Metastasizing and Non-Metastasizing Thick Melanomas.

Cutaneous melanoma (CM) is the most aggressive form of skin cancer, and its worldwide incidence is rapidly increasing. Early stages can be successfully treated by surgery, but once metastasis has occurred, the prognosis is poor. However, some 5-10% of thick (≥2 mm) melanomas do not follow this scenario and run an unpredictable course.

Cooperation between melanoma cell states promotes metastasis through heterotypic cluster formation.

Melanomas can have multiple coexisting cell states, including proliferative (PRO) versus invasive (INV) subpopulations that represent a "go or grow" trade-off; however, how these populations interact is poorly understood. Using a combination of zebrafish modeling and analysis of patient samples, we show that INV and PRO cells form spatially structured heterotypic clusters and cooperate in the seeding of metastasis, maintaining cell state heterogeneity. INV cells adhere tightly to each other and form clusters with a rim of PRO cells.

SFPQ promotes an oncogenic transcriptomic state in melanoma.

The multifunctional protein, splicing factor, proline- and glutamine-rich (SFPQ) has been implicated in numerous cancers often due to interaction with coding and non-coding RNAs, however, its role in melanoma remains unclear. We report that knockdown of SFPQ expression in melanoma cells decelerates several cancer-associated cell phenotypes, including cell growth, migration, epithelial to mesenchymal transition, apoptosis, and glycolysis. RIP-seq analysis revealed that the SFPQ-RNA interactome is reprogrammed in melanoma cells and specifically enriched with key melanoma-associated coding and long non-coding transcripts, including SOX10, AMIGO2 and LINC00511 and in most cases SFPQ is required for the efficient expression of these genes.