Marker For Cutaneous Melanoma Research Articles

Methylation Markers in Cutaneous Melanoma: Unravelling the Potential Utility of Their Tracking by Liquid Biopsy.

Simple SummaryMalignant melanoma is the most lethal form of skin cancer. While new therapeutic approaches have improved survival in patients with metastatic melanoma, responses are rarely sustained due to the high degree of heterogeneity at the inter- and intra-metastatic levels. The development of reliable biomarkers to monitor therapeutic response and disease progression is critical. While attention has been focused on dissecting the molecular basis responsible for treatment resistance, it is clear that epigenetic changes warrant further in-depth investigation. Indeed, many aberrantly methylated genes play a role in cell cycle control, apoptosis, and cell invasion, as well as in melanoma progression. Longitudinal monitoring of DNA methylation via liquid biopsy can provide real-time information on the behavior and stage of melanoma.Malignant melanoma is the most serious, life-threatening form of all dermatologic diseases, with a poor prognosis in the presence of metastases and advanced disease. Despite recent advances in targeted therapy and immunotherapy, there is still a critical need for a better understanding of the fundamental mechanisms behind melanoma progression and resistance onset. Recent advances in genome-wide methylation methods have revealed that aberrant changes in the pattern of DNA methylation play an important role in many aspects of cancer progression, including cell proliferation and migration, evasion of cell death, invasion, and metastasization. The purpose of the current review was to gather evidence regarding the usefulness of DNA methylation tracking in liquid biopsy as a potential biomarker in melanoma. We investigated the key genes and signal transduction pathways that have been found to be altered epigenetically in melanoma. We then highlighted the circulating tumor components present in blood, including circulating melanoma cells (CMC), circulating tumor DNA (ctDNA), and tumor-derived extracellular vesicles (EVs), as a valuable source for identifying relevant aberrations in DNA methylation. Finally, we focused on DNA methylation signatures as a marker for tracking response to therapy and resistance, thus facilitating personalized medicine and decision-making in the treatment of melanoma patients.

The Evaluation of Estrogen Receptor β as a Potential Prognosis Factor in Melanoma

Differences across sexes in cutaneous melanoma incidence, metastatic pathways and disease outcome are consistently observed, with women having a significant survival advantage compared with men. This suggests that gender could play a role as a prognostic indicator through sex hormone signaling, but the mechanism is still unclear. This article focuses on available literature data concerning the influence of estrogen receptor beta (ERβ) expression as a host-related biological protective factor for female patients with melanoma. Furthermore, it highlights the potential role of estrogen receptor beta (ERβ) as a prognostic biologic marker in cutaneous melanoma. Keywords: melanoma, sex, hormone receptors, estrogen receptor β

476 GJB5 association with BRAF mutation and survival in cutaneous melanoma

Gap junctional intercellular communication is crucial for epidermal cellular homeostasis. Inability to establish melanocyte-keratinocytes contacts and loss of intercellular junction’s integrity may contribute to melanoma development. Connexins, laminins and desmocollins have been implicated in the control of melanoma growth where their reduced expression has been reported in metastatic lesions. We have investigated Connexin 31.1 (GJB5) expression and looked for any association with BRAF mutational status, patient prognosis and MAPK inhibitors (MAPKi) treatment. GJB5 expression was measured at RNA and protein level in melanoma clinical samples and established cell lines treated or not with BRAF and MEK inhibitors as well as in cell lines which developed MAPKi resistance. Our analysis reveals significant downregulation of GJB5 expression in metastatic compared to primary melanoma lesions and in BRAF mutated versus wild-type melanomas. Likewise GJB5 expression is significantly lower (almost undetectable) in BRAFV600E compared with BRAF WT cell lines, and slightly increases upon MAPKi treatment. MAPKi-resistant melanoma cells display a similar expression pattern to BRAF WT cells with a significant increased GJB5 expression. Enhancement of BRAF signalling by transient transfection of BRAFV600E in CHL1 cells, significantly upregulates miR-335 expression with consequent downregulation of one of its target, GJB5. This was further validated using the TCGA-SKCM dataset, where BRAF mutations significantly associate with increased miR-335 expression and inversely correlate with GJB5 expression. In clinical samples, GJB5 expression also correlates with patient overall survival. Our results identify a novel mechanism of Gap-junctional regulation, highlighting GJB5 as a potential marker in cutaneous melanoma

Prognostic metabolic markers in cutaneous melanoma

Melanoma is the most aggressive skin tumour, being the leading cause of death from skin cancer. Its incidence has increased more rapidly than for any of the top 10 cancers. A low percentage of patients with metastasis (meaning it has spread to other parts of the body) survive over one year after diagnosis, due to the lack of efficient therapy. Not all melanomas are the same, they can vary in how aggressive they are (how quickly they develop and potentially spread) and in their appearance. The authors of this study, from Spain, studied cultured (grown in the lab from a sample) melanoma cells with different aggressiveness features and patients with different types of melanoma lesions. They aimed to find metabolic markers in melanoma that could predict the evolution of the disease. Cellular metabolism is the set of chemical reactions that occur in living organisms in order to maintain life. It is known that the metabolism of cancer cells is different from that of normal cells since they grow and divide rapidly, needing high‐energy supply. In this context, the authors found that proteins (enzymes) related with energy production are altered. These proteins are: the ATP synthase (β‐F1‐ATPase), the heat‐shock protein 60 (HSP60), the glycolytic glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) and the pyruvate kinase M2 (PKM2). These proteins provide the bioenergetic signature (BEC index=β‐F1‐ATPase/HSP60/GAPDH ratio) of cancer. A reduction in BEC index correlates with the aggressiveness of cultured melanoma cells and tumours and worse overall survival in melanoma patients. The authors conclude that the level of metabolic enzymes and BEC status are markers of (indicators of) melanoma stage (how adavanced it is, e.g. if it has spread and by how much) and overall survival in melanoma patients.

Prospective Validation of Molecular Prognostic Markers in Cutaneous Melanoma: A Correlative Analysis of E1690.

Purpose: To validate the prognostic impact of combined expression levels of three markers (SPP1, RGS1, and NCOA3) in melanoma specimens from patients enrolled in the E1690 clinical trial of high-dose or low-dose IFNα-2b versus observation.Experimental Design: Tissue was available from 248 patients. Marker expression was determined by digital imaging of immunohistochemically stained slides. The prognostic impact of each marker was first assessed by recording its expression value relative to the median. A multimarker index was then developed to combine marker expression levels by counting for each patient the number of markers with high expression. The impact of the multimarker index on relapse-free survival (RFS) and overall survival (OS) was assessed using Kaplan-Meier analysis, and both univariate and multivariate Cox regression analyses.Results: By Kaplan-Meier analysis, high multimarker expression scores were significantly predictive of RFS (P < 0.001) and OS (P < 0.001). Stepwise multivariate Cox regression analysis with backward elimination that included routine clinical and histologic prognostic factors revealed high multimarker expression scores and tumor thickness as the only factors significantly and independently predicting RFS and OS. Stepwise multivariate Cox regression analyses that also included treatment type and number of positive lymph nodes generated identical results for both RFS and OS. In the molecularly defined low-risk subgroup, patients treated with high-dose IFN had a significantly improved RFS compared with patients in the other two subgroups (P < 0.05).Conclusions: These results validate the independent impact of combined expression levels of SPP1, RGS1, and NCOA3 on survival of melanoma in a prospectively collected cohort. Clin Cancer Res; 23(22); 6888-92. ©2017 AACR.

Inflammation markers in cutaneous melanoma - edgy biomarkers for prognosis.

There is a fine balance between inflammation and tumorigenesis. While environmentally induced inflammatory condition can precede a malignant transformation, in other cases an oncogenic change of unknown origin can induce an inflammatory microenvironment that promotes the development of tumors. Regardless of its origin, maintaining the inflammation milieu has many tumor-promoting effects. As a result, inflammation can aid the proliferation and survival of malignant cells, can promote angiogenesis and metastasis, can down-regulate innate/adaptive immune responses, and can alter responses to hormones and chemotherapeutic agents. There is an abundance of studies unveiling molecular pathways of cancer-related inflammation; this wealth of information brings new insights into biomarkers domain in the diagnosis and treatment improvement pursue. In cutaneous tissue there is an established link between tissue damage, inflammation, and cancer development. Inflammation is a self-limiting process in normal healthy physiological conditions, while tumorigenesis is a complex mechanism of constitutive pathway activation. Once more, in cutaneous melanoma, there is an unmet need for inflammatory biomarkers that could improve prognostication. Targeting inflammation and coping with the phenotypic plasticity of melanoma cells represent rational strategies to specifically interfere with metastatic progression. We have shown that there is a prototype of intratumor inflammatory infiltrate depicting a good prognosis, infiltrate that is composed of numerous T cells CD3+, Langerhans cells, few/absent B cells CD20+ and few/absent plasma cells. Circulating immune cells characterized by phenotype particularities are delicately linked to the stage melanoma is diagnosed in. Hence circulatory immune sub-populations, with activated or suppressor phenotype would give the physician a more detailed immune status of the patient. A panel of tissue/circulatory immune markers can complete the immune status, can add value to the overall prognostic of the patient and, as a result direct/redirect the therapy choice. The future lies within establishing low-cost, affordable/available, easily reproducible assays that will complete the pre-clinical parameters of the patient.

TSLC1 expression discriminates cutaneous melanomas from dysplastic nevi

Cutaneous melanoma is a malignant tumor of melanocytes that causes the majority of skin cancer-related deaths. However, sometimes, discrimination between dysplastic nevi and early melanomas is difficult, even for experienced pathologists. Besides histology, the silencing of tumor suppressor genes aids in the diagnosis of melanoma. We have shown previously that tumor suppressor in lung cancer 1 (TSLC1) is a tumor suppressor gene, and its silencing through aberrant promoter methylation is associated with the generation of cutaneous melanoma. To examine TSLC1 expression in melanocytic skin lesions to determine whether it can serve as a diagnostic marker in histologically questionable lesions. Cytoplasmic localization of the expression of the TSLC1 gene was detected by immunohistochemistry; the levels of TSLC1 mRNA and protein were detected by quantitative real-time reverse transcription-PCR and western blot, respectively. Using immunohistochemistry, the average TSLC1 expression levels in cutaneous melanomas decreased approximately 3.6-fold (n=20) as compared with dysplastic nevi (n=30) and 3.7-fold as compared with normal skin (n=25). The average expression levels of TSLC1 mRNA and protein in dysplastic nevi lesions and normal skin were significantly higher than the levels in cutaneous melanomas. No significant changes in TSLC1 mRNA and protein expressions were found between normal skin and dysplastic nevi. Our results show that a loss of TSLC1 frequently occurs in cutaneous melanoma, and indicate that it could serve as a diagnostic marker for cutaneous melanoma in histologically questionable lesions.

Le mélanome malin cutané et le rôle de la protéine paradoxale Microphthalmia transcription factor

Mitf protein is a transcription factor involved all along the life of pigmented cells. This protein is located in the center of multiple signaling pathways which control differentiation, morphology, proliferation and survival of the various cells of the melanocyte lineage: melanoblasts, melanocytes and melanoma. Mitf plays a major role in melanoblasts differentiation, by inducing the key enzyme of melanogenesis, tyrosinase, and its secondary enzymes, Tyrp1 and Dct. Mitf regulates morphology and migration of melanocytes, particularly by regulating cytoskeleton organization and cell-cell adhesion. Mitf plays a double role of inducer/repressor of cellular proliferation. This protein inhibits cell cycle progression and prevents non-proper cell division. In few cases, Mitf can also induce cell cycle. A minimal quantity/activity of Mitf is necessary for melanoblast survival. Essential protein of the melanocyte lineage, Mitf was proposed as diagnostic/pronostic marker for cutaneous melanoma. However, could we then consider MITF as the unique marker of such a cancer?

Expression of c-myc oncoprotein represents a new prognostic marker in cutaneous melanoma

Overexpression of the c-myc oncoprotein has been observed to be of prognostic significance in several human cancers. This study was undertaken to establish whether c-myc has any prognostic significance in melanoma. Expression of c-myc oncoprotein was studied in a prospective series of primary and secondary malignant melanomas. Ethanol-fixed tissue was digested into nuclei and stained for flow cytometric analysis using a pan-myc antibody. Overexpression of the c-myc oncoprotein was prevalent in both disease stages. In primary disease, overexpression was associated with tumour thickness and with the presence of ulceration, age and reduced disease-free interval. Of most importance, high expression of c-myc predicted poor outcome in both primary and metastatic disease. In addition, c-myc was able to discriminate prognosis in melanomas uniformly stratified as thick (greater than 3 mm) lesions. These results indicate an important role for c-myc in melanoma which may lead to better prognostic information and identification of new therapeutic strategies.

C-myc Is Not Useful as Prognostic Immunohistochemical Marker in Cutaneous Melanoma

Background: Several studies indicate that immunohistochemical detection of the c-myc oncogene might serve as an additional prognostic marker in malignant melanoma. Objective: To study c-myc expression in paraffin-embedded cutaneous melanoma and to correlate to metastatic potential and onset of metastases. Methods: Cytoplasmic c-myc protein expression was visualized using the APAPP method, and reactivity (percent total tumor cells stained) was assessed in 62 formalin-fixed paraffin-embedded primary cutaneous melanomas (21 not metastasizing, mean Breslow 3.0 ± 2.9 mm, 41 metastasizing, mean Breslow 3.1 ± 3.0 mm) and 24 metastases of the same patients. Results: There was no significant difference of c-myc reactivity in cutaneous melanoma who did not metastasize (n = 21, c-myc reactivity 32.7 ± 19.3%, follow-up 10.6 ± 1.8 years) and primaries who metastasized (n = 41, c-myc reactivity 27.7 ± 22.4%, p = 0.29). This finding was independent of the thickness of the primary and was found within thin cutaneous melanoma with a Breslow <0.75 mm (range 0.24–0.65 mm, n = 20, c-myc reactivity 29.1 ± 15.7%, p = 0.32) or within thick cutaneous melanoma with a Breslow >1.5 mm (range 1.6–11 mm, n = 41, c-myc reactivity 29.6 ± 23.8%, p = 0.46). No correlation of c-myc expression between thin cutaneous melanoma, thick cutaneous melanoma (p = 0.83) or metastasizing primaries and their metastases (n = 24, c-myc reactivity 29.3 ± 22%) was found (p = 0.64). The time period until development of first metastasis did not correlate with the percentage of cells expressing c-myc in the primary (p = 0.56). Conclusion: c-myc expression is independent of metastatic potential and onset of metastases and, therefore, does not serve as a prognostic immunohistochemical marker in primary cutaneous melanoma.

Serum S-100 protein: a potentially useful prognostic marker in cutaneous melanoma

Serum S-100 protein: a potentially useful prognostic marker in cutaneous melanoma

Serum S-100 protein: a potentially useful prognostic marker in cutaneous melanoma

S-100, an acidic calcium-binding protein, is present within cells of neuroendocrine origin. Its value in the immunohistochemical diagnosis of tumours of melanocytic origin is well established. More recently, a potential role has been proposed for the serum concentration of this protein as a marker of metastatic melanoma disease activity. In the present study, the concentration of serum S-100 protein was measured in 97 patients with histologically proven malignant melanoma who were attending a dermatology and/or oncology department for the follow-up of their disease. Serum S-100 was also measured in 48 control subjects without malignant melanoma. The clinical stage of the patients was classified according to the criteria of the American Joint Committee on Cancer into stages I-IV. The median (range) serum S-100 protein concentration was significantly higher in stage I (0.11 (0.1-0.21) microgram/L, P < 0.001), stage II (0.11 (0.05-0.22) microgram/L, P < 0.001), stage III (0.24 (0.07-0.41) microgram/L, P < 0.0001) and stage IV (0.39 (0.06-15.0) microgram/L, P < 0.0001) compared with the control group (0.1 (0.05-0.15) microgram/L). At a threshold value of 0.2 microgram/L, the sensitivity and specificity for detection of advanced disease were 82% and 91%, respectively. Thus serum S-100 protein may be a valuable prognostic marker for malignant melanoma and for monitoring therapy. Serum S-100 protein concentration was also compared with the Breslow thickness of the tumours. There was a significant correlation between these variables (n = 72, rs = 0.32, P < 0.01). Combining a serum S-100 threshold value of > 0.22 microgram/L and a Breslow thickness of > 4 mm improved the sensitivity and specificity for the presence of secondary spread to 91% and 95%, respectively. Therefore, a combination of both baseline serum S-100 protein and Breslow thickness may provide a better indication of the prognosis at diagnosis.