Survival In Cutaneous Melanoma Research Articles

Clinical characteristics, prognosis, and immunotherapy outcome in pediatric melanoma: Analysis from a large Chinese cohort.

10050 Background: Malignant melanoma in children and adolescents is rare, with limited data on Chinese populations.To assess the clinical characteristics, survival, prognostic factors, and the efficacy of immunotherapy in a real-world cohort of Chinese pediatric patients with melanoma. Methods: This is a retrospective, cohort study included pediatric melanoma patients between February, 2005 and May, 2021, with a median follow-up time of 76.7 months. Data analyses were conducted in May, 2023. This study enrolled patients from Sun Yat-sen University Cancer Center, the biggest cancer institution in South China for cancer prevention, diagnosis and treatment. Inclusion criteria for this study were as follows: 1) histopathologically confirmed diagnosis of melanoma; 2) Age ≤18 year; 3) with complete clinical data on sex, age, histopathological features, etc. The exclusion criteria was secondary malignant melanoma. Main outcomes and measures were patient’s OS and EFS. Results: 43 patients were enrolled, with median age of 138.9 (range 13.1-215.0) months, including 30 cutaneous melanoma, 7 meningeal melanoma, 5 mucosal melanoma, and 1 uveal melanoma. The frequency of BRAF V600E mutation was 16.7% (4/24). Mismatch repair proteins were normally expressed (7/7), and the positive rate of programmed cell death ligand 1 expression was 55.6% (5/9). The event-free survival and overall survival of cutaneous, mucosal and meningeal melanoma were 46.7±9.1% vs 75.0±21.7% vs 16.7±15.2% ( P = 0.010), 65.5±8.9% vs 75.0±21.7% vs 16.7±15.2% (P< 0.001), respectively. Survival of cutaneous melanoma were associated with pathological type, ulceration, Clark level, disease spread, sentinel lymph node status, tumor stage and Ki-67 expression. 5 of 9 patients who were treated with PD-1 inhibitors (5 with PD-1 inhibitors alone, 3 with PD-1 inhibitors plus angiogenesis inhibitors, 1 with combination of anti-PD1, anti-angiogenic inhibitors plus chemotherapy) were evaluable with the overall response rate of 20%. The most common immune-related adverse event was hypothyroidism. Conclusions: This is the largest real-world study in pediatric melanoma patients in Asia. The prognosis of mucosal melanoma was favorable, followed by cutaneous melanoma, and meningeal melanoma had the worst prognosis. PD-1 antibody combined with angiogenesis inhibitors maybe a promising choice in pediatric melanoma.

TNFRSF1B Gene Variants in Clinicopathological Aspects and Prognosis of Patients with Cutaneous Melanoma.

Regulatory T lymphocytes play a critical role in immune regulation and are involved in the aberrant cell elimination by facilitating tumor necrosis factor connection to the TNFR2 receptor, encoded by the TNFRSF1B polymorphic gene. We aimed to examine the effects of single nucleotide variants TNFRSF1B c.587T>G, c.*188A>G, c.*215C>T, and c.*922C>T on the clinicopathological characteristics and survival of cutaneous melanoma (CM) patients. Patients were genotyped using RT-PCR. TNFRSF1B levels were measured using qPCR. Luciferase reporter assay evaluated the interaction of miR-96 and miR-1271 with the 3'-UTR of TNFRSF1B. The c.587TT genotype was more common in patients younger than 54 years old than in older patients. Patients with c.*922CT or TT, c.587TG or GG + c.*922CT or TT genotypes, as well as those with the haplotype TATT, presented a higher risk of tumor progression and death due to the disease effects. Individuals with the c.*922TT genotype had a higher TNFRSF1B expression than those with the CC genotype. miR-1271 had less efficient binding with the 3'-UTR of the T allele when compared with the C allele of the SNV c.*922C>T. Our findings, for the first time, demonstrate that TNFRSF1B c.587T>G and c.*922C>T variants can serve as independent prognostic factors in CM patients.

CSDE1 Intracellular Distribution as a Biomarker of Melanoma Prognosis.

RNA-binding proteins are emerging as critical modulators of oncogenic cell transformation, malignancy and therapy resistance. We have previously found that the RNA-binding protein Cold Shock Domain containing protein E1 (CSDE1) promotes invasion and metastasis of melanoma, the deadliest form of skin cancer and also a highly heterogeneous disease in need of predictive biomarkers and druggable targets. Here, we design a monoclonal antibody useful for IHC in the clinical setting and use it to evaluate the prognosis potential of CSDE1 in an exploratory cohort of 149 whole tissue sections including benign nevi and primary tumors and metastasis from melanoma patients. Contrary to expectations for an oncoprotein, we observed a global decrease in CSDE1 levels with increasing malignancy. However, the CSDE1 cytoplasmic/nuclear ratio exhibited a positive correlation with adverse clinical features of primary tumors and emerged as a robust indicator of progression free survival in cutaneous melanoma, highlighting the potential of CSDE1 as a biomarker of prognosis. Our findings provide a novel feature for prognosis assessment and highlight the intricacies of RNA-binding protein dynamics in cancer progression.

Cutaneous Malignant Melanoma in Chile: Differences in Tumor Thickness and Overall Survival Between Patients From Public and Private Health Care Centers.

A low socioeconomic status (SES) is associated with lower survival rates in cutaneous malignant melanoma (CMM). In South America, there are few studies that analyze CMM data according to SES. To determine the differences in microstaging and overall survival in CMM between public and private health care centers. Retrospective cohort study. Histopathological reports with a diagnosis of CMM from two public hospitals (PuH) and one private health care center (PrH) in Santiago from 2008 to 2018 were included. Patients' death certificates were obtained to estimate overall survival. 1014 MMC were found. The mean age was 58.6 ± 16.8 years and 59.9% corresponded to female patients. Of these, 33.9% received treatment at PuH and 66.1% at PrH. Patients from PuH had an increased risk of having an invasive CMM and a >1 mm thickness melanoma compared to PrH (odds ratio 2.77 and 6.06, respectively). Patients with invasive CMM from the PuH were 6.29-fold more likely to die than a patient from the PrH. We observed a great disparity in tumor thickness between the socioeconomic status, reflecting a later detection and lower survival rate in PuH. Our results highlight a gap on which National Public Health should focus.

PANoptosis-related prognostic signature predicts overall survival of cutaneous melanoma and provides insights into immune infiltration landscape

Cutaneous melanoma (CM) is a highly malignant tumor originating from melanocytes, and its metastasis and recurrence are the major causes of death in CM patients. PANoptosis is a newly defined inflammatory programmed cell death that crosstalk pyroptosis, apoptosis, and necroptosis. PANoptosis participates in the regulation of tumor progression, especially the expression of PANoptosis related genes (PARGs). Although pyroptosis, apoptosis, and necroptosis have received attention in CM, respectively, the link between them remains elusive. Therefore, this study aimed to investigate the potential regulatory role of PANoptosis and PARGs in CM and the relationship among PANoptosis, PARGs and tumor immunity. We identified 3 PARGs associated with prognosis in CM patients by The Cancer Genome Atlas. Risk model and nomogram were established. Enrichment analysis of differentially expressed genes indicated that CM was immune-related. Subsequent analyses indicated that prognosis-related PARGs were associated with immune scores and infiltration of immune cells in CM patients. In addition, immunotherapy and drug sensitivity results indicated an association between prognosis-related PARGs and drug resistance in CM patients. In conclusion, PARGs play a key role in the progression of tumors in CM patients. PARGs can be used not only for risk assessment and OS prediction in CM patients, but also reflect the immune landscape of CM patients, which can provide a novel reference for individualized tumor treatment.

Clinicopathologic Features and Prognosis of Melanoma in Northeast China: A Region-Based Cohort Study of 229 Consecutive Cases

Melanoma has been reported in many parts of East Asia. However, there are no reports on the epidemiology of melanoma in Northeast China. In this study, we collected demographic, clinicopathologic, and treatment data of patients with melanoma treated at the First Hospital of Jilin University (Changchun, China). A total of 229 consecutive nonselective cases were analyzed for the incidence and clinicopathologic characteristics of melanoma. The median overall survival was 53.5 months. The 1-year, 3-year, and 5-year survival rates were 86.3, 66.4, and 44.8%, respectively. The median disease-free survival was 33.1 months, and the 1-year, 3-year, and 5-year disease-free survival rates were 75.0, 48.5, and 35.8%, respectively. Multivariate analysis showed that disease stage, Eastern Cooperative Oncology Group score, and lactic dehydrogenase were independent prognostic factors of overall survival. Pathologic subtype and stage were independent prognostic factors of disease-free survival. Furthermore, vascular invasion was a prognostic factor for overall survival in acral melanoma and a prognostic factor for disease-free survival in cutaneous melanoma. Compared with the Caucasian population, the population of Northeast China showed significant differences in disease location, pathologic subtype, gene status, and survival prognosis. In summary, our study showed that vascular invasion might be a prognostic factor in patients with acral and cutaneous melanoma.

Risk Factors and Treatments Impacts for the Gene of Two Different Types of Skin Cancer: Survival Analysis

Two distinct types of skin cancer are Cutaneous Melanoma and Melanoma of Uncertain Primary. Their causes may be distinct. Several variables, including genetic mutation, UV exposure, sex, age, and others, will affect the survival months. In this study, the Kaplan-Meier method and the Cox model will be used to compare the two types of skin cancer. For the KM technique, one unique variable will be employed to assess its association with the survival months. Cox model will employ multiple variables to describe the overall association between several variables and the survival months. In conclusion, the difference on sex will have a distinct impact on two different kinds of skin cancer. Genetic expression does not clearly differentiate between them. UV exposure and therapy have a substantial impact on the number of months of survival for Cutaneous Melanoma. The results of the study indicate that additional research and prevention are required. Prevention is almost always more effective than treatment for cancer. For specific patient populations, clinicians should prioritize skin cancer prevention and therapy.

Early inflammatory biomarkers and melanoma survival

Few studies have investigated the role of inflammatory markers in predicting cutaneous melanoma survival. The aim of the study was to identify, if any, early inflammatory markers in the prognosis of all stages of primary cutaneous melanoma. We conducted a 10-year cohort study among 2,141 melanoma patients from the same geographic area (Lazio) with primary cutaneous melanoma diagnosed between January 2005 and December 2013. In situ cutaneous melanoma was excluded from the analysis (N=288), leaving 1,853 cases of invasive cutaneous melanoma. The following hematological markers were obtained from clinical records: white blood cells count (WBC), count and percentages of neutrophils, basophils, monocytes, lymphocytes, and large unstained cells (LUC). Survival probability was estimated by Kaplan-Meier methods, and prognostic factors were evaluated by multivariate analysis (Cox proportional hazards model). In the multivariate analysis, high levels of NLR (>2.1 vs. ≤2.1, HR: 1.61; 95% CI: 1.14-2.29, P=0.007) and high levels of d-NLR (>1.5 vs. ≤1.5, HR: 1.65; 95% CI: 1.16-2.35, P=0.005) were independently associated with an increased risk of 10-year melanoma mortality. However, when we stratified by Breslow thickness and clinical stage, we observed that NLR and d-NLR were good markers of prognosis only for patients with Breslow thickness of 2.0 mm and more (NLR, HR: 1.62; 95% CI: 1.04-2.50; d-NLR, HR: 1.69; 95% CI: 1.09-2.62) or clinical stage II-IV (NLR, HR: 1.55; 95% CI: 1.01-2.37; d-NLR, HR: 1.72; 95% CI: 1.11-2.66), independent of other prognostic factors. We suggest that a combination of NLR and Breslow thickness may be a useful, cheap, and readily available prognostic marker for cutaneous melanoma survival.

Smoking is an Independent Marker of Poor Prognosis in Cutaneous Melanoma.

Previous studies have suggested that persistent tobacco smoking impairs survival in cutaneous melanoma, but the effects of smoking and other prognostic factors have not been described in detail. This study examined the association of smoking (persistent, former, or never) with melanoma-specific (MSS) and overall survival (OS) in patients with cutaneous melanoma treated in Southwest Finland during 2005 to 2019. Clinical characteristics were obtained from electronic health records for 1,980 patients. Smoking status was available for 1,359 patients. Patients were restaged according to the 8th edition of the tumour-node-metastasis (TNM) classification. Smoking remained an independent prognostic factor for inferior melanoma-specific survival regardless of age, sex, stage, and comorbidities. The hazard ratio of death from melanoma was 1.81 (1.27-2.58, p = 0.001) in persistent and 1.75 (1.28-2.40, p = 0.001) in former smokers compared with never smokers. In 351 stage IV patients, smoking was associated with increased melanoma-specific and overall mortality: median MSS 10.4 (6.5-14.3), 14.6 (9.1-20.1), and 14.9 (11.4-18.4) months, p = 0.01 and median OS 10.4 (6.5-14.3), 13.9 (8.6-19.2), and 14.9 (11.7-18.1) months, p = 0.01 in persistent, former, and never smokers, respectively. In conclusion, since smoking represents an independent modifiable poor prognostic factor in patients with cutaneous melanoma, smoking habits should be proactively asked about by healthcare professionals, in order to support smoking cessation.

Cutaneous melanoma survival rates of the elderly are not worse than those of the young, yet they have some specific differences.

The incidence of cutaneous melanoma among the elderly has increased significantly. Unfavorable survival rates are associated with insufficient patient managements and poor prognostic features in the elderly. We aimed to compare elderly (≥75 years) and younger (<75 years) patients with cutaneous melanoma to determine the differences and the prognostic significance of age. The retrospective data of 117 elderly and 232 younger patients with cutaneous melanoma were compared. The median age of the elderly patients was 78 years (75-104), and 51.3% of the patients were female. Of the patients, 14.5% were in the metastatic stages. Clinicopathologic factors such as extremity melanomas (P = 0.01), Clark levels IV-V (P = 0.04), ulceration (P = 0.009), and neurotropism (P = 0.03) were significantly more common in elderly patients. However, BRAF mutation was significantly more common in younger patients (P = 0.003). Overall survival (OS) and recurrence-free survival (RFS) rates of both the groups were similar. Lymph node involvement (P < 0.005), distant metastasis (P < 0.005), and relapse of disease (P = 0.02) were associated with poor OS in elderly patients. Tumor-infiltrating lymphocytes was associated with prolonged RFS (P = 0.05), while extremity melanomas (P = 0.01), lymphovascular invasion (P = 0.006), and lymph node involvement (P < 0.005) had negative impact on RFS. Although elderly patients with cutaneous melanoma had different clinicopathologic features in our series, their survival rates are similar to those of younger patients, which shows that age alone is inadequate to determine the prognosis. Disease stage and a comprehensive geriatric assessment might assist to determine appropriate management.

Pan-cancer analysis of forkhead box Q1 as a potential prognostic and immunological biomarker.

Forkhead box Q1 (FOXQ1) is a member of the forkhead transcription factor family involved in the occurrence and development of different tumors. However, the specific expression patterns and functions of FOXQ1 in pan-cancer remain unclear. Therefore, we collected the expression, mutation, and clinical information data of 33 tumors from The Cancer Genome Atlas database. Via public pan-cancer transcriptome data analysis, we found that FOXQ1 is differentially expressed in various tumors at tissue and cell levels, such as liver hepatocellular carcinoma, colon adenocarcinoma, lung adenocarcinoma, lung squamous cell carcinoma, thyroid carcinoma, and kidney renal clear cell carcinoma. Kaplan–Meier and Cox analyses suggested that FOXQ1 expression was associated with poor overall survival of cutaneous melanoma and thymoma. Its expression was also associated with good disease-specific survival (DSS) in prostate adenocarcinoma but poor DSS in liver hepatocellular carcinoma. In addition, FOXQ1 expression was associated with poor disease-free survival of pancreatic adenocarcinoma. Moreover, FOXQ1 expression was closely related to the tumor mutational burden in 14 tumor types and microsatellite instability (MSI) in 8 tumor types. With an increase in stromal and immune cells, FOXQ1 expression was increased in breast invasive carcinoma, pancreatic adenocarcinoma, thyroid carcinoma, lung adenocarcinoma, and ovarian serous cystadenocarcinoma, while its expression was decreased in pancreatic adenocarcinoma, bladder urothelial carcinoma, and stomach adenocarcinoma. We also found that FOXQ1 expression was related to the infiltration of 22 immune cell types in different tumors (p < 0.05), such as resting mast cells and resting memory CD4 T cells. Last, FOXQ1 was coexpressed with 47 immune-related genes in pan-cancer (p < 0.05). In conclusion, FOXQ1 expression is closely related to prognosis, clinicopathological parameters, cancer-related pathway activity, the tumor mutational burden, MSI, the tumor microenvironment, immune cell infiltration, and immune-related genes and has the potential to be a diagnostic and prognostic biomarker as well as an immunotherapy target for tumors. Our findings provide important clues for further mechanistic research into FOXQ1.

Does the morphology of cutaneous melanoma help to explain the international differences in survival? Results from 1 578 482 adults diagnosed during 2000–2014 in 59 countries (CONCORD-3)

BackgroundCONCORD‐3 highlighted wide disparities in population‐based 5‐year net survival for cutaneous melanoma during 2000–2014. Clinical evidence suggests marked international differences in the proportion of lethal acral and nodular subtypes of cutaneous melanoma.ObjectivesWe aimed to assess whether the differences in morphology may explain global variation in survival.MethodsPatients with melanoma were grouped into the following seven morphological categories: malignant melanoma, not otherwise specified (International Classification of Diseases for Oncology, third revision morphology code 8720), superficial spreading melanoma (8743), lentigo maligna melanoma (8742), nodular melanoma (8721), acral lentiginous melanoma (8744), desmoplastic melanoma (8745) and other morphologies (8722–8723, 8726–8727, 8730, 8740–8741, 8746, 8761, 8770–8774, 8780). We estimated net survival using the nonparametric Pohar Perme estimator, correcting for background mortality by single year of age, sex and calendar year in each country or region. All‐ages survival estimates were standardized using the International Cancer Survival Standard weights. We fitted a flexible parametric model to estimate the effect of morphology on the hazard of death.ResultsWorldwide, the proportion of nodular melanoma ranged between 7% and 13%. Acral lentiginous melanoma accounted for less than 2% of all registrations but was more common in Asia (6%) and Central and South America (7%). Overall, 36% of tumours were classified as superficial spreading melanoma. During 2010–2014, age‐standardized 5‐year net survival for superficial spreading melanoma was 95% or higher in Oceania, North America and most European countries, but was only 71% in Taiwan. Survival for acral lentiginous melanoma ranged between 66% and 95%. Nodular melanoma had the poorest prognosis in all countries. The multivariable analysis of data from registries with complete information on stage and morphology found that sex, age and stage at diagnosis only partially explain the higher risk of death for nodular and acral lentiginous subtypes.ConclusionsThis study provides the broadest picture of distribution and population‐based survival trends for the main morphological subtypes of cutaneous melanoma in 59 countries. The poorer prognosis for nodular and acral lentiginous melanomas, more frequent in Asia and Latin America, suggests the need for health policies aimed at specific populations to improve awareness, early diagnosis and access to treatment. What is already known about this topic? The histopathological features of cutaneous melanoma vary markedly worldwide.The proportion of melanomas with the more aggressive acral lentiginous or nodular histological subtypes is higher in populations with predominantly dark skin than in populations with predominantly fair skin. What does this study add? We aimed to assess the extent to which these differences in morphology may explain international variation in survival when all histological subtypes are combined.This study provides, for the first time, international comparisons of population‐based survival at 5 years for the main histological subtypes of melanoma for over 1.5 million adults diagnosed during 2000–2014.This study highlights the less favourable distribution of histological subtypes in Asia and Central and South America, and the poorer prognosis for nodular and acral lentiginous melanomas.We found that later stage at diagnosis does not fully explain the higher excess risk of death for nodular and acral lentiginous melanoma compared with superficial spreading melanoma.

Racial and ethnic differences in tumor characteristics and overall survival of women with melanoma: A national cancer database retrospective cohort study

To the Editor: Despite a lower risk of acquiring melanoma, racial/ethnic minorities with melanoma experience worse outcomes than White individuals. 1 Cormier J.N. Xing Y. Ding M. et al. Ethnic differences among patients with cutaneous melanoma. Arch Intern Med. 2006; 166: 1907-1914https://doi.org/10.1001/archinte.166.17.1907 Crossref PubMed Scopus (245) Google Scholar , 2 Wu X.C. Eide M.J. King J. et al. Racial and ethnic variations in incidence and survival of cutaneous melanoma in the United States, 1999-2006. J Am Acad Dermatol. 2011; 65: S26-S37https://doi.org/10.1016/j.jaad.2011.05.034 Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar , 3 Lam M. Zhu J.W. Hu A. Beecker J. Racial differences in the prognosis and survival of cutaneous melanoma from 1990 to 2020 in North America: A systematic review and meta-analysis. J Cutan Med Surg. 2022; 26: 181-188https://doi.org/10.1177/12034754211052866 Crossref Scopus (2) Google Scholar Additionally, women experience better overall survival (OS) than men. 4 Behbahani S. Maddukuri S. Cadwell J.B. Lambert W.C. Schwartz R.A. Gender differences in cutaneous melanoma: demographics, prognostic factors, and survival outcomes. Dermatol Ther. 2020; 33: e14131-e14132https://doi.org/10.1111/dth.14131 Crossref Scopus (12) Google Scholar However, much remains unknown about racial/ethnic differences in women with melanoma, which is investigated here.

Construction of Circadian Clock Signature for Tumor Microenvironment in Predicting Survival for Cutaneous Melanoma.

We explored circadian clock-related genes (CCRG) to establish a risk model and identify associations with the tumor immune microenvironment in cutaneous melanoma (CM). Circadian clock genes were downloaded from Circadian Gene Database. To explore CM-related circadian clock genes, we combined multivariate cox regression associated with least absolute shrinkage and selection operator (LASSO) regression in the Cancer Genome Atlas (TCGA) and validated it in the GSE65904 dataset. Time-dependent receiver operating characteristic curve (ROC) and Kaplan-Meier analysis were calculated to determine a CCRG risk score model. In addition, the overall survival nomograms of clinicopathological factors and circadian clock-related gene signatures. Additionally, we evaluated the connection between circadian clock-related genes with immune checkpoint inhibitors and immune cell infiltration. Two circadian clock-related signatures were established. The risk model included SEMA4D (p<0.001, HR: 0.709, 95% CI: 0.581 to 0.867) and SOD-2 (p=0.009, HR: 0.790, 95% CI: 0.663 to 0.944) in patients with TCGA melanoma. The risk model was based on two CCRGs enriched in base excision repair, glycosylphosphatidyl (GPI), and one carbon of the folate pathway. The overall survival was lower in the high-risk group. In addition, the circadian-clock signature may be able to evaluate the immunotherapy response. We developed and validated a circadian signature to characterize the clinical significance and tumor microenvironment of cutaneous melanoma, revealing that circadian rhythms may impact cutaneous melanoma.

Vulvovaginal melanoma or vulvar and vaginal melanoma: Can these tumors be considered the same? (009)

<b>Objectives:</b> Vulvovaginal melanoma (VVM) is a rare but aggressive subtype of melanoma. VVM is considered to be less immunogenic and less responsive to immune-oncology therapy (IO) than cutaneous melanomas (CM). Vulvar and vaginal melanomas are typically grouped together due to the rare nature of the disease, though limited data suggest worse outcomes with vaginal melanomas. There is a paucity of data regarding molecular differences between these two melanoma subtypes. Our goal was to explore molecular profiles and survival between vaginal and vulvar melanomas. <b>Methods:</b> Samples were analyzed using next-generation sequencing (NGS) (TruSeq, 45 genes; NextSeq, 592 genes and NovaSeq, WES), IHC, and WTS (NovaSeq) (Caris Life Sciences, Phoenix, AZ). PD-L1 expression was tested by IHC using 28-8 (Agilent) and SP-142 (Spring Biosciences) (positive cut-off ≥1%). Microsatellite instability (MSI) was tested by fragment analysis (FA), immunohistochemistry (IHC), and NGS. Tumor mutational burden (TMB) was measured by totaling somatic mutations per tumor (TMB-high cut-off ≥10 mutations/MB). Immune cell fraction was calculated by QuantiSeq (Finotello 2019, Genome Medicine). Real-world overall survival (OS) was extracted from insurance claims data and calculated from the time of IO treatment to the last contact using Kaplan-Meier survival curves for molecularly defined cohorts. Statistical significance was determined using Chi-square and Wilcoxon rank-sum test and adjusted for multiple comparisons (q<0.05). <b>Results:</b> A total of 183 VVM were included in this analysis: 137 (74.9%) vulvar and 46 (25.1%) vaginal. Rates of gene mutations between these tumors were similar. Vaginal tumors trended toward increased frequency of <i>ATRX</i> (47.1 vs 23.2%) and <i>TP53</i> (29.0 vs 16.1%) mutations compared to vulvar tumors. Vulvar tumors trended toward higher rates of <i>SF3B1</i> mutations (33.8 vs 4%) as well as more <i>KIT</i> mutations (17.7 vs 8.8%) and amplification (16.7 vs 8.0%). PD-L1 expression was similar in vaginal and vulvar tumors (40 vs 32.7%). MMR deficiency and high TMB were absent in both groups. Vulvar melanoma trended towards increased immune checkpoint gene expression compared to vaginal melanoma, most notably a 2-fold increase in both <i>IFNG</i> and <i>IDO1</i> expression. No difference was seen in immune cell infiltrates. Treatment and survival data were available for 78 vulvar and 40 vaginal melanomas (OS: 34 vs 21 mo). In total, 15% of vulvar patients (<i>n</i>=12) and 18% of vaginal patients (<i>n</i>=7) received IO therapy. Median survival was similar between groups (vulvar 18 mo vs vaginal 19 mo, p=0.9). The survival of cutaneous melanoma (CM) patients receiving IO therapy (<i>n</i>=1047) was roughly twice as long (36.6 mo,p=0.038). <b>Conclusions:</b> This is one of the largest VVM cohorts to be studied to date. Overall, we found that these tumors were very similar in their molecular profiles and immunogenicity. Survival and response to IO therapy appeared similar between vulvar and vaginal melanomas. Our findings support continuing study of VVM as a single entity in light of the rarity of this disease.Fig. 1

EIF6 as a Promising Diagnostic and Prognostic Biomarker for Poorer Survival of Cutaneous Melanoma.

BackgroundSkin cutaneous melanoma (SKCM) is the deadliest skin cancer and has the most rapidly increasing incidences among all cancer types. Previous research elucidated that melanoma can only be successfully treated with surgical abscission in the early stage. Therefore, reliable and specific biomarkers are crucial to melanoma diagnosis since it often looks like nevi in the clinical manifestations. Moreover, identifying key genes contributing to melanoma progression is also highly regarded as a potential strategy for melanoma therapy. In this respect, translation initiator eIF6 has been proved as a pro-tumor factor in several cancers. However, the role of eIF6 in the skin cutaneous melanoma progression and its potential as a prognostic marker is still unexplored.MethodsThe immunochemical analysis of clinical specimens were served to assess eIF6 expression levels. Gene Expression Profiling Interactive Analysis (GEPIA) database consultations allowed us to find the survival rates of the eIF6-overexpressed patients. eIF6 cellular effects were evaluated in an eIF6-overexpressed A375 cell line constructed with a lentivirus. The analysis of down-stream effectors or pathways was conducted using C-Bioportal and STRING databases.ResultsOur results revealed that eIF6 was highly over-expressed in melanomas compared to normal skin specimens, and thus the abnormally high level of eIF6 can be a diagnostic marker for melanoma. The in silica analysis indicated that patients with eIF6 over-expression had lower survival rates than that low-expression in SKCM. Meanwhile, similar results also could be found in the other four types of cancers. In vitro, over-expression of eIF6 increased the proliferation and migration of melanoma cells. Correspondingly, pan-cancer clustering analysis indicated the expression level of intermediate filament proteins was correlated with that of eIF6 expression. In our study, all over-expressed keratin proteins, in accordance with over-expressed eIF6, had a negative correlation with melanoma prognosis. Moreover, the decreased methylation level of keratin genes suggested a new potential regulation mode of eIF6.ConclusionsThe up-regulated eIF6 could be a potential diagnostic and prognostic biomarker of melanoma. This study also provides insights into the potential role of eIF6 in pan-cancer epigenetic regulation.

Incisional Biopsy Technique Is Associated With Decreased Overall Survival for Cutaneous Melanoma.

Previous studies examining melanoma biopsy technique have not demonstrated an effect on overall survival. To examine overall survival of patients with cutaneous melanoma diagnosed by shave, punch, incisional, or excisional techniques from the National Cancer Database (NCDB). Melanoma data from the 2004 to 2016 NCDB data set were analyzed. A Cox proportional hazards model was constructed to assess the risk of 5-year all-cause mortality. In total, 42,272 cases of melanoma were reviewed, with 27,899 (66%) diagnosed by shave biopsy, 8,823 (20.9%) by punch biopsy, and 5,550 (13.1%) by incisional biopsy. Both the univariate and multivariate analyses demonstrated that tumors diagnosed by incisional biopsy had significantly (p = .001) lower overall 5-year survival compared with shave techniques (hazard ratio [HR] = 1.140, 95% confidence interval [CI] 1.055 to 1.231). We found no difference (p = .109) between shave and punch biopsy techniques (HR 1.062, 95% CI 0.987-1.142) or between punch and incisional techniques (HR 1.074, 95% CI 0.979-1.177, p = .131). Incisional biopsies were associated with decreased overall 5-year survival in the NCDB. No difference was observed between shave and punch biopsy techniques. These findings support current melanoma management guidelines.

Comprehensive analysis of ferroptosis-related genes and prognosis of cutaneous melanoma

BackgroundCutaneous Melanoma (CM) is a malignant disease with increasing incidence and high mortality. Ferroptosis is a new kind of cell death and related to tumor blood and lymphatic metastasis. This study aims at using bioinformatics technology to construct a prognostic signature and identify ferroptosis-related biomarkers to improve the prognosis and treatment of cutaneous melanoma.MethodsWe used bioinformatics tools to analyze RNA sequencing expression data with clinical information from multiple databases, utilized varieties of statistical methods to construct a ferroptosis-related prognostic signature of cutaneous melanoma and screened out specific genes with independent prognostic ability.ResultsWe obtained 22 ferroptosis-related (P < 0.05) prognostic DEGs in the uniCox regression analysis, among which 10 high-expressed genes (ATG5, CHAC1, FANCD2, FBXL5, HMOX2, HSPB1, NQO1, PEBP1, PRNP, SLC3A2) were screened out by LASSO regression analysis to establish a predictive model. Meanwhile, the ferroptosis-related signature and the nomogram we drew performed an excellent performance based on Kaplan–Meier (K–M), Receiver operating characteristic (ROC) and calibration curves. Univariate and multivariable cox analyses displayed that our model was greater than other prognostic features. GO and KEGG analyses revealed that 10-biomarker signature was mainly related to epidermis differentiation and immunity. ssGSEA analysis indicated that the immune status between the two risk groups was highly different. Besides, we found that two genes (CP, ZEB1) had independent prognostic ability and can be applied for drug research. Both genes were highly related to immunity. GSEA illustrated that ZEB1 may be involved in cellular functions such as proliferation, apoptosis, and migration, while CP was closely connected to immune cell related functions.ConclusionThe present study suggested a 10-biomarker signature can be clinically used to predict the prognosis of cutaneous melanoma, which was better than conventional factors. CP and ZEB1 were independent prognostic genes and can be applied to guide treatment. In addition, ZEB1 mutation was highly related to overall survival in cutaneous melanoma, while CP may be associated with tumor progression. Our study comprehensively analyzed the relationship between iron metabolism, ferroptosis-related genes, and the prognosis of cutaneous melanoma, provided new insight for molecular mechanisms and treatment of ferroptosis and cutaneous melanoma.

Improved cutaneous melanoma survival stratification through integration of 31-gene expression profile testing with the American Joint Committee on Cancer 8th Edition Staging.

Cutaneous melanoma (CM) survival is assessed using averaged data from the American Joint Committee on Cancer 8th edition (AJCC8). However, subsets of AJCC8 stages I-III have better or worse survival than the predicted average value. The objective of this study was to determine if the 31-gene expression profile (31-GEP) test for CM can further risk-stratify melanoma-specific mortality within each AJCC8 stage. This retrospective multicenter study of 901 archival CM samples obtained from patients with stages I-III CM assessed 31-GEP test predictions of 5-year melanoma-specific survival (MSS) using Kaplan-Meier and Cox proportional hazards. In stage I-III CM population, patients with a Class 2B result had a lower 5-year MSS (77.8%) than patients with a Class 1A result (98.7%) and log-rank testing demonstrated significant stratification of MSS [χ2 (2df, n = 901) = 99.7, P < 0.001). Within each stage, 31-GEP data provided additional risk stratification, including in stage I [χ2 (2df, n = 415) = 11.3, P = 0.004]. Cox regression multivariable analysis showed that the 31-GEP test was a significant predictor of melanoma-specific mortality (MSM) in patients with stage I-III CM [hazard ratio: 6.44 (95% confidence interval: 2.61-15.85), P < 0.001]. This retrospective study focuses on Class 1A versus Class 2B results. Intermediate results (Class 1B/2A) comprised 21.6% of cases with survival rates between Class 1A and 2B, and similar to 5-year MSS AJCC stage values. Data from the 31-GEP test significantly differentiates MSM into lower (Class 1A) and higher risk (Class 2B) groups within each AJCC8 stage. Incorporating 31-GEP results into AJCC8 survival calculations has the potential to more precisely assess survival and enhance management guidance.

GJB5 association with BRAF mutation and survival in cutaneous malignant melanoma.

Gap-junctional intercellular communication is crucial for epidermal cellular homeostasis. Inability to establish melanocyte-keratinocyte contact and loss of the 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. The aim of this study was to investigate connexin 31·1 (GJB5) expression and identify any association with BRAF mutational status, prognosis of patients with melanoma and mitogen-activated protein kinase (MAPK) inhibitor (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 (MEKi), as well as in cell lines which developed MAPKi resistance. Findings were further validated and confirmed by analysis of independent datasets. Our analysis reveals significant downregulation of GJB5 expression in metastatic melanoma lesions compared with primary ones and in BRAF-mutated vs. BRAF-wildtype (BRAFWT ) melanomas. Likewise, GJB5 expression is significantly lower in BRAFV600E compared with BRAFWT cell lines and increases on MAPKi treatment. MAPKi-resistant melanoma cells display a similar expression pattern compared with BRAFWT cells, with increased GJB5 expression associated with morphological changes. Enhancement of BRAFV600E expression in BRAFWT melanoma cells significantly upregulates miR-335-5p expression with consequent downregulation of GJB5, one of its targets. Furthermore, overexpression of miR-335-5p in two BRAFWT cell lines confirms specific GJB5 protein downregulation. Reverse transcriptase quantitative polymerase chain reaction analysis also revealed upregulation of miR-335 in BRAFV600E melanoma cells, which is significantly downregulated in cells resistant to MEKi. Our data were further validated using the TCGA_SKCM dataset, where BRAF mutations associate with increased miR-335 expression and inversely correlate with GJB5 expression. In clinical samples, GJB5 underexpression is also associated with patient overall worse survival, especially at early stages. We identified a significant association between metastases/BRAF mutation and low GJB5 expression in melanoma. Our results identify a novel mechanism of gap-junctional protein regulation, suggesting a prognostic role for GJB5 in cutaneous melanoma.