Survival In Cutaneous Melanoma Research Articles

Association between tumor characteristics and second primary cancers with cutaneous melanoma survival: A nationwide cohort study.

The increased survival in malignant cutaneous melanoma (melanoma) is probably due to early diagnosis combined with improved treatment most recently. National health campaigns and screening programs for melanoma detection were started in Sweden several decades ago. We want to assess the influence of tumor characteristics, based on the TNM classification, and of second primary cancers on overall survival in melanoma. We used the Swedish Cancer Registry to assess all-cause survival in melanoma from 2003 to 2015. Hazard ratios (HRs) were estimated using multivariable Cox regression models. A total of 19,773 melanoma patients were diagnosed with TNM data. Survival showed a strong improving trend over time (p-trend <.001). T1a was the most common classification (48.0% of all), while higher T class was associated systematically with worse survival (p-trend <.001). For distant metastases, the HR was 3.17, accounting for 0.9% of the patients. Any types of second primary cancers, other than melanoma, were associated with an HR of 2.00, accounted for 6.7% of all cases. Even if melanoma survival in Sweden ranks among the best national rates, the large percentage of patients with advanced tumors (T3b, T4a, and T4b, 17%) and 21% of deaths with T1a call for improved preventive and follow-up strategies.

Novel Genetic Variants of ALG6 and GALNTL4 of the Glycosylation Pathway Predict Cutaneous Melanoma-Specific Survival.

Because aberrant glycosylation is known to play a role in the progression of melanoma, we hypothesize that genetic variants of glycosylation pathway genes are associated with the survival of cutaneous melanoma (CM) patients. To test this hypothesis, we used a Cox proportional hazards regression model in a single-locus analysis to evaluate associations between 34,096 genetic variants of 227 glycosylation pathway genes and CM disease-specific survival (CMSS) using genotyping data from two previously published genome-wide association studies. The discovery dataset included 858 CM patients with 95 deaths from The University of Texas MD Anderson Cancer Center, and the replication dataset included 409 CM patients with 48 deaths from Harvard University nurse/physician cohorts. In the multivariable Cox regression analysis, we found that two novel single-nucleotide polymorphisms (SNPs) (ALG6 rs10889417 G>A and GALNTL4 rs12270446 G>C) predicted CMSS, with an adjusted hazards ratios of 0.60 (95% confidence interval = 0.44–0.83 and p = 0.002) and 0.66 (0.52–0.84 and 0.004), respectively. Subsequent expression quantitative trait loci (eQTL) analysis revealed that ALG6 rs10889417 was associated with mRNA expression levels in the cultured skin fibroblasts and whole blood cells and that GALNTL4 rs12270446 was associated with mRNA expression levels in the skin tissues (all p < 0.05). Our findings suggest that, once validated by other large patient cohorts, these two novel SNPs in the glycosylation pathway genes may be useful prognostic biomarkers for CMSS, likely through modulating their gene expression.

Survival between synchronous and non-synchronous multiple primary cutaneous melanomas-a SEER database analysis.

BackgroundThere is no criterion to distinguish synchronous and non-synchronous multiple primary cutaneous melanomas (MPMs). This study aimed to distinguish synchronous and non-synchronous MPMs and compare the survivals of them using the Surveillance, Epidemiology, and End Results database.MethodsSynchronous and non-synchronous MPMs were distinguished by fitting the double log transformed distribution of the time interval between the first and second primary cutaneous melanomas (TIFtS) through a piecewise linear regression. The overall and melanoma-specific survivals were compared by the Kaplan–Meier method and Cox proportional hazard model through modeling the occurrence of synchronous MPMs as a time-dependent variable.ResultsThe distribution of TIFtS was composed by three power-law distributions. According to its first inflection point, synchronous MPMs were defined as tumors that occurred within 2 months. The Kaplain–Meier plot revealed a significant inferior survival for synchronous MPMs than non-synchronous MPMs (P < 0.0001), and the occurrence of synchronous MPM was a risk factor for overall survival of cutaneous melanoma (CM) (hazard ratio: 2.213; (95% CI [2.087–2.346]); P < 0.0001).ConclusionsThis study provided data analysis evidences for using 2 months to distinguish synchronous MPMs and non-synchronous MPMs. Furthermore, the occurrence of synchronous MPM was a risk factor for prognosis of patients with CM.

Correlation of Tumor Burden in Sentinel Lymph Nodes with Tumor Burden in Nonsentinel Lymph Nodes and Survival in Cutaneous Melanoma.

In patients with cutaneous melanoma, metastasis in a nonsentinel lymph node (non-SLN) is a strong independent adverse prognostic factor. However, patients with a tumor-involved SLN no longer routinely undergo completion lymph node dissection (CLND). We hypothesized that SLN tumor burden may predict non-SLN tumor burden. We compared tumor burden parameters between SLN and non-SLN in patients with cutaneous melanoma who underwent SLN biopsy with a positive SLN during 2003 to 2008 at The University of Texas MD Anderson Cancer Center. We identified 336 eligible patients with a positive SLN. Of these, 308 (92%) underwent CLND, and 35 (10%) had non-SLN metastasis. The median follow-up time was 6.0 years. For patients with maximum diameter of tumor in the SLN ≤2.0 mm, >2.0-5.0 mm, and >5.0 mm, non-SLN metastasis was detected in 5 of 200 patients (3%), 10 of 63 patients (16%), and 20 of 57 patients (35%), and the mean maximum diameters of the non-SLN tumor deposits were 0.09, 1.56, and 2.71 mm, respectively (P < 0.0001). The percentage of patients with both subcapsular and intraparenchymal non-SLN tumor was higher for patients with SLN tumor in both locations than for patients with SLN tumor in only one location (P < 0.0001). Extranodal extension in a non-SLN was more common in patients with extranodal extension in an SLN (P = 0.003). In patients with cutaneous melanoma who undergo CLND, SLN tumor burden predicts non-SLN tumor burden. SLN tumor burden parameters provide accurate prognostic stratification independent of non-SLN status and should be considered for incorporation into future staging systems and integrated risk models.

1486 Rectal Melanoma Occurring in a Properly CRC Screened Patient

INTRODUCTION: Rectal melanoma is a very rare, highly aggressive malignancy. Anal melanoma is the 3rd most common melanoma after the cutaneous and ocular varieties. It is the most common site of primary GI melanoma. Cutaneous melanoma metastasizes to the GI tract only 2% of the time, and only 2% of these metastases are to the rectum. CASE DESCRIPTION/METHODS: A 68-year-old male with a past medical history of HTN presented for evaluation of changed bowel movements. His stool diameter had decreased, and he noticed bright red blood mixed with his stool. He sometimes experienced fecal urgency, with no output. Rectal bleeding occurred just before or with bowel movements. He recently changed his diet, because of constipation. He recently lost 10 lbs. unintentionally. He did not use NSAIDs aside from aspirin 81 mg qd. He had a colonoscopy 5 years ago, with a 2 mm polyp removed (no abnormality seen on pathology). He had no family history of colon cancer. He was a retired chiropractor. A colonoscopy was performed, which found a suspicious lesion in the rectum (biopsied). Pathology showed pigmented melanoma. EUS staged the rectal mass as uT2uN1. Immunostains of the biopsy were performed: CK20-, CDX2-, p63-, S100 focally positive, HMB45 diffuse and strongly positive. No evidence of cutaneous melanoma was found. He was referred for surgical and oncology evaluation and treatment. He successfully underwent laparoscopic abdominal perineal resection with end colostomy. 9/10 sampled lymph nodes during surgery were positive for melanoma. He was started on nivolumab/ipilimumab dual therapy. He proceeded to undergo chemotherapy as outpatient (currently on chemotherapy cycle 2). DISCUSSION: Anorectal melanoma is a rare disease, accounting for ∼ 0.05% of all colorectal malignancies, and 1% of all anal cancers. Risk factors for anorectal mucosal melanoma are not currently known, although there is an increased risk associated with HIV infection. Survival is poor, depending on staging (Stage I – 24 month median survival; 5-year survival 26.7%, Stage II – median survival 17 months; 5-year survival 9.8%, Stage III – median survival 8 months; 5-year survival 0%). Adjuvant therapy consists of radiotherapy, however adjuvant immunotherapy with nivolumab has an established role in treating lymph node involvement. Anti-CTLA4 monoclonal antibody ipilimumab has been shown to significantly prolong survival in cutaneous melanoma, however more investigation is necessary to clarify role of ipilimumab in patients with mucosal melanoma.

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

No association between smoking and sentinel lymph node metastasis and survival in cutaneous melanoma.

There is little evidence that smoking is associated with metastasis in patients with cutaneous melanoma. Using a propensity score matching analysis, we assessed whether smoking was associated with a higher rate of sentinel lymph node (SLN) metastasis and worse survival in these patients. Retrospective cohort study at a referral hospital for melanoma. We studied 762 patients with known smoking status from the melanoma database of the Instituto Valenciano de Oncología who underwent SLN biopsy between 1 January 2000 and 31 December 2016. The patients were matched by smoking status. The matching procedure was implemented using three logistic regression models featuring never vs. former smokers, never vs. current smokers and former vs. current smokers. The study outcomes were disease-free survival (DFS), melanoma-specific survival (MSS), overall survival (OS) and SLN status. The following groups were formed based on the propensity matching scores: 114 pairs of smokers vs. never smokers, 113 pairs of smokers vs. former smokers and 174 pairs of never smokers vs. former smokers. Smoking status was not associated with SLN metastasis or with DFS, MSS or OS in any of the three groups. Smoking does not influence SLN metastasis or survival in patients with cutaneous melanoma.

Identification of a functional polymorphism within the 3′-untranslated region of denticleless E3 ubiquitin protein ligase homolog associated with survival in acral melanoma

BackgroundHigh expression of denticleless E3 ubiquitin protein ligase homologue (DTL) correlates with poor disease-free survival and overall survival in cutaneous melanoma, but the molecular features and clinical significance of this gene in acral melanoma (AM) remain unclear. MethodsThe expression levels of DTL were compared between AM and benign melanocytic nevi using existing Gene Expression Omnibus data and validated in fresh frozen tissues. Two candidate tag single-nucleotide polymorphisms (SNPs) in the 3′-untranslated region (3′UTR) of DTL in patients with AM were sequenced and analysed for their association with survival in a discovery cohort (n = 570), and the significant SNP was subjected to a replication cohort (n = 201). The expression of DTL was evaluated by immunohistochemistry. The microRNA interacting with rs11275300:C > G was predicted using in silico target prediction tools and validated by in vitro analysis. ResultsDTL was overexpressed in AM compared with benign melanocytic nevi. rs11275300:C > G was found to be significantly associated with progression-free survival and overall survival of patients with AM in both cohorts and the combined cohort. Furthermore, the DTL expression level in the patients with the rs11275300:G allele was higher than that in patients with the CC genotype. In vitro analysis demonstrated that DTL was a direct target of hsa-miR-4672, and the rs11275300:G allele interfered with the binding affinity of hsa-miR-4672 with the 3′UTR of DTL and thereby increased DTL expression. ConclusionThe rs11275300:G allele in the 3′UTR of DTL may lead to a poor prognosis and allele-specific increase in the expression of DTL by post-transcriptional regulation in AM.

Expressions of HLA Class II Genes in Cutaneous Melanoma Were Associated with Clinical Outcome: Bioinformatics Approaches and Systematic Analysis of Public Microarray and RNA-Seq Datasets.

Major histocompatibility complex (MHC) class II molecules, encoded by human leukocyte antigen (HLA) class II genes, play important roles in antigen presentation and initiation of immune responses. However, the correlation between HLA class II gene expression level and patient survival and disease progression in cutaneous melanoma is still under investigation. In the present study, we analyzed microarray and RNA-Seq data of cutaneous melanoma from The Cancer Genome Atlas (TCGA) using different bioinformatics tools. Survival analysis revealed higher expression level of HLA class II genes in cutaneous melanoma, especially HLA-DP and -DR, was significantly associated with better overall survival. Furthermore, the expressions of HLA class II genes were most closely associated with survival in cutaneous melanoma as compared with other cancer types. The expression of HLA class II co-expressed genes, which were found to associate with antigen processing, immune response, and inflammatory response, was also positively associated with overall survival in cutaneous melanoma. Therefore, the results indicated that increased HLA class II expression may contribute to enhanced anti-tumor immunity and related inflammatory response via presenting tumor antigens to the immune system. The expression pattern of HLA class II genes may serve as a prognostic biomarker and therapeutic targets in cutaneous melanoma.

Burden of unique and low prevalence somatic mutations correlates with cancer survival

Tumor mutational burden correlates with improved survival and immunotherapy response in some malignancies, and with tumor aggressiveness in others. To study the link between mutational burden and survival, we analyzed survival effects of tumor exonic missense mutation burden (TEMMB) across 6947 specimens spanning 31 cancers which have undergone whole exome sequencing as part of TCGA. We adjusted TEMMB for age, sex, stage, and recruitment center, and computed Cox-proportional models of TEMMB survival effects. We assigned a recurrence score (RS) to each cohort, defining RS as the burden of recurrent mutations exceeding 1% population prevalence. High TEMMB was associated with improved survival in cutaneous melanoma: hazard ratio (HR) = 0.71 [0.60–0.85], p = 0.0002, urothelial bladder carcinoma: HR = 0.74 [0.59–0.93], p = 0.01, and ovarian carcinoma: HR = 0.80 [0.70–0.93], p = 0.003. High TEMMB was associated with decreased survival in colorectal adenocarcinoma: HR = 1.32 [1.00–1.74], p < 0.05. We identified that TEMMB survival effects were governed by the balance of recurrent and non-recurrent mutations. In cancers with a low RS, high TEMMB was correlated with better survival outcomes (r = 0.49, p = 0.02). In conclusion, TEMMB effects on survival depend on recurrent mutation enrichment; tumor types that are highly enriched in passenger mutations show a survival benefit in the setting of high tumor mutational burden.

Lymph node ratio has impact on relapse and outcome in patients with stage III melanoma.

Even though both the involvement of regional lymph nodes and the number of metastatic lymph nodes are regarded as major determinants of survival in cutaneous melanoma, the extent of node dissection has been analyzed as an independent prognostic indicator in only a few studies. This study aims to determine how the lymph node ratio (NR) (ratio of positive nodes to total nodes removed) might predict the disease relapse and survival in node-positive melanoma. A total of 317 patients with stage III primary melanoma were included in the study and reviewed retrospectively. All patients had nodal staging (N) by radical lymph node dissection. Patients were divided into three groups based on NR1 ≤ 10%, NR2 10-25%, and NR3 > 25%. The median age was 50years (range 16-86) and men were predominant (59.3%). The majority of the patients had thicker Breslow depth (> 2mm) (83.3%), higher mitotic rate (> 2/mm2) (64.1%) and ulcerated lesions (69.4%). The median number of positive nodes was 1 (range 1-32). The largest group was N1 (52.4%), which was followed by N2 (29.6%) and N3 (18%). The ratios of patients were 37.5%, 35.3%, and 27.1% in NR1, NR2, and NR3, respectively. The median number of excised lymph nodes was 13 (range 1-73). For all patients the estimated 5-and 10-year relapse-free survival (RFS) rates were 41% and 39%, respectively; and the estimated 5-and 10-year overall survival (OS) rates were 51% and 42%, respectively. Nodular histopathology, ulcerated lesions, higher mitotic rates, and higher node substages were the independent variables that were inversely correlated with survival for all patients; and NR was one of the significant prognostic factors and strongest predictors of relapse and survival (p = 0.03 and p = 0.01, respectively). Our results suggest that, apart from the conventional nodal status, NR is an independent prognostic factor-regarding both RFS and OS in stage III cutaneous melanoma.

Development and Validation of Autophagy-Related-Gene Biomarker and Nomogram for Predicting the Survival of Cutaneous Melanoma

Development and Validation of Autophagy-Related-Gene Biomarker and Nomogram for Predicting the Survival of Cutaneous Melanoma

Long-Term Survival of Cutaneous Malignant Melanoma with Metastasis to Paranasal Sinuses: A Case Report and Literature Review

Background: Malignant melanoma (MM) usually present with metastases to unexpected regions of the body. Metastatic MM is a highly lethal condition, and the median survival in this setting is 6 to 7.5 months; however, few reports rarely describe long-term after chemotherapy.Case Report: We describe a 31-year-old man with MM, which got metastatic (to paranasal sinuses) after local and systemic therapy showed complete responses with long-term survival after endonasal endoscopic metastasectomy and radiotherapy of the nasal cavity, paranasal sinuses, and base of the skull.Conclusion: Although long-term survival is rare, few reports describe cases after chemotherapy. MM could be associated with metastasis to any regions and clinicians should be aware of its behavior and perform complete investigation in the presence of any suspicious symptoms, and this should be reinforced periodically. However, the survival is poor in the metastatic setting, and the treatment of choice is debatable, some patients may benefit from metastasectomy and local radiotherapy. [GMJ.2018;7:e860]

Long-Term Survival of Cutaneous Malignant Melanoma with Metastasis to Paranasal Sinuses: A Case Report and Literature Revie

&#x0D; Background: Malignant melanoma (MM) usually present with metastases to unexpected regions of the body. Metastatic MM is a highly lethal condition, and the median survival in this setting is 6 to 7.5 months; however, few reports rarely describe long-term after chemotherapy.Case Report: We describe a 31-year-old man with MM, which got metastatic (to paranasal sinuses) after local and systemic therapy showed complete responses with long-term survival after endonasal endoscopic metastasectomy and radiotherapy of the nasal cavity, paranasal sinuses, and base of the skull.Conclusion: Although long-term survival is rare, few reports describe cases after chemotherapy. MM could be associated with metastasis to any regions and clinicians should be aware of its behavior and perform complete investigation in the presence of any suspicious symptoms, and this should be reinforced periodically. However, the survival is poor in the metastatic setting, and the treatment of choice is debatable, some patients may benefit from metastasectomy and local radiotherapy. [GMJ.2018;7:e860]&#x0D;

Aquaporin-1 Protein Expression of the Primary Tumor May Predict Cerebral Progression of Cutaneous Melanoma.

Brain metastasis is a frequent complication of the progression of malignant melanoma. In a previous study aquaporin 1 (AQP1) protein expression was found to be associated with increased mortality and decreased progression free survival in cutaneous melanoma. To explore further the potential of this marker we studied the AQP1 protein expression in 67 metastatic melanoma patients using immunohistochemistry. Primary tumor samples were acquired from patients with brain (BR) (n = 44) and extra-cranial (EC) (n = 23) metastases, while brain metastatic samples were collected during neurosurgical resection (n = 5). Patients with brain metastases had shorter overall survival (p = 0.02) and significantly higher AQP1 expression in the primary tumors (median H-score = 250 vs. 140, p = 0.044) as compared to patients of the EC metastasis group. AQP1 expression was found to be significantly lower in the brain metastases compared to the corresponding primary tumors (median H-score = 35 vs. 300 p = 0.01). However, in brain metastases AQP1 expression was heterogenous, AQP1 protein was more abundant in the melanoma cells far away from the capillaries as compared to tumor cells adjacent to vessels indicating a hypoxia-driven expression of AQP1. We suggest that AQP1 expression could well be a prognostic marker of brain metastatic potential of human cutaneous melanoma.

Baseline Neutrophil\u2013Lymphocyte and Platelet\u2013Lymphocyte Ratios as Biomarkers of Survival in Cutaneous Melanoma: A Multicenter Cohort Study

BackgroundIn the peripheral blood, the neutrophil–lymphocyte ratio (NLR) and platelet–lymphocyte ratio (PLR) change in response to malignancy. These biomarkers are associated with adverse outcomes in numerous cancers, but the evidence is limited in relation to melanoma. This study sought to investigate the association between these biomarkers and survival in Stages I–III cutaneous melanoma.MethodsThis multicenter cohort study investigated a consecutive series of patients who underwent wide excision of biopsy-proven cutaneous melanoma and sentinel lymph node biopsy during a 10-year period. The baseline NLR and PLR were calculated immediately before sentinel lymph node biopsy. Adjusted hazard ratios (HRs) for overall and melanoma-specific survival were generated.ResultsOverall, 1351 patients were included in the study. During surveillance, 184 of these patients died (14%), with 141 of the deaths (77%) attributable to melanoma. Worse overall survival was associated with a baseline NLR lower than 2.5 [HR 2.2; 95% confidence interval (CI) 2.0 to 2.3; p < 0.001] and a baseline PLR lower than 100 (HR 1.8; 95% CI 1.7 to 1.8; p < 0.001). Melanoma-specific survival also was worse, with a baseline NLR lower than 2.5 (HR 1.9; 95% CI 1.6 to 2.2; p < 0.001) and a baseline PLR lower than 100 (HR 1.9; 95% CI 1.7 to 2.2; p < 0.001). The 5-year survival for patients with sentinel lymph node metastases and a low NLR and PLR was approximately 50%.ConclusionThis study provides important new data on biomarkers in early-stage melanoma, which contrast with biomarker profiles in advanced disease. These biomarkers may represent the host inflammatory response to melanoma and therefore could help select patients for adjuvant therapy and enhanced surveillance.

Patterns of increased incidence and survival of cutaneous melanoma in Girona (Spain) 1994-2013: a population-based study.

We conducted a population-based study on the Girona Cancer Registry (Spain) for the period 1994-2013 to determine patterns of change in the incidence of melanoma, which is increasing in many countries, and patient survival in our geographical area. Using the standard registration rules for cancer registries, we calculated crude and standardized incidence rates as well as their trends. We also analysed the observed survival, 1-year conditioned survival and relative survival at 3, 5 and 10years. Our crude incidence rate was 9.13 cases/100,000 inhabitants for invasive and 2.59 for "in situ" melanomas. A statistically significant increase in incidence was found for melanomas of less than 1mm in Breslow index and in males. 10-year observed and relative survival rates were 64.1 and 83.1%, respectively. We found an increasing trend in the incidence of low-risk melanoma and a survival rate similar to that reported elsewhere in Europe.

Aberrant DNA methylation is associated with aggressive clinicopathological features and poor survival in cutaneous melanoma.

Promoter methylation of tumour suppressor genes (TSGs) has recently been implicated in the pathogenesis of several types of cancer. Regarding melanoma, over 100 genes that contribute to its pathogenesis have been identified to be aberrantly hypermethylated. This is a retrospective observational study that aims to analyse the prevalence of CpG island methylation in a series of primary melanomas, to identify the associations with the main clinicopathological features, and to explore the prognostic significance of methylation in melanoma survival. DNA methylation was analysed using methylation-specific multiplex ligation-dependent probe amplification in a series of 170 melanoma formalin-fixed paraffin-embedded tumour samples. The relationship between the methylation status, known somatic mutations and clinicopathological features was evaluated. Disease-free survival (DFS) and overall survival (OS) were displayed by the Kaplan-Meier method. In the entire cohort, one or more genes were detected to be methylated in 55% of the patients. The most prevalent methylated genes were RARB 31%, PTEN 24%, APC 16%, CDH13 16%, ESR1 14%, CDKN2A 6% and RASSF1 5%. An association between aberrant methylation and aggressive clinicopathological features was observed (older age, increased Breslow thickness, presence of mitosis and ulceration, fast-growing melanomas, advancing stage and TERT mutations). Furthermore, Kaplan-Meier survival analysis showed a correlation of methylation and poorer DFS and OS. Aberrant methylation of TSGs is a frequent event in melanoma. It is associated with aggressive clinicopathological features and poorer survival. Epigenetic alterations may represent a significant prognostic marker with utility in routine practice.

Immediate Lymph Node Dissection on Detection of Sentinel Lymph Node Involvement Does Not Increase Survival in Cutaneous Melanoma

Immediate Lymph Node Dissection on Detection of Sentinel Lymph Node Involvement Does Not Increase Survival in Cutaneous Melanoma

Genetic variants in RORA and DNMT1 associated with cutaneous melanoma survival.

Cutaneous melanoma (CM) is considered as a steroid hormone-related malignancy. However, few studies have evaluated the roles of genetic variants encoding steroid hormone receptor genes and their related regulators (SHR-related genes) in CM-specific survival (CMSS). Here, we performed a pathway-based analysis to evaluate genetic variants of 191 SHR-related genes in 858 CMSS patients using a dataset from a genome-wide association study (GWAS) from The University of Texas MD Anderson Cancer Center (MDACC), and then validated the results in an additional dataset of 409 patients from the Harvard GWAS. Using multivariate Cox proportional hazards regression analysis, we identified three-independent SNPs (RORA rs782917 G > A, RORA rs17204952 C > T and DNMT1 rs7253062 G > A) as predictors of CMSS, with a variant-allele attributed hazards ratio (HR) and 95% confidence interval of 1.62 (1.25-2.09), 1.60 (1.20-2.13) and 1.52 (1.20-1.94), respectively. Combined analysis of risk genotypes of these three SNPs revealed a decreased CMSS in a dose-response manner as the number of risk genotypes increased (ptrend < 0.001); however, no improvement in the prediction model was observed (area under the curve [AUC] = 79.6-80.8%, p = 0.656), when these risk genotypes were added to the model containing clinical variables. Our findings suggest that genetic variants of RORA and DNMT1 may be promising biomarkers for CMSS, but these results needed to be validated in future larger studies.