Outcome In Cutaneous Melanoma Research Articles

Association of lipid-lowering drug targets with risk of cutaneous melanoma: a mendelian randomization study

BackgroundMelanoma proliferation is partly attributed to dysregulated lipid metabolism. The effectiveness of lipid-lowering drugs in combating cutaneous melanoma (CM) is a subject of ongoing debate in both in vitro and clinical studies.MethodThis study aims to evaluate the causal relationship between various lipid-lowering drug targets, namely 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR, targeted by statins), Proprotein convertase subtilisin/kexin type 9 (PCSK9, targeted by alirocumab and evolocumab), and Niemann-Pick C1-like 1 (NPC1L1, targeted by ezetimibe), and the outcomes of cutaneous melanoma. To mimic the effects of lipid-lowering drugs, we utilized two genetic tools: analysis of polymorphisms affecting the expression levels of drug target genes, and genetic variations linked to low-density lipoprotein cholesterol levels and drug target genes. These variations were sourced from genome-wide association studies (GWAS). We applied Summary-data-based Mendelian Randomization (SMR) and Inverse Variance Weighted Mendelian Randomization (IVW-MR) to gauge the effectiveness of these drugs.ResultsOur findings, with SMR results showing an odds ratio (OR) of 1.44 (95% CI: 1.08–1.92; P = 0.011) and IVW-MR results indicating an OR of 1.56 (95% CI: 1.10–2.23; P = 0.013), demonstrate a positive correlation between PCSK9 expression and increased risk of CM. However, no such correlations were observed in other analyses.ConclusionThe study concludes that PCSK9 plays a significant role in the development of CM, and its inhibition is linked to a reduced risk of the disease.

A phase Ib study of endogenous T cell therapy using SLC45A2-specific CD8 T cells for patients with metastatic uveal melanoma.

9588 Background: Overall survival (OS) for patients (pts) with advanced uveal melanoma (UM) is poor compared with outcomes in cutaneous melanoma. Roughly half of all pts with UM will develop distant metastatic disease despite effective treatment of the primary tumor. Antigen-specific endogenous T cells (ETC) can be expanded and infused successfully in pts with many different types of cancer. Our group has identified epitopes of SLC45A2, a melanosomal transport protein, which are highly expressed in UM and are present at low levels in normal melanocytes. In vitro, we showed that cytotoxic T cells against SLC45A2 were able to kill HLA-matched UM cell lines. In vivo, we hypothesize that infused ETC can traffic to tumor sites. Methods: Between 6/2017 and 12/2022, we conducted a single-center, IRB-approved, first-in-human phase 1b dose escalation study of ETC targeting SLC45A2 in pts with metastatic UM (NCT03068624). Eligible pts with metastatic UM who express HLA-A*02:01 or A*24:02 underwent apheresis to collect peripheral T cells which were then selected and expanded (Turnstile 1). For Turnstile 2, conditioning with low-dose cyclophosphamide (300 mg/m2) occurred on Day -2. For pts in the radiation cohort, radiation occurred between Day -7 and Day -1. Infusion of ETC was done via hepatic arterial or central venous catheter on Day 0 followed by low dose subcutaneous interleukin-2 (IL-2) twice daily for 14 days +/- ipilimumab. The study utilized a 3+3 design with a starting dose level of 3.3 x 109 cells/m2 of ETC alone. The primary objective was to evaluate the safety and tolerability of infusing ETC targeting SLC45A2. Secondary objectives were to evaluate the in vivo persistence and anti-tumor efficacy of this regimen. Results: With a median age of 58 years (30-77), 34 pts were enrolled, 16 (47%) men and 18 (53%) women. 33 (97%) pts underwent apheresis and 11 (32%) received infusion of ETC. One dose limiting toxicity (DLT) thought to be unrelated to treatment or underlying cancer (cardiac disorder Grade 5) occurred at the starting dose level with no additional DLTs. The maximum tolerated dose was established as 1 x 1010 cells/m2. The most common treatment-related grade 3 and 4 toxicities were lymphocyte count decrease 9 (82%), hyponatremia 1 (9%), and hypophosphatemia 1 (9%). Per immune-related response criteria (irRC), 4 (36%) pts had stable disease (SD), 6 (55%) had progression of disease (PD), and 1 (9%) was not evaluable for best response. Median overall survival (OS) was 8.9 weeks (wks). OS was 91% at 4 wks, 55% at 8 wks and 46% at 13 wks. Median progression-free survival was 5.9 wks. In the 4 patients with stable disease, the median duration of SD was 5.7 months. Conclusions: ETC targeting SLC45A2 is safe and well-tolerated in pts with metastatic UM. Further analyses are underway to evaluate T cell trafficking and persistence. Clinical trial information: NCT03068624 .

Abstract 5169: Sentinel lymph node gene expression signature predicts survival outcome in cutaneous melanoma

Abstract Background: Sentinel lymph node status is an important prognostic factor for melanoma progression. We sought to develop a sentinel lymph node gene expression signature score predictive of disease progression in patients with cutaneous melanoma. Methods: Cases were retrieved from University of Pittsburgh protocol “Sentinel Node and Non-Sentinel Lymph Nodes (SLN and non-SLN) Procurement from Melanoma Subjects for Molecular Profiling.” Gene expression profiling was performed on SLN biopsies using U133A 2.0 Affymetrix gene chips. The top 25 genes associated with progression-free survival (PFS) were selected and a penalized regression function was used to select genes with a non-zero coefficient. A risk score was calculated from a 12 gene signature. A proportional hazards regression model was used to evaluate the association between clinical covariates, gene signature score, and PFS. Results: In total, 45 patients were included [female=18 (40%), median age (range)= 56 (16-81) years]. The median Breslow thickness (IQR) was 4.1 (3.3-6.0) mm, ulceration was present in 29 (67%) cases, and 25 (56%) lesions had nodular histology. Among patients, 23 (51%) had a positive SLN via H&E. Twenty-one (46.7%) patients developed disease recurrence/progression with a median follow-up of 8.3 years. The median time to progression was 9.6 years. Among the top 25 genes, 12 non-zero penalized coefficients were estimated (CLGN, C1QTNF3, ADORA3, ARHGAP8, ZNF223, PDE6G, CXCL3, CHRFAM7A, HLA-DRB-decreased risk, DCTN1, ASPSCR1, HEXIM1-increased risk). A 12-gene signature score was significantly associated with PFS (p<0.0001) and produced a bootstrap cross-validated C index of 0.888. Stratifying by SLN status the gene signature risk score remained highly significant (p<0.0001). In univariate analysis, Breslow thickness (HR=1.41), presence of ulceration (HR=3.61), SLN positivity (HR=2.50), and acral-lentiginous histology compared to nodular (HR=4.07) were each significantly associated with PFS (all p<0.05). After simultaneously adjusting for all of these factors plus the gene signature, the 12-gene score remained a significant predictor for PFS (p<0.0001). Conclusion: A SLN 12-gene signature risk score is associated with melanoma progression regardless of SLN status and can be used as a prognostic factor for PFS of patients. External validation of the gene signature is warranted. Citation Format: Lilit Karapetyan, William Gooding, Xi Yang, Andrew Knight, Aofei Li, Cindy Sander, Monica Panelli, Walter J. Storkus, Ahmad A. Tarhini, John M. Kirkwood. Sentinel lymph node gene expression signature predicts survival outcome in cutaneous melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5169.

Melanoma in Singapore: A 20-year review of disease and treatment outcomes

Melanomas in Asians have different clinicopathological characteristics and prognosis from melanomas in Caucasians. This study reviewed the epidemiology and treatment outcomes of cutaneous melanoma diagnosed at a tertiary referral dermatology centre in Singapore, which has a multiracial population. The study also determined whether Asians had comparable relapse-free and overall survival periods to Caucasians in Singapore. This is a retrospective review of cutaneous melanoma cases in our centre between 1996 and 2015. Sixty-two cases of melanoma were diagnosed in 61 patients: 72.6% occurred in Chinese, 19.4% in Caucasians and 3.2% in Indians, with an over-representation of Caucasians. Superficial spreading melanoma, acral lentiginous melanoma and nodular melanoma comprised 37.1%, 35.5% and 22.6% of the cases, respectively. The median time interval to diagnosis was longer in Asians than Caucasians; median Breslow's thickness in Asians were significantly thicker than in Caucasians (2.6mm versus 0.9mm, P=0.018) and Asians tend to present at a later stage. The mortality rates for Asians and Caucasians were 52% and 0%, respectively. More physician and patient education on skin cancer awareness is needed in our Asian-predominant population for better outcomes.

Utility of a 31-gene expression profile for predicting outcomes in patients with primary cutaneous melanoma referred for sentinel node biopsy

BackgroundA 31-gene genetic expression profile (31-GEP; Class 1 = low risk, Class 2 = high risk) developed to predict outcome in cutaneous melanoma (CM) has been validated by retrospective, industry-sponsored, or small series. MethodsTumor features, sentinel node biopsy (SNB) results, and outcomes were extracted from a prospective database of 383 C M patients who underwent SNB and had a 31-GEP run on their primary tumor. Groups were compared by uni- and multi-variable analysis. Relapse-free and distant metastasis-free survival (RFS, DMFS) were estimated by Kaplan-Meier method. ResultsBreslow thickness, T stage, and SNB positivity were significantly higher in Class 2 patients. Recurrence rates were higher for Class 2 vs Class 1 patients and highest in patients who were Class 2 and SNB positive. GEP class was predictive of RFS and DMFS and independently predicted relapse in AJCC “low risk” (stages IA-IIA) patients. Conclusions31-GEP adds prognostic information in CM patents undergoing SNB.

Identification of Prognostic Biomarkers of Cutaneous Melanoma Based on Analysis of Tumor Mutation Burden.

Background Immunotherapy offers a novel approach for the treatment of cutaneous melanoma, but the clinical efficiency varies for individual patients. In consideration of the high cost and adverse effects of immunotherapy, it is essential to explore the predictive biomarkers of outcomes. Recently, the tumor mutation burden (TMB) has been proposed as a predictive prognosticator of the immune response. Method RNA-seq and somatic mutation datasets of 472 cutaneous melanoma patients were downloaded from The Cancer Genome Atlas (TCGA) database to analyze mutation type and TMB. Differently expressed genes (DEGs) were identified for functional analysis. TMB-related signatures were identified via LASSO and multivariate Cox regression analysis. The association between mutants of signatures and immune cells was evaluated from the TIMER database. Furthermore, the Wilcox test was applied to assess the difference in immune infiltration calculated by the CIBERSORT algorithm in risk groupings. Results C>T substitutions and TTN were the most common SNV and mutated gene, respectively. Patients with low TMB presented poor prognosis. DEGs were mainly implicated in skin development, cell cycle, DNA replication, and immune-associated crosstalk pathways. Furthermore, a prognostic model consisting of eight TMB-related genes was developed, which was found to be an independent risk factor for treatment outcome. The mutational status of eight TMB-related genes was associated with a low level of immune infiltration. In addition, the immune infiltrates of CD4+ and CD8+ T cells, NK cells, and M1 macrophages were higher in the low-risk group, while those of M0 and M2 macrophages were higher in the high-risk group. Conclusion Our study demonstrated that a higher TMB was associated with favorable survival outcome in cutaneous melanoma. Moreover, a close association between prognostic model and immune infiltration was identified, providing a new potential target for immunotherapy.

Medical Immunosuppression and Outcomes in Cutaneous Melanoma: A Population-Based Cohort Study.

Melanoma and the immune system are intimately related. However, the association of immunosuppressive medications (ISMs) with survival in melanoma is not well understood. The study evaluated this at a population level. A cohort of patients with a diagnosis of invasive cutaneous melanoma (2007-2015) was identified from the Ontario Cancer Registry and linked to identify demographics, stage at diagnosis, prescription of immunosuppressive medications (both before and after diagnosis), and outcomes. The demographics of patients with and without prescriptions for ISM were compared. Patients eligible for Ontario's Drug Benefit Plan were included to ensure accurate prescription data. The primary outcome was overall survival. Cox Proportional Hazards Regression models identified factors associated with mortality, including use of ISM as a time-varying covariate. Of the 4954 patients with a diagnosis of cutaneous melanoma, 1601 had a prescription for ISM. The median age of the patients was 74years. Overall, 58.4% of the patients were men (60.5% of those without ISM and 54% of those using ISM; p < 0.001). The use of oral immunosuppression was associated with an increased hazard of death (hazard ratio, 5.84; 95% confidence interval, 5.11-6.67; p < 0.0001) when control was used for age, disease stage at diagnosis, anatomic site, comorbidity, and treatment. Other factors associated with death were increasing age, male sex, increased disease stage, truncal location of primary melanoma, and inadequate treatment. In sensitivity analysiswith steroid-onlyISM use excluded, survival did not differ significantly (p = 0.355). The use of immunosuppressive steroids for melanoma is associated with worse overall survival. Use of steroids should be limited when possible.

Seasons influence diagnosis and outcome of cutaneous melanoma.

The effects of season changes on the diagnosis of cutaneous melanoma have already been concluded; however, its clinical significance has yet to be defined. The aim of this study was to assess the effects of seasons on both the diagnosis and outcome of melanoma. A total of 1258 adult Caucasian Turkish cutaneous melanoma patients who had been treated and followed up in a single tertiary cancer referral center were included in the study. The most frequently affected season was summer (29%) followed by spring (26.6%), autumn (23.1%), and winter (21.3%). Similarly, rate of the patients diagnosed in July compared to January was significantly higher (11% vs 6%). Most of the clinicopathological characteristics were not correlated with seasons. The 5-year overall survival rate was significantly higher for patients diagnosed in August (81%) than other months, and especially January (47%) (P = .002 and P = .0001, respectively). Similarly, the patients of July (65%) survived longer than those of January (P = .02). Furthermore, similar favorable outcomes for summer (70%) compared to other seasons and winter (51%) were shown (P = .005 and P = .001, respectively). In conclusion, there are seasonal fluctuations in diagnosis of melanoma with a peak in summer, and those diagnosed in summer have favorable survival outcomes.

Computing Skin Cutaneous Melanoma Outcome From the HLA-Alleles and Clinical Characteristics.

Human leukocyte antigen (HLA) are essential components of the immune system that stimulate immune cells to provide protection and defense against cancer. Thousands of HLA alleles have been reported in the literature, but only a specific set of HLA alleles are present in an individual. The capability of the immune system to recognize cancer-associated mutations depends on the presence of a particular set of alleles, which elicit an immune response to fight against cancer. Therefore, the occurrence of specific HLA alleles affects the survival outcome of cancer patients. In the current study, prediction models were developed, using 401 cutaneous melanoma patients, to predict the overall survival (OS) of patients using their clinical data and HLA alleles. We observed that the presence of certain favorable superalleles like HLA-B∗55 (HR = 0.15, 95% CI 0.034–0.67), HLA-A∗01 (HR = 0.5, 95% CI 0.3–0.8), is responsible for the improved OS. In contrast, the presence of certain unfavorable superalleles such as HLA-B∗50 (HR = 2.76, 95% CI 1.284–5.941), HLA-DRB1∗12 (HR = 3.44, 95% CI 1.64–7.2) is responsible for the poor survival. We developed prediction models using key 14 HLA superalleles, demographic, and clinical characteristics for predicting high-risk cutaneous melanoma patients and achieved HR = 4.52 (95% CI 3.088–6.609, p-value = 8.01E-15). Eventually, we also provide a web-based service to the community for predicting the risk status in cutaneous melanoma patients (https://webs.iiitd.edu.in/raghava/skcmhrp/).

Relationship of patient age to tumor factors and outcomes among patients undergoing sentinel node biopsy for melanoma

IntroductionPatient age has been intermittently associated with demographics and outcomes in cutaneous melanoma. We looked at the association of age and patient demographics, tumor features, and melanoma-related outcomes in patients undergoing sentinel lymph node (SLN) biopsy for melanoma. MethodsWe reviewed demographics (age, gender), tumor features (mean Breslow thickness, ulceration, SLN positivity rates), and outcomes (all-site relapse, progression to stage IV, death from melanoma, complications) from a university-based prospective database of 1633 patients. Patients were grouped by decade of age and the impact of age was examined by univariable and multivariable analyses. ResultsIncreasing age was directly associated with number of patients referred for SLN biopsy, male gender, head and neck (H&N) tumor location, mean Breslow thickness, tumor ulceration, and with all –site relapse, progression to stage IV, death from melanoma and complication rates. Increasing age was indirectly associated with SLN positivity rates. Comparing ages <30 with ages >60, these trends reached statistical significance for male gender, H&N location, SLN positivity, all-site relapse, progression to stage IV (development of metastases) and death from melanoma. ConclusionsReferrals for SLN biopsy increase with increasing patient age, yet increasing age is associated with lower SLN positivity rates. This occurs despite the fact that older patients have thicker, more ulcerated tumors, and higher melanoma-related relapse and death rates.

Induction of G0/G1 phase arrest and apoptosis by CRISPR/Cas9-mediated knockout of CDK2 in A375 melanocytes.

Cutaneous melanoma is one of the most common malignant skin tumors, with a continuously increasing incidence. Cyclin-dependent kinase (CDK) 2 is a key regulator of G1-S transition and modulation of G2 progression; however, its role in cancer is a matter of debate. In the present study, a lentivirus expressing single-guide RNA (sgRNA) was constructed to knock out CDK2 using CRISP/Cas9 technology, in order to confirm the role of CDK2 in A375 human melanoma cells. The results demonstrated that CDK2 knockout induced G0/G1 phase arrest and early apoptosis by downregulating the expression of CDK4 and cyclin A2, and by upregulating the expression of cyclin D1. These results suggest that therapeutic strategies designed to target CDK2 using CRISP/Cas9 may improve the treatment outcome of cutaneous melanoma.

Environmental Exposures Such as Smoking and Low Vitamin D Are Predictive of Poor Outcome in Cutaneous Melanoma rather than Other Deprivation Measures

A lack of basic resources within a society (deprivation) is associated with increased cancer mortality, and this relationship has been described for melanoma. We have previously reported the association of smoking and low vitamin D levels with melanoma death. In this study, we further explored the associations of these with melanoma in addition to deprivation and socio-economic stressors. In this analysis of 2,183 population-ascertained primary cutaneous melanoma patients, clinical, demographic, and socio-economic variables were assessed as predictors of tumor thickness, melanoma death and overall death. Using the Townsend deprivation score, the most deprived group did not have thicker tumors compared to the least deprived. Of the World Health Organization 25x25 risk factors for premature death, smoking and body mass index (BMI) were independently associated with thicker tumors. Low vitamin D was also independently associated with thicker tumors. No socio-economic stressors were independent predictors of thickness. Smoking was confirmed as a key predictor of melanoma death and overall death, as were low vitamin D levels, independent of other measures of deprivation. Neither BMI nor the Townsend deprivation score were predictive in either survival analysis. We report evidence for the role of smoking, vitamin D, and BMI in melanoma progression independent of a postcode-derived measure of deprivation.

Solar Lentigines are Associated with Better Outcome in Cutaneous Melanoma.

The rising incidence of cutaneous melanoma and its stable high mortality rates despite innovative cancer care, require better prediction of the clinical outcome. In a large cutaneous melanoma population we explored whether the known clinical risk factors for melanoma susceptibility (nevus phenotype, phototype, family and personal history of melanoma and sun damage) affect melanoma outcomes. A total of 1,530 melanoma patients were included. Multivariable analysis adjusted for age, gender, melanoma stage, localization and subtype showed that familial melanoma, solar lentigines on head and neck, the back of hands, arms and shoulders were associated with a better relapse free survival. The presence of atypical naevi was associated with an increased risk of relapse. After Bonferroni correction, the correlation between presence of solar lentigines on the back of the hands and arms remained the most robust and significant prognostic factor for the relapse free survival in cutaneous melanoma patients.

Disparities in the Presentation and Management of Cutaneous Melanoma That Required Admission

Objective: In this study, we aimed to examine the association of demographic and socioeconomic factors with cutaneous melanoma that required admission. Methods: A cross-sectional study utilizing the Nationwide Inpatient Sample database, 2003–2009, was merged with County Health Rankings Data. Results: A total of 2,765 discharge ­records were included. Men were more likely to have melanoma in the head, neck, and trunk regions (p < 0.001), while extremities melanoma was more common in women (p < 0.001). Males had a higher risk of lymph node metastasis on presentation (OR 1.54, 95% CI [1.27–1.89]). Blacks and Hispanics were more likely to present with extremities melanoma. Patients with low annual income were more likely to be treated by low-volume surgeons and in hospitals located in high-risk communities (p < 0.05 each). Patients with Medicaid coverage were twice as likely to present with distant metastasis and were more likely to be managed by low-volume surgeons (p < 0.05 each). Conclusions: The presentation and outcomes of cutaneous melanoma have a distinct pattern of distribution based on patients’ characteristics.

Expression profiles analysis of long non-coding RNAs identified novel lncRNA biomarkers with predictive value in outcome of cutaneous melanoma.

Recent advancements in cancer biology have identified a large number of lncRNAs that are dysregulated expression in the development and tumorigenesis of cancers, highlighting the importance of lncRNAs as a key player for human cancers. However, the prognostic value of lncRNAs still remains unclear and needs to be further investigated. In the present study, we aim to assess the prognostic value of lncRNAs in cutaneous melanoma by integrated lncRNA expression profiles from TCGA database and matched clinical information from a large cohort of patients with cutaneous melanoma. We finally identified a set of six lncRNAs that are significantly associated with survival of patients with cutaneous melanoma. A linear combination of six lncRNAs (LINC01260, HCP5, PIGBOS1, RP11-247L20.4, CTA-292E10.6 and CTB-113P19.5) was constructed as a six-lncRNA signature which classified patients of training cohort into the high-risk group and low-risk group with significantly different survival time. The prognostic value of the six-lncRNA signature was validated in both the validation cohort and entire TCGA cohort. Moreover, the six-lncRNA signature is independent of known clinic-pathological factors by multivariate Cox regression analysis and demonstrated good performance for predicting three- and five-year overall survival by time-dependent receiver operating characteristic (ROC) analysis. Our study provides novel insights into the molecular heterogeneity of cutaneous melanoma and also shows potentially important implications of lncRNAs for prognosis and therapy for cutaneous melanoma.

Impact of Time Between Diagnosis and SLNB on Outcomes in Cutaneous Melanoma

Hypothetically, delay between melanoma diagnosis and SLNB could affect outcomes, either adversely by allowing growth and dissemination of metastases, or beneficially by allowing development of an anti-melanoma immune response. Available data are conflicting about the effect of SLNB delay on patient survival. Our objective was to determine whether delay between initial diagnosis and SLNB affects outcomes in patients with cutaneous melanoma. We performed query and analysis of a large prospectively maintained database of patients with primary cutaneous melanomas undergoing SLNB. An independent dataset from MSLT-1 (Multicenter Selective Lymphadenectomy Trial-1) was used for validation. Primary outcomes included disease-free survival and melanoma-specific survival. Early and delayed SLNB were defined as less than 30 and 30 or more days from initial diagnosis, respectively. There were 2,483 patients that met inclusion criteria. Positive sentinel lymph nodes were identified in 17.4% (n= 432). Among all patients, 42% had SLNB 30 or more days after diagnosis and 37% of positive sentinel lymph nodes were at 30 or more days. No differences in sex, anatomic site, or histopathologic features were identified between the 2 groups. There was no difference in melanoma-specific survival or disease-free survival between those undergoing early or delayed SLNB. Examination of MSLT-1 trial data similarly demonstrated no difference in survival outcomes. This, the largest study on this subject to date, found no adverse impact on long-term clinical outcomes of patients due to delay of SLNB beyond 30 days. The MSLT-1 data confirm this result. Patients can be reassured that if the operation is performed 30 or more days after diagnosis, it will not cause harm.

The Expression Quantitative Trait Loci in Immune Pathways and their Effect on Cutaneous Melanoma Prognosis.

The identification of personalized germline markers with biologic relevance for the prediction of cutaneous melanoma prognosis is highly demanded but to date, it has been largely unsuccessful. As melanoma progression is controlled by host immunity, here we present a novel approach interrogating immunoregulatory pathways using the genome-wide maps of expression quantitative trait loci (eQTL) to reveal biologically relevant germline variants modulating cutaneous melanoma outcomes. Using whole genome eQTL data from a healthy population, we identified 385 variants significantly impacting the expression of 268 immune-relevant genes. The 40 most significant eQTLs were tested in a prospective cohort of 1,221 patients with cutaneous melanoma for their association with overall (OS) and recurrence-free survival using Cox regression models. We identified highly significant associations with better melanoma OS for rs6673928, impacting IL19 expression (HR, 0.56; 95% CI, 0.41-0.77; P = 0.0002) and rs6695772, controlling the expression of BATF3 (HR, 1.64; 95% CI, 1.19-2.24; P = 0.0019). Both associations map in the previously suspected melanoma prognostic locus at 1q32. Furthermore, we show that their combined effect on melanoma OS is substantially enhanced reaching the level of clinical applicability (HR, 1.92; 95% CI, 1.43-2.60; P = 2.38e-5). Our unique approach of interrogating lymphocyte-specific eQTLs reveals novel and biologically relevant immunomodulatory eQTL predictors of cutaneous melanoma prognosis that are independent of current histopathologic markers. The significantly enhanced combined effect of identified eQTLs suggests the personalized utilization of both SNPs in a clinical setting, strongly indicating the promise of the proposed design for the discovery of prognostic or risk germline markers in other cancers. Clin Cancer Res; 22(13); 3268-80. ©2016 AACR.

Risk factors and outcomes of cutaneous melanoma in women less than 50 years of age

Melanoma is the fifth most common cancer in the United States, with recent reports indicating increasing incidence among young women. This study sought to investigate histopathology, staging, risk factors, and outcomes of cutaneous melanoma in women younger than 50 years. All female patients aged up to 49 years with biopsy-proven diagnosis of melanoma between 1988 and 2012 were included. Patients with a follow-up of less than 2 years were excluded. A total of 462 patients were identified, with mean age of 34.7 years. Invasive melanoma was less common in women 19 years of age or younger (P < .0008). Positive sentinel node status (P < .008), recurrence rates, metastatic disease (P < .001), and death rates (P < .008) were higher for women ages 40 to 49 years. The 41 patients with a pregnancy-associated melanoma had a significantly worse prognosis in comparison with a control group of nonpregnant patients, with a 9-fold increase in recurrence (P < .001), 7-fold increase in metastasis (P = .03) and 5-fold increase in mortality (P = .06). This was a retrospective study. The increasing incidence of melanoma for women younger than 50 years suggests that regular skin checks and self-examinations are warranted. In addition, in women given the diagnosis of melanoma during or within 1 year after childbirth, regular follow-up and monitoring for recurrence are recommended.

Germline determinants of clinical outcome of cutaneous melanoma.

Cutaneous melanoma (CM) is the most lethal form of skin cancer. Despite the constant increase in melanoma incidence, which is in part due to incremental advances in early diagnostic modalities, mortality rates have not improved over the last decade and for advanced stages remain steadily high. While conventional prognostic biomarkers currently in use find significant utility for predicting overall general survival probabilities, they are not sensitive enough for a more personalized clinical assessment on an individual level. In recent years, the advent of genomic technologies has brought the promise of identification of germline DNA alterations that may associate with CM outcomes and hence represent novel biomarkers for clinical utilization. This review attempts to summarize the current state of knowledge of germline genetic factors studied for their impact on melanoma clinical outcomes. We also discuss ongoing problems and hurdles in validating such surrogates, and we also project future directions in discovery of more powerful germline genetic factors with clinical utility in melanoma prognostication.

XPC (A2920C), XPF (T30028C), TP53 (Arg72Pro), and GSTP1 (Ile105Val) polymorphisms in prognosis of cutaneous melanoma.

This study aimed to evaluate whether XPC A2920C, XPF T30028C, TP53 Arg72Pro, and GSTP1 Ile105Val polymorphisms alter outcomes of cutaneous melanoma (CM) patients. DNA from 237 CM patients seen at the University of Campinas Teaching Hospital from April 2000 to February 2014 was analyzed by polymerase chain reaction and restriction fragment length polymorphism assays. The prognostic impact of genotypes of polymorphisms on progression-free survival (PFS) and overall survival (OS) of CM patients were examined using the Kaplan-Meier probability estimates and univariate and multivariate Cox regression analyses. At 60months of follow-up, shorter PFS and OS were seen in patients with XPF CC genotype (48.9 vs. 66.7%, P = 0.002; 77.9 vs. 83.5%, P = 0.006, respectively) and XPF CC + TP53 ArgArg (43.6 vs. 65.9%, P = 0.007; 71.6 vs. 84.8%, P = 0.006, respectively) compared with those with remaining genotypes (Kaplan-Meier estimates). Patients with XPF CC (hazard ratio (HR) 2.45, P = 0.002; HR 3.77, P = 0.005) and XPF CC + TP53 ArgArg (HR 2.67, P = 0.009; HR 4.04, P = 0.03) genotypes had more chance to present tumor progression in univariate and multivariate analyses, whereas patients with XPF CC (HR 2.78, P = 0.009) and XPF CC + TP53 ArgArg (HR 3.84, P = 0.01) genotypes were under greater risk of progressing to death in univariate analysis, compared with those with the remaining genotypes. The data suggest, for the first time, that inherited abnormalities in DNA repair pathway related to XPF 30028C and TP53 Arg72Pro polymorphisms act as prognostic factors for PFS and OS of CM patients.