Acceptability and appropriateness of a risk-tailored organised melanoma screening program: Qualitative interviews with key informants.

INTRODUCTION: In Australia, opportunistic screening (occurring as skin checks) for the early detection of melanoma is common, and overdiagnosis is a recognised concern. Risk-tailored cancer screening is an approach to cancer control that aims to provide personalised screening tailored to individual risk. This study aimed to explore the views of key informants in Australia on the acceptability and appropriateness of risk-tailored organised screening for melanoma, and to identify barriers, facilitators and strategies to inform potential future implementation. Acceptability and appropriateness are crucial, as successful implementation will require a change of practice for clinicians and consumers. METHODS: This was a qualitative study using semi-structured interviews. Key informants were purposively selected to ensure expertise in melanoma early detection and screening, prioritising senior or executive perspectives. Consumers were expert representatives. Data were analysed deductively using the Tailored Implementation for Chronic Diseases (TICD) checklist. RESULTS: Thirty-six participants were interviewed (10 policy makers; 9 consumers; 10 health professionals; 7 researchers). Key informants perceived risk-tailored screening for melanoma to be acceptable and appropriate in principle. Barriers to implementation included lack of trial data, reluctance for low-risk groups to not screen, variable skill level in general practice, differing views on who to conduct screening tests, confusing public health messaging, and competing health costs. Key facilitators included the perceived opportunity to improve health equity and the potential cost-effectiveness of a risk-tailored screening approach. A range of implementation strategies were identified including strengthening the evidence for cost-effectiveness, engaging stakeholders, developing pathways for people at low risk, evaluating different risk assessment criteria and screening delivery models and targeted public messaging. CONCLUSION: Key informants were supportive in principle of risk-tailored melanoma screening, highlighting important next steps. Considerations around risk assessment, policy and modelling the costs of current verses future approaches will help inform possible future implementation of risk-tailored population screening for melanoma.

The landscape of genomic structural variation in Indigenous Australians.

Indigenous Australians harbour rich and unique genomic diversity. However, Aboriginal and Torres Strait Islander ancestries are historically under-represented in genomics research and almost completely missing from reference datasets1-3. Addressing this representation gap is critical, both to advance our understanding of global human genomic diversity and as a prerequisite for ensuring equitable outcomes in genomic medicine. Here we apply population-scale whole-genome long-read sequencing4 to profile genomic structural variation across four remote Indigenous communities. We uncover an abundance of large insertion-deletion variants (20-49 bp; n = 136,797), structural variants (50 b-50 kb; n = 159,912) and regions of variable copy number (>50 kb; n = 156). The majority of variants are composed of tandem repeat or interspersed mobile element sequences (up to 90%) and have not been previously annotated (up to 62%). A large fraction of structural variants appear to be exclusive to Indigenous Australians (12% lower-bound estimate) and most of these are found in only a single community, underscoring the need for broad and deep sampling to achieve a comprehensive catalogue of genomic structural variation across the Australian continent. Finally, we explore short tandem repeats throughout the genome to characterize allelic diversity at 50 known disease loci5, uncover hundreds of novel repeat expansion sites within protein-coding genes, and identify unique patterns of diversity and constraint among short tandem repeat sequences. Our study sheds new light on the dimensions and dynamics of genomic structural variation within and beyond Australia.

Follow-up assessment of sleep-related symptoms in patients after treatment for cancer: responses to continuous positive airway pressure treatment for co-morbid obstructive sleep apnoea.

PURPOSE: To assess changes in sleep-related symptoms in patients with breast cancer, endometrial cancer and melanoma previously examined for sleep-related symptoms and the presence of PSG (polysomnography)-determined OSA, ≥ 3 years post-treatment; and to evaluate how CPAP treatment affects sleep-related symptoms in patients previously diagnosed with OSA. METHODS: Patients initially recruited from breast cancer, endometrial cancer, and melanoma follow-up clinics at Westmead Hospital (Sydney, Australia) participated in this questionnaire-based study. Demographic and change in cancer status data were collected at follow-up. Patients completed the Pittsburgh Sleep Quality Index [poor sleep quality, PSQITOTAL ≥ 5au], Insomnia Severity Index, Epworth Sleepiness Scale and Functional Outcomes of Sleep Questionnaire; with ΔPSQITOTAL ≥ 3au indicating a clinically meaningful change in sleep quality over follow-up. PSG-determined OSA was confirmed using the apnoea-hypopnoea index. CPAP compliance was determined via self-report (CPAP compliant, CPAP; not compliant, non-CPAP). Logistic regression models determined if changes in cancer status, AHI, cancer subgroup or CPAP treatment was predictive of ΔPSQITOTAL ≥ 3 au and p < 0.05 indicated statistical significance. RESULTS: The 60 patients recruited had breast cancer (n = 22), endometrial cancer (n = 15), and melanoma (n = 23). Cancer subgroups were similarly aged, and all had median follow-up PSQITOTAL scores ≥ 5au; breast cancer patients scoring the highest (p < 0.05). The CPAP group had significantly reduced PSQITOTAL scores (p = 0.02) at follow-up, unlike the non-CPAP group. Cancer subgroups had similar median ISITOTAL, ESSTOTAL and FOSQ-10TOTAL scores at follow-up, regardless of CPAP treatment. There were no significant predictors of ΔPSQITOTAL ≥ 3 au at follow-up. CONCLUSION: Sleep-related symptoms persist in patients with cancer ≥ 3 years after treatment, although these symptoms improve with CPAP. Future studies should evaluate how CPAP affects survival outcomes in cancer patients with comorbid OSA.

Uncovering the complex relationship between balding, testosterone and skin cancers in men.

Male-pattern baldness (MPB) is related to dysregulation of androgens such as testosterone. A previously observed relationship between MPB and skin cancer may be due to greater exposure to ultraviolet radiation or indicate a role for androgenic pathways in the pathogenesis of skin cancers. We dissected this relationship via Mendelian randomization (MR) analyses, using genetic data from recent male-only meta-analyses of cutaneous melanoma (12,232 cases; 20,566 controls) and keratinocyte cancers (KCs) (up to 17,512 cases; >100,000 controls), followed by stratified MR analysis by body-sites. We found strong associations between MPB and the risk of KC, but not with androgens, and multivariable models revealed that this relationship was heavily confounded by MPB single nucleotide polymorphisms involved in pigmentation pathways. Site-stratified MR analyses revealed strong associations between MPB with head and neck squamous cell carcinoma and melanoma, suggesting that sun exposure on the scalp, rather than androgens, is the main driver. Men with less hair covering likely explains, at least in part, the higher incidence of melanoma in men residing in countries with high ambient UV.

ACEMID cohort study: protocol of a prospective cohort study using 3D total body photography for melanoma imaging and diagnosis.

INTRODUCTION: Three-dimensional (3D) total body photography may improve early detection of melanoma and facilitate surveillance, leading to better prognosis and lower healthcare costs. The Australian Centre of Excellence in Melanoma Imaging and Diagnosis (ACEMID) cohort study will assess long-term outcomes from delivery of a precision strategy of monitoring skin lesions using skin surface imaging technology embedded into health services across Australia. METHODS AND ANALYSIS: A prospective cohort study will enrol 15 000 participants aged 18 years and above, across 15 Australian sites. Participants will attend study visits according to their melanoma risk category: very high risk, high risk or low/average risk, every 6, 12 and 24 months, respectively, over 3 years. Participants will undergo 3D total body photography and dermoscopy imaging at study visits. A baseline questionnaire will be administered to collect sociodemographic, phenotypic, quality of life and sun behaviour data. A follow-up questionnaire will be administered every 12 months to obtain changes in sun behaviour and quality of life. A saliva sample will be collected at the baseline visit from a subsample. ETHICS AND DISSEMINATION: The ACEMID cohort study was approved by the Metro South Health Human Research Ethics Committee (approval number: HREC/2019/QMS/57206) and the University of Queensland Human Research Ethics Committee (approval number: 2019003077). The findings will be reported through peer-reviewed and lay publications and presentations at conferences. TRIAL REGISTRATION NUMBER: ACTRN12619001706167.

InterMEL: An international biorepository and clinical database to uncover predictors of survival in early-stage melanoma.

INTRODUCTION: We are conducting a multicenter study to identify classifiers predictive of disease-specific survival in patients with primary melanomas. Here we delineate the unique aspects, challenges, and best practices for optimizing a study of generally small-sized pigmented tumor samples including primary melanomas of at least 1.05mm from AJTCC TNM stage IIA-IIID patients. We also evaluated tissue-derived predictors of extracted nucleic acids' quality and success in downstream testing. This ongoing study will target 1,000 melanomas within the international InterMEL consortium. METHODS: Following a pre-established protocol, participating centers ship formalin-fixed paraffin embedded (FFPE) tissue sections to Memorial Sloan Kettering Cancer Center for the centralized handling, dermatopathology review and histology-guided coextraction of RNA and DNA. Samples are distributed for evaluation of somatic mutations using next gen sequencing (NGS) with the MSK-IMPACTTM assay, methylation-profiling (Infinium MethylationEPIC arrays), and miRNA expression (Nanostring nCounter Human v3 miRNA Expression Assay). RESULTS: Sufficient material was obtained for screening of miRNA expression in 683/685 (99%) eligible melanomas, methylation in 467 (68%), and somatic mutations in 560 (82%). In 446/685 (65%) cases, aliquots of RNA/DNA were sufficient for testing with all three platforms. Among samples evaluated by the time of this analysis, the mean NGS coverage was 249x, 59 (18.6%) samples had coverage below 100x, and 41/414 (10%) failed methylation QC due to low intensity probes or insufficient Meta-Mixed Interquartile (BMIQ)- and single sample (ss)- Noob normalizations. Six of 683 RNAs (1%) failed Nanostring QC due to the low proportion of probes above the minimum threshold. Age of the FFPE tissue blocks (p<0.001) and time elapsed from sectioning to co-extraction (p = 0.002) were associated with methylation screening failures. Melanin reduced the ability to amplify fragments of 200bp or greater (absent/lightly pigmented vs heavily pigmented, p<0.003). Conversely, heavily pigmented tumors rendered greater amounts of RNA (p<0.001), and of RNA above 200 nucleotides (p<0.001). CONCLUSION: Our experience with many archival tissues demonstrates that with careful management of tissue processing and quality control it is possible to conduct multi-omic studies in a complex multi-institutional setting for investigations involving minute quantities of FFPE tumors, as in studies of early-stage melanoma. The study describes, for the first time, the optimal strategy for obtaining archival and limited tumor tissue, the characteristics of the nucleic acids co-extracted from a unique cell lysate, and success rate in downstream applications. In addition, our findings provide an estimate of the anticipated attrition that will guide other large multicenter research and consortia.

Association of germline variants in telomere maintenance genes (POT1, TERF2IP, ACD, and TERT) with spitzoid morphology in familial melanoma: A multi-center case series.

Background: Spitzoid morphology in familial melanoma has been associated with germline variants in POT1, a telomere maintenance gene (TMG), suggesting a link between telomere biology and spitzoid differentiation. Objective: To assess if familial melanoma cases associated with germline variants in TMG (POT1, ACD, TERF2IP, and TERT) commonly exhibit spitzoid morphology. Methods: In this case series, melanomas were classified as having spitzoid morphology if at least 3 of 4 dermatopathologists reported this finding in ≥25% of tumor cells. Logistic regression was used to calculate odds ratios (OR) of spitzoid morphology compared to familial melanomas from unmatched noncarriers that were previously reviewed by a National Cancer Institute dermatopathologist. Results: Spitzoid morphology was observed in 77% (23 of 30), 75% (3 of 4), 50% (2 of 4), and 50% (1 of 2) of melanomas from individuals with germline variants in POT1, TERF2IP, ACD, and TERT, respectively. Compared to noncarriers (n = 139 melanomas), POT1 carriers (OR = 225.1, 95% confidence interval: 51.7-980.5; P < .001) and individuals with TERF2IP, ACD, and TERT variants (OR = 82.4, 95% confidence interval: 21.3-494.6; P < .001) had increased odds of spitzoid morphology. Limitations: Findings may not be generalizable to nonfamilial melanoma cases. Conclusion: Spitzoid morphology in familial melanoma could suggest germline alteration of TMG.

Cell death and barrier disruption by clinically used iodine concentrations.

Povidone-iodine (PVP-I) inactivates a broad range of pathogens. Despite its widespread use over decades, the safety of PVP-I remains controversial. Its extended use in the current SARS-CoV-2 virus pandemic urges the need to clarify safety features of PVP-I on a cellular level. Our investigation in epithelial, mesothelial, endothelial, and innate immune cells revealed that the toxicity of PVP-I is caused by diatomic iodine (I2), which is rapidly released from PVP-I to fuel organic halogenation with fast first-order kinetics. Eukaryotic toxicity manifests at below clinically used concentrations with a threshold of 0.1% PVP-I (wt/vol), equalling 1 mM of total available I2 Above this threshold, membrane disruption, loss of mitochondrial membrane potential, and abolition of oxidative phosphorylation induce a rapid form of cell death we propose to term iodoptosis. Furthermore, PVP-I attacks lipid rafts, leading to the failure of tight junctions and thereby compromising the barrier functions of surface-lining cells. Thus, the therapeutic window of PVP-I is considerably narrower than commonly believed. Our findings urge the reappraisal of PVP-I in clinical practice to avert unwarranted toxicity whilst safeguarding its benefits.

The MC1R r allele does not increase melanoma risk in MITF E318K carriers.

BACKGROUND: Population-wide screening for melanoma is not cost-effective, but genetic characterization could facilitate risk stratification and targeted screening. Common Melanocortin-1 receptor (MC1R) red hair colour (RHC) variants and Microphthalmia-associated transcription factor (MITF) E318K separately confer moderate melanoma susceptibility, but their interactive effects are relatively unexplored. OBJECTIVES: To evaluate whether MC1R genotypes differentially affect melanoma risk in MITF E318K+ vs. E318K- individuals. MATERIALS AND METHODS: Melanoma status (affected or unaffected) and genotype data (MC1R and MITF E318K) were collated from research cohorts (five Australian and two European). In addition, RHC genotypes from E318K+ individuals with and without melanoma were extracted from databases (The Cancer Genome Atlas and Medical Genome Research Bank, respectively). χ2 and logistic regression were used to evaluate RHC allele and genotype frequencies within E318K+/- cohorts depending on melanoma status. Replication analysis was conducted on 200 000 general-population exomes (UK Biobank). RESULTS: The cohort comprised 1165 MITF E318K- and 322 E318K+ individuals. In E318K- cases MC1R R and r alleles increased melanoma risk relative to wild type (wt), P < 0.001 for both. Similarly, each MC1R RHC genotype (R/R, R/r, R/wt, r/r and r/wt) increased melanoma risk relative to wt/wt (P < 0.001 for all). In E318K+ cases, R alleles increased melanoma risk relative to the wt allele [odds ratio (OR) 2.04 (95% confidence interval 1.67-2.49); P = 0.01], while the r allele risk was comparable with the wt allele [OR 0.78 (0.54-1.14) vs. 1.00, respectively]. E318K+ cases with the r/r genotype had a lower but not significant melanoma risk relative to wt/wt [OR 0.52 (0.20-1.38)]. Within the E318K+ cohort, R genotypes (R/R, R/r and R/wt) conferred a significantly higher risk compared with non-R genotypes (r/r, r/wt and wt/wt) (P < 0.001). UK Biobank data supported our findings that r did not increase melanoma risk in E318K+ individuals. CONCLUSIONS: RHC alleles/genotypes modify melanoma risk differently in MITF E318K- and E318K+ individuals. Specifically, although all RHC alleles increase risk relative to wt in E318K- individuals, only MC1R R increases melanoma risk in E318K+ individuals. Importantly, in the E318K+ cohort the MC1R r allele risk is comparable with wt. These findings could inform counselling and management for MITF E318K+ individuals.

Screening for obstructive sleep apnoea in post-treatment cancer patients.

BACKGROUND AND AIMS: For cancer patients, comorbid obstructive sleep apnea (OSA) poses additional risk to their surgical/anaesthetic outcomes, quality of life, and survival. However, OSA screening is not well-established in oncology settings. We tested two screening tools (STOP-Bang questionnaire [SBQ] and the at-home monitoring device, ApneaLink™Air), for predicting polysomnography (PSG) confirmed OSA in post-treatment cancer patients. METHODS: Breast (n = 56), endometrial (n = 37) and melanoma patients (n = 50) were recruited from follow-up clinics at Westmead Hospital (Sydney, Australia). All underwent overnight PSG, 137 completed SBQ, and 99 completed ApneaLink™Air. Positive (PPV) and negative (NPV) predictive values for PSG-determined moderate-to-severe OSA and severe OSA, were calculated using an SBQ threshold ≥3 au and ApneaLink™Air apnoea-hypopnea index thresholds of ≥10, ≥15 and ≥30 events/h. RESULTS: Both SBQ and ApneaLink™Air had high NPVs (92.7% and 85.2%-95.6% respectively) for severe OSA, but NPVs were lower for moderate-to-severe OSA (69.1% and 59.1%-75.5%, respectively). PPV for both tools were relatively low (all <73%). Combining both tools did not improve screening performance. CONCLUSIONS: These screening tools may help identify cancer patients without severe OSA, but both are limited in identifying those with moderate-to-severe or severe OSA. PSG remains optimal for adequately identifying and managing comorbid OSA in cancer patients.

Genomic and proteomic findings in early melanoma and opportunities for early diagnosis.

Overdiagnosis of early melanoma is a significant problem. Due to subtle unique and overlapping clinical and histological criteria between pigmented lesions and the risk of mortality from melanoma, some benign pigmented lesions are diagnosed as melanoma. Although histopathology is the gold standard to diagnose melanoma, there is a demand to find alternatives that are more accurate and cost-effective. In the current "omics" era, there is gaining interest in biomarkers to help diagnose melanoma early and to further understand the mechanisms driving tumor progression. Genomic investigations have attempted to differentiate malignant melanoma from benign pigmented lesions. However, genetic biomarkers of early melanoma diagnosis have not yet proven their value in the clinical setting. Protein biomarkers may be more promising since they directly influence tissue phenotype, a result of by-products of genomic mutations, posttranslational modifications and environmental factors. Uncovering relevant protein biomarkers could increase confidence in their use as diagnostic signatures. Currently, proteomic investigations of melanoma progression from pigmented lesions are limited. Studies have previously characterised the melanoma proteome from cultured cell lines and clinical samples such as serum and tissue. This has been useful in understanding how melanoma progresses into metastasis and development of resistance to adjuvant therapies. Currently, most studies focus on metastatic melanoma to find potential drug therapy targets, prognostic factors and markers of resistance. This paper reviews recent advancements in the genomics and proteomic fields and reports potential avenues, which could help identify and differentiate melanoma from benign pigmented lesions and prevent the progression of melanoma.

MSGANet-RAV: A multiscale guided attention network for artery-vein segmentation and classification from optic disc and retinal images.

BACKGROUND: Retinal and optic disc images are used to assess changes in the retinal vasculature. These can be changes associated with diseases such as diabetic retinopathy and glaucoma or induced using ophthalmodynamometry to measure arterial and venous pressure. Key steps toward automating the assessment of these changes are the segmentation and classification of the veins and arteries. However, such segmentation and classification are still required to be manually labelled by experts. Such automated labelling is challenging because of the complex morphology, anatomical variations, alterations due to disease and scarcity of labelled data for algorithm development. We present a deep machine learning solution called the multiscale guided attention network for retinal artery and vein segmentation and classification (MSGANet-RAV). METHODS: MSGANet-RAV was developed and tested on 383 colour clinical optic disc images from LEI-CENTRAL, constructed in-house and 40 colour fundus images from the AV-DRIVE public dataset. The datasets have a mean optic disc occupancy per image of 60.6% and 2.18%, respectively. MSGANet-RAV is a U-shaped encoder-decoder network, where the encoder extracts multiscale features, and the decoder includes a sequence of self-attention modules. The self-attention modules explore, guide and incorporate vessel-specific structural and contextual feature information to segment and classify central optic disc and retinal vessel pixels. RESULTS: MSGANet-RAV achieved a pixel classification accuracy of 93.15%, sensitivity of 92.19%, and specificity of 94.13% on LEI-CENTRAL, outperforming several reference models. It similarly performed highly on AV-DRIVE with an accuracy, sensitivity and specificity of 95.48%, 93.59% and 97.27%, respectively. CONCLUSION: The results show the efficacy of MSGANet-RAV for identifying central optic disc and retinal arteries and veins. The method can be used in automated systems designed to assess vascular changes in retinal and optic disc images quantitatively.

Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes.

Melanoma is a cancer of melanocytes, with multiple subtypes based on body site location. Cutaneous melanoma is associated with skin exposed to ultraviolet radiation; uveal melanoma occurs in the eyes; mucosal melanoma occurs in internal mucous membranes; and acral melanoma occurs on the palms, soles, and nail beds. Here, we present the largest whole-genome sequencing study of melanoma to date, with 570 tumors profiled, as well as methylation and RNA sequencing for subsets of tumors. Uveal melanoma is genomically distinct from other melanoma subtypes, harboring the lowest tumor mutation burden and with significantly mutated genes in the G-protein signaling pathway. Most cutaneous, acral, and mucosal melanomas share alterations in components of the MAPK, PI3K, p53, p16, and telomere pathways. However, the mechanism by which these pathways are activated or inactivated varies between melanoma subtypes. Additionally, we identify potential novel germline predisposition genes for some of the less common melanoma subtypes. SIGNIFICANCE: This is the largest whole-genome analysis of melanoma to date, comprehensively comparing the genomics of the four major melanoma subtypes. This study highlights both similarities and differences between the subtypes, providing insights into the etiology and biology of melanoma. This article is highlighted in the In This Issue feature, p. 2711.

SurvBenchmark: comprehensive benchmarking study of survival analysis methods using both omics data and clinical data.

Survival analysis is a branch of statistics that deals with both the tracking of time and the survival status simultaneously as the dependent response. Current comparisons of survival model performance mostly center on clinical data with classic statistical survival models, with prediction accuracy often serving as the sole metric of model performance. Moreover, survival analysis approaches for censored omics data have not been thoroughly investigated. The common approach is to binarize the survival time and perform a classification analysis. Here, we develop a benchmarking design, SurvBenchmark, that evaluates a diverse collection of survival models for both clinical and omics data sets. SurvBenchmark not only focuses on classical approaches such as the Cox model but also evaluates state-of-the-art machine learning survival models. All approaches were assessed using multiple performance metrics; these include model predictability, stability, flexibility, and computational issues. Our systematic comparison design with 320 comparisons (20 methods over 16 data sets) shows that the performances of survival models vary in practice over real-world data sets and over the choice of the evaluation metric. In particular, we highlight that using multiple performance metrics is critical in providing a balanced assessment of various models. The results in our study will provide practical guidelines for translational scientists and clinicians, as well as define possible areas of investigation in both survival technique and benchmarking strategies.

Cross-Platform Omics Prediction procedure: a statistical machine learning framework for wider implementation of precision medicine.

In this modern era of precision medicine, molecular signatures identified from advanced omics technologies hold great promise to better guide clinical decisions. However, current approaches are often location-specific due to the inherent differences between platforms and across multiple centres, thus limiting the transferability of molecular signatures. We present Cross-Platform Omics Prediction (CPOP), a penalised regression model that can use omics data to predict patient outcomes in a platform-independent manner and across time and experiments. CPOP improves on the traditional prediction framework of using gene-based features by selecting ratio-based features with similar estimated effect sizes. These components gave CPOP the ability to have a stable performance across datasets of similar biology, minimising the effect of technical noise often generated by omics platforms. We present a comprehensive evaluation using melanoma transcriptomics data to demonstrate its potential to be used as a critical part of a clinical screening framework for precision medicine. Additional assessment of generalisation was demonstrated with ovarian cancer and inflammatory bowel disease studies.

Landscape of mutations in early stage primary cutaneous melanoma: An InterMEL study.

It is unclear why some melanomas aggressively metastasize while others remain indolent. Available studies employing multi-omic profiling of melanomas are based on large primary or metastatic tumors. We examine the genomic landscape of early-stage melanomas diagnosed prior to the modern era of immunological treatments. Untreated cases with Stage II/III cutaneous melanoma were identified from institutions throughout the United States, Australia and Spain. FFPE tumor sections were profiled for mutation, methylation and microRNAs. Preliminary results from mutation profiling and clinical pathologic correlates show the distribution of four driver mutation sub-types: 31% BRAF; 18% NRAS; 21% NF1; 26% Triple Wild Type. BRAF mutant tumors had younger age at diagnosis, more associated nevi, more tumor infiltrating lymphocytes, and fewer thick tumors although at generally more advanced stage. NF1 mutant tumors were frequent on the head/neck in older patients with severe solar elastosis, thicker tumors but in earlier stages. Triple Wild Type tumors were predominantly male, frequently on the leg, with more perineural invasion. Mutations in TERT, TP53, CDKN2A and ARID2 were observed often, with TP53 mutations occurring particularly frequently in the NF1 sub-type. The InterMEL study will provide the most extensive multi-omic profiling of early-stage melanoma to date. Initial results demonstrate a nuanced understanding of the mutational and clinicopathological landscape of these early-stage tumors.