<p>Supplementary Table S1. Probability ratios (95% CI) for disagreement between self-reported and clinically-measured hair, eye and skin color phenotype.</p>

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.

<p>Supplementary Figure S1: The 30 body sites for which separate counts of melanocytic nevi were made.</p>

Introduction: Cutaneous melanoma (CM) is one of the most aggressive types of skin cancer, with a poor prognosis for advanced stages. Despite the advances in immunotherapy (IO) treatment, robust predictive biomarkers are still required. The aim of this study was to identify a prognostic and predictive protein-based signature for advanced CM. Methods: A training cohort of 142 pretreatment tumor samples from 71 patients with metastatic CM treated with IO (anti-PD-1) and an independent validation cohort from 67 patients with stage III treatment-naïve CM were analyzed by data-independent acquisition mass spectrometry (DIA-MS). Survival analysis based initially on univariate regression and subsequently on 100 runs of 20-fold cross-validation of multivariate Cox regression with Least Absolute Shrinkage and Selection Operator (LASSO) was performed to obtain a reduced list of candidate proteins associated with melanoma-specific survival. A risk score was built from the final six proteins. The prognostic ability of this 6-protein signature for melanoma-specific survival was demonstrated by a time-dependent receiver operating characteristic curve (AUROC) and validated by four independent datasets. The predictive ability of the 6-protein signature was also explored in the training dataset using response to IO as the outcome of interest. Finally, differential expression analyses were conducted on the training data to identify the top proteins associated with response to IO. Proteins that were highly correlated (Pearson R2 >0.9) with the 6-protein signature were identified and subjected to pathway enrichment analysis (PEA). Results: Proteomic analyses identified 4298 and 4577 proteins in the training and validation cohorts respectively, with 81.1% overlap between the two sets. Using LASSO multivariate Cox modeling, six proteins were identified in the training cohort, from which a risk score was calculated that dichotomized patients into high- and low-risk groups (Hazard ratio (HR) 2.7, 95% confidence interval (CI) 1.9-3.9, and, AUROC 0.86). The 6-protein signature’s prognostic performance was validated using the RNAseq dataset from the same training cohort (HR 2.7, p<0.001), a second RNASeq dataset from The Cancer Genome Atlas (HR 1.7, p<0.001), a single-cell RNASeq dataset from patients treated with IO (HR 1.2, p<0.001) and finally a proteomic dataset in an independent cohort (stage III treatment-naïve CM) (HR 2.4, p<0.001). The 6-protein signature was also associated with response to IO (HR 2.3, p=0.005). PEA showed that the highly correlated proteins were mostly related to DNA repair and DNA metabolic pathways. PEA revealed activation of immune-related pathways in patients who achieved a good response to IO. Conclusion: A 6-protein signature identified a sub-group of patients with advanced CM who are at higher risk of progression on IO and death from melanoma. Citation Format: Srikanth Manda, Adel T. Aref, Erin K. Sykes, Steven G. Williams, Jennifer M. Koh, Erin M. Humphries, Daniel Bucio-Noble, Daniela Lee-Smith, Natasha Lucas, Dylan Xavier, Alexander Menzies, Ines Da Silva, Felicity Newell, Rosemary Balleine, Peter G. Hains, Graham Mann, Phil J. Robinson, Georgina V. Long, James Wilmott, Qing Zhong, Richard A. Scolyer, Roger R. Reddel. A six-protein signature predicts response and survival in patients with advanced cutaneous melanoma treated with immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5479.

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.

Introduction Australia has the highest incidence of melanoma in the world with variable care provided by a diverse range of clinicians. Clinical quality registries aim to identify these variations in care and provide anonymised, benchmarked feedback to clinicians and institutions to improve patient outcomes. The Australian Melanoma Clinical Outcomes Registry (MelCOR) aims to collect population-wide, clinical-level data for the early management of cutaneous melanoma and provide anonymised feedback to healthcare providers.Methods and analysis A modified Delphi process will be undertaken to identify key clinical quality indicators for inclusion in the MelCOR pilot. MelCOR will prospectively collect data relevant to these quality indicators, initially for all people over the age of 18 years living in Victoria and Queensland with a melanoma diagnosis confirmed by histopathology, via a two-stage recruitment and consent process. In stage 1, existing State-based cancer registries contact the treating clinician and provide an opportunity for them to opt themselves or their patients out of direct contact with MelCOR. After stage 1, re-identifiable clinical data are provided to the MelCOR under a waiver of consent. In stage 2, the State-based cancer registry will approach the patient directly and invite them to opt in to MelCOR and share identifiable data. If a patient elects to opt in, MelCOR will be able to contact patients directly to collect patient-reported outcome measures. Aggregated data will be used to provide benchmarked, comparative feedback to participating institutions/clinicians.Ethics and dissemination Following the successful collection of pilot data, the feasibility of an Australia-wide roll out will be evaluated. Key quality indicator data will be the core of the MelCOR dataset, with additional data points added later. Annual reports will be issued, first to the relevant stakeholders followed by the public. MelCOR is approved by the Alfred Ethics Committee (58280/127/20).

Background Clinical quality registries aim to identify significant variations in care and provide anonymised feedback to institutions to improve patient outcomes. Thirty-six Australian organisations with an interest in melanoma, raised funds through three consecutive Melanoma Marches, organised by Melanoma Institute Australia, to create a national Melanoma Clinical Outcomes Registry (MelCOR). This study aimed to formally develop valid clinical quality indicators for the diagnosis and early management of cutaneous melanoma as an important step in creating the registry. Methods Potential clinical quality indicators were identified by examining the literature, including Australian and international melanoma guidelines, and by consulting with key melanoma and registry opinion leaders. A modified two-round Delphi survey method was used, with participants invited from relevant health professions routinely managing melanoma as well as relevant consumer organisations. Results Nineteen participants completed at least one round of the Delphi process. 12 of 13 proposed clinical quality indictors met the validity criteria. The clinical quality indicators included acceptable biopsy method, appropriate excision margins, standardised pathology reporting, indications for sentinel lymph node biopsy, and involvement of multidisciplinary care and referrals. Conclusion This study provides a multi-stakeholder consensus for important clinical quality indicators that define optimal practice that will now be used in the Australian Melanoma Clinical Outcomes Registry (MelCOR).

Purpose Ataxia–Telangiectasia Mutated ( ATM ) has been implicated in the risk of several cancers, but establishing a causal relationship is often challenging. Although ATM single-nucleotide polymorphisms have been linked to melanoma, few functional alleles have been identified. Therefore, ATM impact on melanoma predisposition is unclear. Methods From 22 American, Australian, and European sites, we collected 2,104 familial, multiple primary (MPM), and sporadic melanoma cases who underwent ATM genotyping via panel, exome, or genome sequencing, and compared the allele frequency (AF) of selected ATM variants classified as loss-of-function (LOF) and variants of uncertain significance (VUS) between this cohort and the gnomAD non-Finnish European (NFE) data set. Results LOF variants were more represented in our study cohort than in gnomAD NFE, both in all (AF = 0.005 and 0.002, OR = 2.6, 95% CI = 1.56–4.11, p < 0.01), and familial + MPM cases (AF = 0.0054 and 0.002, OR = 2.97, p < 0.01). Similarly, VUS were enriched in all (AF = 0.046 and 0.033, OR = 1.41, 95% CI = 1.6–5.09, p < 0.01) and familial + MPM cases (AF = 0.053 and 0.033, OR = 1.63, p < 0.01). In a case–control comparison of two centers that provided 1,446 controls, LOF and VUS were enriched in familial + MPM cases ( p = 0.027, p = 0.018). Conclusion This study, describing the largest multicenter melanoma cohort investigated for ATM germline variants, supports the role of ATM as a melanoma predisposition gene, with LOF variants suggesting a moderate-risk.

The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE [1] partner repository with the dataset identifier PXD025791. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Background: Cancer patients often describe poor sleep quality and sleep disruption as contributors to poor quality of life (QoL). In a cross-sectional study of post-treatment breast, endometrial, and melanoma cancer patients, we used actigraphy to quantify sleep regularity using the sleep regularity index (SRI), and examined relationships with reported sleep symptoms and QoL. Methods: Participants were recruited post-primary treatment (35 diagnosed with breast cancer, 24 endometrial cancer, and 29 melanoma) and wore an actigraphy device for up to 2 weeks and SRI was calculated. Self-report questionnaires for cancer-related QoL [European Organization for Research and Treatment of Cancer EORTC (QLQ-C30)] were completed. Data were compared using analysis of variance (ANOVA) or Chi-Square tests. Multivariate linear regression analysis was used to determine independent variable predictors for questionnaire-derived data. Results: Age distribution was similar between cohorts. Endometrial and breast cancer cohorts were predominantly female, as expected, and body mass index (BMI) was higher in the endometrial cancer cohort, followed by breast and melanoma. There were no differences between tumor groups in: total sleep time, sleep onset latency, bedtime, and SRI (breast 80.9 ± 8.0, endometrial 80.3 ± 12.2, and melanoma 81.4 ± 7.0) (all p > 0.05). A higher SRI was associated with both better functional and symptom scores, including increased global QoL, better physical functioning, less sleepiness and fatigue, better sleep quality, and associated with less nausea/vomiting, dyspnea, and diarrhea (all p < 0.05). Conclusion: In cancer patients post-treatment, greater sleep regularity is associated with increased global QoL, as well as better physical functioning and fewer cancer related symptoms. Improving sleep regularity may improve QoL for cancer patients.

Background: Elevated serum LDH is a poor prognostic factor in pts with MM. It is currently unknown if serum LDH levels correlate with molecular or immune differences in tumors, including LDH expression. We analyzed resected melanoma metastases to identify features that correlate with serum LDH elevation. Methods: Metastases with serum LDH levels measured within 30 days of surgery were included in the study: (1) a TMA of resected stage IV metastases from MD Anderson (MDACC) (n=207); (2) resected stage IV metastases from MDACC with previously acquired RNA-sequencing (RNA-seq) and CD8+ immunohistochemistry (IHC) data (n=24); (3) publicly available data for regional metastases from the melanoma TCGA (n=104) from MDACC and the Melanoma Institute of Australia. IHC was performed for LDHA, LDHB, PTEN, PD-L1, MITF, and Ki67 on the stage IV TMA, and publicly available data for DNA, RNA, and proteins for the TCGA samples were downloaded. Data were analyzed to identify features that differed between tumors with elevated and normal serum LDH levels. TCGA and stage IV tumors expressing the 25% highest and lowest LDHA and LDHB by RNA-seq were also compared. Results: IHC of the stage IV TMA identified no significant associations with serum LDH levels, including tumor LDHA (p=0.69) and LDHB (p=0.93) expression. Serum LDH was elevated in 33.3% of stage IV metastases with RNA-seq data and 21.6 % of TCGA regional metastases, which by Ensemble of Gene Set Enrichment Analyses (EGSEA) correlated with decreased expression of interferon alpha (q=8.26 × 10−14 and q=2.31 × 10−14), interferon gamma (q=9.46 × 10−14 and q=2.34 × 10−19), and inflammatory response (q= 1.26 × 10−20 and q=4.17 × 10−28) gene sets. Fewer (p=0.0464) CD8+ T cells were detected in stage IV tumors from pts with elevated serum LDH. Comparison of stage IV and TCGA tumors with high vs. low LDHA and LDHB mRNA expression levels did not correlate with serum LDH status, but significant enrichment of oxidative phosphorylation (q=6.32 × 10−21 and q=5.69 × 10−19), pyruvate metabolism (q= 7.90 × 10−16 and q=1.78 × 10−14), and citrate cycle (q= 1.51 × 10−06 and q=5.44 × 10−06) gene sets were detected in LDHA-high tumors. Increased LDHB expression correlated with enrichment of citrate cycle (q= 4.04 × 10−16 and q= 1.68 × 10−14), pyruvate metabolism (q= 2.34 × 10−11 and q=1.50 × 10−10), and glycolysis (q= 2.92 × 10−9 and q=1.55 × 10−8) gene sets. Conclusions: Elevated serum LDH levels correlated with decreased expression of immune response genes, but not LDHA or LDHB expression, in melanoma regional and distant metastases. Elevated serum LDH also correlated with decreased CD8+ T cell infiltrates by IHC. LDHA and LDHB expression levels in regional metastases correlated with distinct metabolic pathways, but not serum LDH levels. Citation Format: Fernando Cintra Lopes Carapet, Grant Fischer, Aron Joon, Huiqin Chen, Lauren Haydu, Sandra Lee, Melissa Saul, Savi Appana, John Thompson, Graham Mann, Jennifer McQuade, Alexander Lazar, Michael Tetzlaff, John Kirkwood, Richard Scolyer, Georgina Long, Michael Davies. Analysis of molecular and immune features that correlate with serum lactate dehydrogenase (LDH) levels in patients (pts) with metastatic melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A04.

Multi-color emissive carbon dots (CDs) with intrinsic ternary doping were synthesized by a hydrothermal process from a single precursor, vitamin B1 derivative, thiamine pyrophosphate or ThPP. The origin of the multi-color photoluminescence was ascribed to the hybrid doping (N, S, P) in a carbon framework. The subsequent conjugation of CDs with folic acid (FA) enabled targeted bioimaging and photosensitization of the human melanoma cancer cells, SK-MEL28. The unique excitation-dependent multi-color emission of CD-FA probes allowed wide spectral resolution and targeting for amplified whole cell bioimaging including the nucleus. The photosensitization of cancer cells in the multi-color window was accomplished in a deep tissue cell culture setting. The synthesized CD-FAs showed excellent biocompatibility, photostability, and notably, their cellular targeting with enhanced uptake by folate receptor positive (FR+) cancer cells, SK-MEL28 over folate receptor negative (FR-), HEK293T ones in a co-culture model having both diseased and normal cells. The results demonstrate excellent potential for melanoma diagnostic, mapping and phototherapeutic applications with multi-spectral sensitivity.

Melanoma is a cancer that develops in the melanocytes, the pigment cells of the skin. Melanoma incidence rates, which show how common it is, have been increasing in people with fair skin, with the highest rates in Australia, New Zealand, North America and Europe. In Australia, one in 14 men and one in 24 women will be diagnosed with melanoma during their lifetime. Risk factors for melanoma include sun exposure, sunbed use, the number of moles on the skin, the skin's sensitivity to the sun, the number of freckles, skin colour, eye colour, hair colour, family history and a number of susceptibility genes (genes that place you at higher risk). Melanoma risk prediction models, which combine many individual melanoma risk factors into an overall risk, may be useful in the prevention of melanoma by matching prevention strategies (interventions) to the patient's melanoma risk levels. Many melanoma risk prediction models use self-assessed risk factors because it is quicker and less costly compared to the clinical (medical) assessment of risk factors, but many people underestimate the number of moles they have. This study aims to derive a melanoma risk prediction model, which includes the number of moles on the body and solar lentigines (darker skin patches caused by the sun) as clinically-assessed risk factors, and pigmentation (skin colour) characteristics, sun exposure, family history and history of skin cancer as self-assessed risk factors. The number of moles is the strongest risk factor in the model. The model performs well on discrimination, the model's ability to distinguish between individuals with and without melanoma. In a clinical setting, this model may help clinicians identify patients for targeted prevention strategies based on the patient's melanoma risk. This is a summary of the study: Development and external validation study of a melanoma risk prediction model incorporating clinically assessed naevi and solar lentigines

黑色素瘤是一种在黑素细胞(皮肤的色素细胞)中发生的癌症。黑色素瘤发生率(表示其常见程度)在皮肤白皙人群中增加,其中澳大利亚、新西兰、北美和欧洲的发病率最高。 在澳大利亚,14 名男性中有 1 名和 24 名女性中有 1 名将在其一生中被诊断患有黑色素瘤。黑色素瘤的危险因素包括日晒、日光浴、皮肤上痣的数量、皮肤对阳光的敏感度、雀斑数量、肤色、眼睛颜色、头发颜色、家族史和许多易感基因(使您面临更高风险的基因)。 黑色素瘤风险预测模型(将许多个体黑色素瘤危险因素结合到总体风险中)可能有助于通过匹配预防策略(干预)与患者的黑色素瘤风险水平来预防黑色素瘤。 许多黑色素瘤风险预测模型使用自我评估的危险因素,因为与临床(医学)危险因素评估相比,这样更快且成本更低,但很多人低估了他们的痣数。本研究旨在推导一个黑色素瘤风险预测模型,其中包括身上痣的数量和日光性雀斑痣(阳光引起的深色皮肤斑)作为临床评估的危险因素,以及色素(肤色)特征、日晒、家族史和皮肤癌病史作为自我评估的危险因素。 痣的数量是模型中最强的危险因素。该模型在识别能力(模型区分患有和未患黑色素瘤的个体的能力)方面表现出色。在临床环境中,该模型可能有助于临床医生根据患者的黑色素瘤风险确定适合针对性预防策略的患者。 本摘要涉及研究:一项关于纳入临床评估的痣和日光性雀斑痣的黑色素瘤风险预测模型的开发和外部验证研究

Locoregional relapse of HNSCC accounts for approximately 80% of primary treatment failures (Ridge et al, Cancer Management 2016). The primary source of morbidity and mortality in HNSCC is locoregional progression. Prognosis for pts with locally advanced rHNSCC who have failed chemoradiation therapy is very poor. In pts with recurrent or metastatic disease, the 1-year survival rates after anti-PD-1 therapy (nivolumab[N] or pembrolizumab[P]) was 36% to 37% compared to 17% to 27% after treatment with methotrexate, docetaxel, or cetuximab[C] (Ferris et al, NEJM 2016; Cohen et al, Lancet 2018). In a recent phase 1/2a study of Cetuximab-IR700 photoimmunotherapy (PIT)-treated pts with locoregional rHNSCC, 14 of 30 (47%) pts in the Phase 2a portion of the study were alive at 1 year and the median overall survival was 9.3 months (Cognetti et al, ASCO 2019). Here we seek to further characterize the rHNSCC pts that had survival > 22 months following PIT treatment.

People with melanoma want and need effective interventions for living with fear of cancer recurrence (FCR).

Background: Mucosal melanomas are a rare subtype of melanoma that account for ∼1% of all melanomas. Mucosal melanoma patients often have poor clinical outcomes due to advanced stage at diagnosis and lack of effective systemic drug therapies. In contrast to cutaneous melanomas, mucosal melanomas are rarely BRAF mutant. Identifying recurrently mutated driver genes in mucosal melanoma will open novel opportunities for effective systemic therapies.

Background People at high risk of developing melanoma are usually identified by pigmentary and naevus phenotypes. Objective We examined whether associations of these phenotypes with melanoma risk differed by ambient sun exposure or participant characteristics in two population-based, case-control studies with comparable ancestry but different ambient sun exposure. Methods Data were analysed from 616 cases and 496 controls from the Australian Melanoma Family Study and 2012 cases and 504 controls from the Leeds (UK) case-control study. Questionnaire, interview and dermatological skin examination data were collected using the same measurement protocols. Relative risks were estimated as odds ratios using unconditional logistic regression, adjusted for potential confounders. Results Hair and skin colour were the strongest pigmentary phenotype risk factors. All associations of pigmentary phenotype with melanoma risk were similar across countries. The median number of clinically assessed naevi was approximately three times higher in Australia than Leeds, but the relative risks for melanoma associated with each additional common or dysplastic naevus were higher for Leeds than Australia, especially for naevi on the upper and lower limbs. Higher naevus counts on the head and neck were associated with a stronger relative risk for melanoma for women than men. The two countries had similar relative risks for melanoma based on self-reported naevus density categories, but personal perceptions of naevus number differed by country. There was no consistent evidence of interactions between phenotypes on risk. Conclusions Classifying people at high risk of melanoma based on their number of naevi should ideally take into account their country of residence, type of counts (clinical or self-reported), body site on which the naevus counts are measured and sex. The presence of naevi may be a stronger indicator of a genetic predisposition in the UK than in Australia based on less opportunity for sun exposure to influence naevus development.

AbstractPurpose: BRAF V600E and V600K melanomas have distinct clinicopathologic features, and V600K appear to be less responsive to BRAFi±MEKi. We investigated mechanisms for this and explored whether genotype affects response to immunotherapy. Experimental Design: Pretreatment formalin-fixed paraffin-embedded tumors from patients treated with BRAFi±MEKi underwent gene expression profiling and DNA sequencing. Molecular results were validated using The Cancer Genome Atlas (TCGA) data. An independent cohort of V600E/K patients treated with anti–PD-1 immunotherapy was examined. Results: Baseline tissue and clinical outcome with BRAFi±MEKi were studied in 93 patients (78 V600E, 15 V600K). V600K patients had numerically less tumor regression (median, −31% vs. −52%, P = 0.154) and shorter progression-free survival (PFS; median, 5.7 vs. 7.1 months, P = 0.15) compared with V600E. V600K melanomas had lower expression of the ERK pathway feedback regulator dual-specificity phosphatase 6, confirmed with TCGA data (116 V600E, 17 V600K). Pathway analysis showed V600K had lower expression of ERK and higher expression of PI3K-AKT genes than V600E. Higher mutational load was observed in V600K, with a higher proportion of mutations in PIK3R1 and tumor-suppressor genes. In patients treated with anti–PD-1, V600K (n = 19) had superior outcomes than V600E (n = 84), including response rate (53% vs. 29%, P = 0.059), PFS (median, 19 vs. 2.7 months, P = 0.049), and overall survival (20.4 vs. 11.7 months, P = 0.081). Conclusions: BRAF V600K melanomas appear to benefit less from BRAFi±MEKi than V600E, potentially due to less reliance on ERK pathway activation and greater use of alternative pathways. In contrast, these melanomas have higher mutational load and respond better to immunotherapy.