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Melanoma is difficult to treat once it becomes metastatic. However, the precise ancestral relationship between primary tumors and their metastases is not well understood. We performed whole-exome sequencing of primary melanomas and multiple matched metastases from eight patients to elucidate their phylogenetic relationships. In six of eight patients, we found that genetically distinct cell populations in the primary tumor metastasized in parallel to different anatomic sites, rather than sequentially from one site to the next. In five of these six patients, the metastasizing cells had themselves arisen froma common parental subpopulation in the primary, indicating that the ability to establish metastases is a late-evolving trait. Interestingly, we discovered that individual metastases were sometimes founded by multiple cell populations of the primary that were genetically distinct. Such establishment of metastases by multiple tumor subpopulations could help explain why identical resistance variants are identified in different sites after initial response to systemic therapy. One primary tumor harbored two subclones with different oncogenic mutations inCTNNB1, which were both propagated to the same metastasis, raising the possibility that activation of wingless-type mouse mammary tumor virus integration site (WNT) signaling may be involved, as has been suggested by experimental models.

Purpose We evaluated the impact of personal melanoma genomic risk information on sun-related behaviors and psychological outcomes. Methods In this parallel group, open, randomized controlled trial, 1,025 Australians of European ancestry without melanoma and aged 18–69 years were recruited via the Medicare database (3% consent). Participants were randomized to the intervention ( n  = 513; saliva sample for genetic testing, personalized melanoma risk booklet based on a 40-variant polygenic risk score, telephone-based genetic counseling, educational booklet) or control ( n  = 512; educational booklet). Wrist-worn ultraviolet (UV) radiation dosimeters (10-day wear) and questionnaires were administered at baseline, 1 month postintervention, and 12 months postbaseline. Results At 12 months, 948 (92%) participants completed dosimetry and 973 (95%) the questionnaire. For the primary outcome, there was no effect of the genomic risk intervention on objectively measured UV exposure at 12 months, irrespective of traditional risk factors. For secondary outcomes at 12 months, the intervention reduced sunburns (risk ratio: 0.72, 95% confidence interval: 0.54–0.96), and increased skin examinations among women. Melanoma-related worry was reduced. There was no overall impact on general psychological distress. Conclusion Personalized genomic risk information did not influence sun exposure patterns but did improve some skin cancer prevention and early detection behaviors, suggesting it may be useful for precision prevention. There was no evidence of psychological harm.

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. 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. 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. 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.

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. Male-pattern baldness (MPB) is related to dysregulation of androgens. Here, authors show that MPB (but not androgens) is associated with skin cancer risk, particularly in the scalp region, suggesting that sun exposure, rather than androgens, is the main driver.

ObjectivesTo identify patient-reported outcome measures (PROMs) and patient-reported experience measures (PREMs) in clinical quality registries, for people with cutaneous melanoma, to inform a new Australian Melanoma Clinical Outcomes Registry; and describe opportunities and challenges of routine PROM/PREM collection, especially in primary care.DesignSystematic review.Primary and secondary outcome measuresWhich PROMs and PREMs are used in clinical quality registries for people with cutaneous melanoma, how they are collected, frequency of collection, participant recruitment methods and funding models for each registry.Results1134 studies were identified from MEDLINE, PreMEDLINE, Embase, PsychInfo, Cochrane Database of Abstracts of Reviews of Effects databases and TUFTS Cost-Effectiveness Analysis Registry, alongside grey literature, from database inception to 5th February 2020. Following screening, 14 studies were included, identifying four relevant registries: Dutch Melanoma Registry, Adelphi Real-World Disease-Specific Programme (Melanoma), Patient-Reported Outcomes Following Initial treatment and Long-term Evaluation of Survivorship Registry, and Cancer Experience Registry. These used seven PROMs: EuroQol-5 Dimensions, Functional Assessment of Cancer-General (FACT-G) and FACT-Melanoma (FACT-M), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Cancer 30 (EORTC QLQ-C30), Fatigue Assessment Scale Hospital Anxiety and Depression Scale, Patient-Reported Outcome Measures Information System-29 and one PREM; EORTC QLQ-Information Module 26. PROMs/PREMs in registries were reported to improve transparency of care; facilitate clinical auditing for quality assessment; enable cost-effectiveness analyses and create large-scale research platforms. Challenges included resource burden for data entry and potential collection bias toward younger, more affluent respondents. Feedback from patients with melanoma highlighted the relevance of PROMs/PREMs in assessing patient outcomes and patient experiences.ConclusionsClinical registries indicate PROMs/PREMs for melanoma care can be incorporated and address important gaps, however cost and collection bias may limit generalisability.PROSPERO registration numberCRD42018086737.

Background Standardization of the clinical management of melanoma through the formulation of national guidelines, based on interpretation of the existing evidence and consensus expert opinion, seeks to improve quality of care; however, adherence to national guidelines has not been well studied. Methods A population-based, cross-sectional study of the clinical management of all patients with newly notified primary melanomas in the state of New South Wales, Australia, during 2006/2007 was conducted using cancer registry identification and questionnaires completed by treating physicians. Results Surgical margin guidelines were adhered to in 35% of cases; 45% were over treated and 21% were undertreated. Factors independently associated with non-concordance on multivariate analysis were lower Breslow thickness, lower socio-economic status of the physician’s practice location, older physician age, lower physician caseload, and physicians who biopsied the lesion and then referred for definitive management. Complications were not related to over- or under-treatment on multivariate analysis ( p  = 0.72). Sentinel lymph node biopsy was performed in 17% of patients with invasive melanoma, with the main determinant for selection being a Breslow thickness >0.75 mm. Conclusions The low level of concordance with national guidelines for surgical management of melanoma resulted in overtreatment of many patients. However, a fifth of patients were undertreated, which is likely to have resulted in increased locoregional recurrence rates. The better concordance achieved by physicians treating >30 melanomas per year suggests that a minimum caseload threshold for physicians treating melanoma patients would be desirable. High guideline concordance will ensure patients receive optimal care and minimize morbidity and health service costs.

Ultraviolet radiation (UVR) mutagenesis causes nearly all cutaneous melanomas, however, since UVR signatures are largely absent in acral melanoma, as well as melanoma in sun-protected sites, the cause of these melanomas is unknown. Whole-genome sequencing data generated as part of the Australian Melanoma Genome Project was supplemented with a detailed histopathological assessment with the melanomas then classified as UVR or non-UVR related, based on their mutation signatures. The clinicopathological characteristics of melanomas with mutation signatures for their subtype were compared. Three (of 35=8.6%) acral melanomas, all clinically and pathologically verified as arising from acral or subungual locations, had predominant UVR mutation burden, whereas four (of 140=2.9%) cutaneous melanomas showed predominant non-UVR mutations. Among the acral melanomas, the few that were UVR dominant occurred in younger patients, had a higher mutation load and a proportion of mutation burden due to UVR, which was similar to that in melanomas from intermittently UVR-exposed skin. Acral melanomas with a UVR signature occurred most frequently in subungual sites and included tumors harboring BRAF or NF1 mutations. Cutaneous melanomas dominated by non-UVR signatures had lower mutation burdens counts and their primary tumors were thicker and had more mitoses than in other cutaneous melanomas. No histopathological features predicted UVR dominance in acral melanomas or non-UVR dominance in cutaneous melanomas. Our finding of acral/subungual melanomas with predominant UVR mutagenesis suggests that the nail plate and acral skin do not provide complete protection from UVR. Our data also confirm that cutaneous melanomas not caused by UVR are infrequent. Identifying where mutation burden is discordant with primary tumor anatomical site is likely to be clinically significant when determining treatment options for metastatic acral and cutaneous melanoma 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.

Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. However, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma. The number of genes affected by recurrent mutations disrupting non-coding sequences was similar to that affected by recurrent mutations to coding sequences. Significantly mutated genes included BRAF , CDKN2A , NRAS and TP53 in cutaneous melanoma, BRAF , NRAS and NF1 in acral melanoma and SF3B1 in mucosal melanoma. Mutations affecting the TERT promoter were the most frequent of all; however, neither they nor ATRX mutations, which correlate with alternative telomere lengthening, were associated with greater telomere length. Most melanomas had potentially actionable mutations, most in components of the mitogen-activated protein kinase and phosphoinositol kinase pathways. The whole-genome mutation landscape of melanoma reveals diverse carcinogenic processes across its subtypes, some unrelated to sun exposure, and extends potential involvement of the non-coding genome in its pathogenesis. The first large, high-coverage whole-genome sequencing study of melanomas from cutaneous, acral and mucosal sites. Skin cancer subtypes sequenced Melanoma is a highly metastatic cancer with a high mutation load, and signatures in some subtypes are often associated with exposure to ultraviolet radiation. Graham Mann and colleagues report whole-genome sequencing of tumour samples from patients with melanoma, including 75 primary melanomas, 93 melanoma metastases and 15 cell lines derived from melanoma metastases. The authors compare the genomic landscapes of cutaneous, acral and mucosal subtypes of melanoma, identifying distinct mutational signatures by subtype. Cutaneous melanomas showed mutational signatures of ultraviolet radiation exposure, whereas acral and mucosal melanomas showed a lower mutation burden and more frequent complex structural rearrangements in comparison to other melanoma subtypes. Understanding the whole-genome landscapes of all melanoma subtypes is important for investigating melanoma prevention and targeted treatment.

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 datasets 1 – 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 sequencing 4 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 loci 5 , 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. Population-scale whole-genome sequencing across four remote Indigenous Australian communities reveals a large fraction of structural variants that are unique to these populations, emphasizing the genetic distinctiveness of and diversity among Indigenous Australians.