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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

Supplementary Data from 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

Cancers, including cutaneous melanoma, can cluster in families. In addition to environmental etiological factors such as ultraviolet radiation, cutaneous melanoma has a strong genetic component. Genetic risks for cutaneous melanoma range from rare, high-penetrance mutations to common, low-penetrance variants. Known high-penetrance mutations account for only about half of all densely affected cutaneous melanoma families, and the causes of familial clustering in the remainder are unknown. We hypothesize that some clustering is due to the cumulative effect of a large number of variants of individually small effect. Common, low-penetrance genetic risk variants can be combined into polygenic risk scores. We used a polygenic risk score for cutaneous melanoma to compare families without known high-penetrance mutations with unrelated melanoma cases and melanoma-free controls. Family members had significantly higher mean polygenic load for cutaneous melanoma than unrelated cases or melanoma-free healthy controls (Bonferroni-corrected t-test P = 1.5 × 10−5 and 6.3 × 10−45, respectively). Whole genome sequencing of germline DNA from 51 members of 21 families with low polygenic risk for melanoma identified a CDKN2A p.G101W mutation in a single family but no other candidate high-penetrance melanoma susceptibility genes. This work provides further evidence that melanoma, like many other common complex disorders, can arise from the joint action of multiple predisposing factors, including rare high-penetrance mutations, as well as via a combination of large numbers of alleles of small effect.

Forty years after the Mount St Helens eruption galvanized volcano researchers, they are using powerful new tools to spy on the world’s most dangerous mountains. Forty years after the Mount St Helens eruption galvanized volcano researchers, they are using powerful new tools to spy on the world’s most dangerous mountains.

Uveal melanoma (UM) is the most common intraocular tumour in adults and despite surgical or radiation treatment of primary tumours, ~50% of patients progress to metastatic disease. Therapeutic options for metastatic UM are limited, with clinical trials having little impact. Here we perform whole-genome sequencing (WGS) of 103 UM from all sites of the uveal tract (choroid, ciliary body, iris). While most UM have low tumour mutation burden (TMB), two subsets with high TMB are seen; one driven by germline MBD4 mutation, and another by ultraviolet radiation (UVR) exposure, which is restricted to iris UM. All but one tumour have a known UM driver gene mutation (GNAQ, GNA11, BAP1, PLCB4, CYSLTR2, SF3B1, EIF1AX). We identify three other significantly mutated genes (TP53, RPL5 and CENPE)., Uveal melanoma has a propensity to metastasise. Here, the authors report the whole genome sequence of 103 uveal melanomas and find that the tumour mutational burden is variable and that two subsets of tumours are characterised by MBD4 mutations and a UV exposure signature.

Community-engaged research takes place at a complex social site that has both a history and a future as well as encompassing the project activities of the researchers and community members. We argue that a crucial methodological aspect of undertaking such research is the development of trust relationships between researchers and community. We propose that for each research project, this relationship can best be understood as a ‘sphere of engagement’, after Ingold’s ‘sphere of nurture’, and that trust and care are emergent and binding qualities of this sphere. Tracing the development of trust relationships in a case study, using the idea of security-based trust and harmony-based trust, we conclude that trust, and the related concept of care, bind together people, events, histories and futures beyond the dichotomous and time-delimited relationship of a research contract, and carry the sphere of engagement of researchers and community beyond the life of any one project.

Background To report a case of Fuchs’ adenoma occurring in an eye with a large choroidal melanoma. We have reviewed the literature to describe the clinical presentation, ultrasound characteristics and pathological features of these entities. Case presentation A 69-year-old Caucasian man presented with vision loss from a large choroidal melanoma. Enucleation showed an incidental Fuchs’ adenoma in the same eye. Whole-exome sequence analysis was also performed on the patient’s blood and melanoma, which showed a rarely-reported ATRX mutation. Conclusions Fuchs’ adenoma is an under-diagnosed benign age-related hyperplasia of the non-pigmented ciliary epithelium (NPCE). Given its location and characteristics, it can be mistaken for choroidal melanoma and clinicians are reminded how to differentiate between these pathologies and that they may co-exist.

Pathogenic germline variants in protection of telomeres 1 ( POT1 ) result in a tumour predisposition syndrome (POT1-TPDS), which includes cutaneous melanoma (CM), glioma, chronic lymphocytic leukaemia (CLL), colorectal cancer, thyroid cancer and sarcoma.1 Through whole-genome sequencing (WGS) of 20 Australian individuals affected with both CM and uveal melanoma (UM), our study identified two truncating variants in POT1 . Functional analyses assessing telomere length indicated longer telomeres in variant carriers, compared with healthy age-matched controls, similar to observations in CM patients with loss-of-function POT1 variants.2 The risk for development of cancers such as CM and UM is influenced by genetics. In UM, this has mainly been attributed to loss-of-function variants in BAP1 .3 Predisposition in CM is largely due to multiple low-penetrance susceptibility alleles; however, 5%–12% of cases report first-degree or second-degree relatives with CM and in a proportion of these families disease segregates with high-penetrance single gene variants in CDKN2A , CDK4 and the telomere maintenance genes POT1 , ACD , TERF2IP and TERT (reviewed in ref 4). Pathogenic germline variants in POT1 result in an increase in telomere length and susceptibility to many cancer types including CM, glioma, CLL, thyroid cancer, colorectal cancer, angiosarcoma1 and osteosarcoma,5 now termed the POT1-TPDS. There is also recent evidence to suggest histological differences in melanomas of POT1 variant carriers versus non-carriers, highlighting the importance of telomere dysfunction on tumour biology.6 POT1 binds to telomeric single-stranded DNA (ssDNA) overhangs, preventing telomerase accessibility. Highly conserved oligonucleotide/oligosaccharide-binding (OB) folds in POT1 are essential for specific binding to ssDNA, and loss of function of these OB domains leads to increased telomere elongation due to an inability to inhibit telomerase. Certain germline missense variants occurring in these OB domains, and other protein truncating variants, have been reported to disrupt POT1 function, leading to …

Germline mutations of BRCA1 and BRCA2 predispose individuals to a high risk of breast and ovarian cancer, and elevated risk of other cancers, including those of the pancreas and prostate. BRCA2 mutation carriers may have increased risk of uveal melanoma (UM) and cutaneous melanoma (CM), but associations with these cancers in BRCA1 mutation carriers have been mixed. Here, we further assessed whether UM and CM are associated with BRCA1 or BRCA2 by assessing the presence, segregation and reported/predicted pathogenicity of rare germline mutations (variant allele frequency < 0.01) in families with multiple members affected by these cancers. Whole-genome or exome sequencing was performed on 160 CM and/or UM families from Australia, the Netherlands, Denmark and Sweden. Between one and five cases were sequenced from each family, totalling 307 individuals. Sanger sequencing was performed to validate BRCA1 and BRCA2 germline variants and to assess carrier status in other available family members. A nonsense and a frameshift mutation were identified in BRCA1, both resulting in premature truncation of the protein (the first at p.Q516 and the second at codon 91, after the introduction of seven amino acids due to a frameshift deletion). These variants co-segregated with CM in individuals who consented for testing and were present in individuals with pancreatic, prostate and breast cancer in the respective families. In addition, 33 rare missense mutations (variant allele frequency ranging from 0.00782 to 0.000001 in the aggregated ExAC data) were identified in 34 families. Examining the previously reported evidence of functional consequence of these variants revealed all had been classified as either benign or of unknown consequence. Seeking further evidence of an association between BRCA1 variants and melanoma, we examined two whole-genome/exome sequenced collections of sporadic CM patients (total N = 763). We identified one individual with a deleterious BRCA1 variant, however, this allele was lost (with the wild-type allele remaining) in the corresponding CM, indicating that defective BRCA1 was not a driver of tumorigenesis in this instance. Although this is the first time that deleterious BRCA1 mutations have been described in high-density CM families, we conclude that there is an insufficient burden of evidence to state that the increased familial CM or UM susceptibility is because of these variants. In addition, in conjunction with other studies, we conclude that the previously described association between BRCA2 mutations and UM susceptibility represents a rare source of increased risk.

Approximately 1-2% of cutaneous melanoma (CM) is classified as strongly familial. We sought to investigate unexplained CM predisposition in families negative for the known susceptibility genes using next generation sequencing of affected individuals. Segregation of germline variants of interest within families was assessed by Sanger sequencing. Several heterozygous variants in oculocutaneous albinism (OCA) genes: TYR, OCA2, TYRP1 and SLC45A2, were present in our CM cohort. OCA is a group of autosomal recessive genetic disorders, resulting in pigmentation defects of the eyes, hair and skin. Missense variants classified as pathogenic for OCA were present in multiple families and some fully segregated with CM. The functionally compromised TYR p.T373K variant was present in three unrelated families. In OCA2, known pathogenic variants: p.V443I and p.N489D, were present in three families and one family, respectively. We identified a likely pathogenic SLC45A2 frameshift variant that fully segregated with CM in a family of four cases. Another four-case family harboured cosegregating variants (p.A24T and p.R153C) of uncertain functional significance in TYRP1. We conclude that rare, heterozygous variants in OCA genes confer moderate risk for CM. This article is protected by copyright. All rights reserved.

© 2019 Elsevier Ltd We use ideas from futurist Sohail Inayatullah and others to unpack the layers of a values-driven evaluation, and the potential role for such an evaluation strategy to support Aboriginal people in Australia to gain acknowledgement of the past and to support a desired future. Inayatullah's Causal Layered Analysis (CLA) is used as a way of understanding the deep context of evaluation and the way in which a project might meet community priorities emerging from a dark history and its legacy. We present a proposed evaluation strategy centred around the CLA domains of Narrative, Discourse, Systems and Litany. We then use a case study from remote Australia to illustrate the kinds of community priorities that emerge from this deep context, and suggest that in an environment of complex and evolving relations, rather than measuring the contribution of a particular project to economic opportunity or social change, evaluation may need to focus on the ways in which the project becomes integrated into stories of change and other activities, either as a catalyst, an affirmation of commitment, or as part of an array of connected activities enabling change.

Germline mutations in CDKN2A greatly increase risk of developing cutaneous melanoma. We have constructed a risk prediction model, Familial Risk Assessment of Melanoma (FRAMe), for estimating the likelihood of carrying a heritable CDKN2A mutation among Australian families, where the prevalence of these mutations is low. Using logistic regression, we analysed characteristics of 299 Australian families recruited through the Sydney site of GenoMEL (international melanoma genetics consortium) with at least three cases of cutaneous melanoma (in situ and invasive) among first-degree blood relatives, for predictors of the presence of a pathogenic CDKN2A mutation. The final multivariable prediction model was externally validated in an independent cohort of 61 melanoma kindreds recruited through GenoMEL Queensland. Family variables independently associated with the presence of a CDKN2A mutation in a multivariable model were number of individuals diagnosed with melanoma under 40 years of age, number of individuals diagnosed with more than one primary melanoma, and number of individuals blood related to a melanoma case in the first degree diagnosed with any cancer excluding melanoma and non-melanoma skin cancer. The number of individuals diagnosed with pancreatic cancer was not independently associated with mutation status. The risk prediction model had an area under the receiver operating characteristic curve (AUC) of 0.851 (95% CI 0.793, 0.909) in the training dataset, and 0.745 (95%CI 0.612, 0.877) in the validation dataset. This model is the first to be developed and validated using only Australian data, which is important given the higher rate of melanoma in the population. This model will help to effectively identify families suitable for genetic counselling and testing in areas of high ambient ultraviolet radiation. A user-friendly electronic nomogram is available at www.melanomarisk.org.au .

© 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group. Reconciliation between Indigenous and non-Indigenous people in Australia is defined officially as consisting of ‘two-way relationships built on trust and respect’, recognition and acceptance of rights, histories and cultures, and institutional and community support for ‘all dimensions’ of reconciliation. We suggest, after Alexandre Da Costa (2016. The (un)happy objects of affective community. Cultural studies, 30, 24–46), that the burden of supporting reconciliation is borne differentially by Indigenous and non-Indigenous peoples; it is seen by the latter as an apparently ‘happy object’ in Sara Ahmed’s sense, but as an ‘unhappy object’ for many Aboriginal Australians, who have argued that it requires first a process of makarrata, or peace-making. Traditionally this has included some reciprocal pain for perpetrators, and we suggest here that the desire of many Aboriginal people to develop a public heritage of massacre sites and former ‘fringe camps’ offers an opportunity for non-Indigenous people to take hold of, and hold onto, a prickly and difficult past as part of a process of makarrata.

Background: Although rare in the general population, highly penetrant germline mutations in CDKN2A are responsible for 5%-40% of melanoma cases reported in melanoma-prone families. We sought to determine whether MELPREDICT was generalizable to a global series of families with melanoma and whether performance improvements can be achieved.Methods: In total, 2116 familial melanoma cases were ascertained by the international GenoMEL Consortium. We recapitulated the MELPREDICT model within our data (GenoMELPREDICT) to assess performance improvements by adding phenotypic risk factors and history of pancreatic cancer. We report areas under the curve (AUC) with 95% confidence intervals (CIs) along with net reclassification indices (NRIs) as performance metrics.Results: MELPREDICT performed well (AUC 0.752, 95% CI 0.730-0.775), and GenoMELPREDICT performance was similar (AUC 0.748, 95% CI 0.726-0.771). Adding a reported history of pancreatic cancer yielded discriminatory improvement (P < .0001) in GenoMELPREDICT (AUC 0.772, 95% CI 0.750-0.793, NRI 0.40). Including phenotypic risk factors did not improve performance.Conclusion: The MELPREDICT model functioned well in a global data set of familial melanoma cases. Adding pancreatic cancer history improved model prediction. GenoMELPREDICT is a simple tool for predicting CDKN2A mutational status among melanoma patients from melanoma-prone families and can aid in directing these patients to receive genetic testing or cancer risk counseling.

The idea of ‘voice’ as it communicates stories of conflict and trauma, and reimages place as the ‘site’ from which voice emanates, suggests a complex entanglement of social, political, material, human and non-human forces that differs across the voice of history, the collective voice of a community and voice as emerging from the site of an individual life. Focusing specifically on conflict stories obtained from fieldwork in Aceh, Indonesia, Palmer argues that history and collective remembering may function as ‘voice without subject’ (Mazzei in Cultural Studies Critical Methodologies, 16(2): 151–161, 2016). However, in listening to individuals’ stories, ethnographers and oral historians participate in the formation of a voice that is localised at the site of the individual’s life, and that constructs a new ethical-political relation between storyteller and listener.

© The Author(s) 2016. To transgress is ‘to do something that is not allowed’; in a human-constructed world, animals, especially those seen as ‘incompanionate’, are often deemed to be doing something not allowed. We explore the ethical dilemmas of ‘transgression’ in the context of critical reflection on an instructive example of dingo–human relations on Fraser Island, Australia, which has incited ongoing debate from diverse publics about the killing of ‘problem’ dingoes. We outline the historical and ethical complexity of such relations and suggest that human–nonhuman encounters, direct or indirect, have the potential to produce new, less anthropocentric topologies in which transgression is reconstructed, and humans and animals can share space more equitably. The kind of knowledge and ethical re-positioning beginning to emerge in dingo–human relations suggests transgression itself as a metaphor for its further re-imagining: a disruption of spatial, emotional and ethical boundaries to shape more responsive, respectful and less anthropocentric topologies.

BACKGROUND: The BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome (BAP1-TPDS) is a hereditary tumor syndrome caused by germline pathogenic variants in BAP1 encoding a tumor suppressor associated with uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, and cutaneous BAP1-inactivated melanocytic tumors. However, the full spectrum of tumors associated with the syndrome is yet to be determined. Improved understanding of the BAP1-TPDS is crucial for appropriate clinical management of BAP1 germline variant carriers and their families, including genetic counseling and surveillance for new tumors. METHODS: We collated germline variant status, tumor diagnoses, and information on BAP1 immunohistochemistry or loss of somatic heterozygosity on 106 published and 75 unpublished BAP1 germline variant-positive families worldwide to better characterize the genotypes and phenotypes associated with the BAP1-TPDS. Tumor spectrum and ages of onset were compared between missense and null variants. All statistical tests were two-sided. RESULTS: The 181 families carried 140 unique BAP1 germline variants. The collated data confirmed the core tumor spectrum associated with the BAP1-TPDS and showed that some families carrying missense variants can exhibit this phenotype. A variety of noncore BAP1-TPDS -associated tumors were found in families of variant carriers. Median ages of onset of core tumor types were lower in null than missense variant carriers for all tumors combined (P

There is currently no effective treatment for metastasised uveal melanoma (UM). Recently, it was reported that a UM patient was responsive to checkpoint inhibitor (CI) treatment, due to a high tumour mutation burden correlated with a germline loss-of-function MBD4 mutation. Here, we report on another UM patient who carried an MBD4 germline nonsense variant (p.Leu563Ter) and her tumour showed a fivefold higher than average mutation burden. We confirmed the association between germline loss-of-function variant in MBD4 and CI response. The patient experienced stable disease (10 months) and survived 2 years with metastatic disease, which is twice as long as median survival. Additionally, the frequency of MBD4 loss-of-function variants in reported UM cohorts was 20 times higher than in an aggregated population genome database (P 5 × 10

© The Author(s) 2017. Waiting is one of the most common phenomena in ethnographic and other community-based research. Nevertheless, it remains under-explored in academic writing about the theoretical and methodological aspects of fieldwork. While waiting time often allows new data or information to emerge, we argue that such times have a significance independent of knowledge outcomes. We review various conceptions of waiting: as a time for self-awareness; the use of enforced waiting to exert power over the disadvantaged; and its obverse, the choice by the more powerful to ‘wait upon’ another’s needs and priorities. We use stories from our own fieldwork experience to suggest that in the particular context of ethnographic or community-based research, the choice to ‘wait upon’ others is a form of researcher reflexivity that can partially redress historical or current power imbalances.

Next generation sequencing of uveal melanoma (UM) samples has identified a number of recurrent oncogenic or loss-of-function mutations in key driver genes including: GNAQ, GNA11, EIF1AX, SF3B1 and BAP1. To search for additional driver mutations in this tumor type we carried out whole-genome or whole-exome sequencing of 28 tumors or primary cell lines. These samples have a low mutation burden, with a mean of 10.6 protein changing mutations per sample (range 0 to 53). As expected for these sun-shielded melanomas the mutation spectrum was not consistent with an ultraviolet radiation signature, instead, a BRCA mutation signature predominated. In addition to mutations in the known UM driver genes, we found a recurrent mutation in PLCB4 (c.G1888T, p.D630Y, NM_000933), which was validated using Sanger sequencing. The identical mutation was also found in published UM sequence data (1 of 56 tumors), supporting its role as a novel driver mutation in UM. PLCB4 p.D630Y mutations are mutually exclusive with mutations in GNA11 and GNAQ, consistent with PLCB4 being the canonical downstream target of the former gene products. Taken together these data suggest that the PLCB4 hotspot mutation is similarly a gain-of-function mutation leading to activation of the same signaling pathway, promoting UM tumorigenesis.

The overall 5-year survival for melanoma is 91%. However, if distant metastasis occurs (stage IV), cure rates are, Highlights • A seven-miRNA panel (MELmiR-7) detected the presence of melanoma with high sensitivity (93%) and specificity (≥ 82%). • In serially collected stage IV specimens, members of the ‘MELmiR-7’ panel confirmed tumour progression in 100% of cases. • The ‘MELmiR-7’ panel is superior to currently used serological markers for melanoma progression, recurrence, and survival.

// Mitchell S. Stark 1,2 , Vanessa F. Bonazzi 3 , Glen M. Boyle 1 , Jane M. Palmer 1 , Judith Symmons 1 , Catherine M. Lanagan 1 , Christopher W. Schmidt 1 , Adrian C. Herington 2 , Robert Ballotti 3 , Pamela M. Pollock 2 and Nicholas K. Hayward 1 1 QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD, Australia 2 School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia 3 Inserm U1065, Centre Mediterraneen de Medecine Moleculaire, Equipe 1, Biologie et pathologies des melanocytes, Nice, France Correspondence to: Mitchell S. Stark, email: // Keywords : miRNA, microRNA, miR-514a, BRAFi, NF1 Received : March 16, 2015 Accepted : April 07, 2015 Published : April 23, 2015 Abstract To identify ‘melanoma-specific’ microRNAs (miRNAs) we used an unbiased microRNA profiling approach to comprehensively study cutaneous melanoma in relation to other solid malignancies, which revealed 233 differentially expressed (≥ 2 fold, p < 0.05) miRNAs. Among the top 20 most significantly different miRNAs was hsa-miR-514a-3p. miR-514a is a member of a cluster of miRNAs (miR-506-514) involved in initiating melanocyte transformation and promotion of melanoma growth. We found miR-514a was expressed in 38/55 (69%) melanoma cell lines but in only 1/34 (3%) other solid cancers. To identify miR-514a regulated targets we conducted a miR-514a-mRNA ‘pull-down’ experiment, which revealed hundreds of genes, including: CTNNB1 , CDK2 , MC1R , and NF1 , previously associated with melanoma. NF1 was selected for functional validation because of its recent implication inacquired resistance to BRAFV600E -targeted therapy. Luciferase-reporter assays confirmed NF1 as a direct target of miR-514a and over-expression of miR-514a in melanoma cell lines inhibited NF1 expression, which correlated with increased survival of BRAFV600E cells treated with PLX4032. These data provide another mechanism for the dysregulation of the MAPK pathway which may contribute to the profound resistance associated with current RAF-targeted therapies. Mitchell S. Stark

Mutations in Cyclin-Dependent Kinase Inhibitor 2A (CDKN2A) and Cyclin-Dependent Kinase 4 (CDK4) contribute to susceptibility in approximately 40% of high-density cutaneous melanoma (CMM) families and about 2% of unselected CMM cases. BRCA-1 associated protein-1 (BAP1) has been more recently shown to predispose to CMM and uveal melanoma (UMM) in some families; however, its contribution to CMM development in the general population is unreported. We sought to determine the contribution of these genes to CMM susceptibility in a population-based sample of cases from Australia. We genotyped 1,109 probands from Queensland families and found that approximately 1.31% harbored mutations in CDKN2A, including some with novel missense mutations (p.R22W, p.G35R and p.I49F). BAP1 missense variants occurred in 0.63% of cases but no CDK4 variants were observed in the sample. This is the first estimate of the contribution of BAP1 and CDK4 to a population-based sample of CMM and supports the previously reported estimate of CDKN2A germline mutation prevalence.

Scientists investigate why mountain slopes can slip slowly for years and then suddenly speed up, with potentially fatal effects.

The paper argues that life stories and histories offer different perspectives on the past, with implications for studying the future. A life is proposed as a form of 'social site' (Marston, S.A., J.P. Jones III & K. Woodward 2005, 'Human geography without scale', Transactions of the Institute of British Geographers, vol. 30, pp. 416-432.) where the future is met and negotiated. Unlike the broad sweep of historical narrative, a focus on the site of a life can reveal cumulative losses, futures denied and paths not taken. Life stories challenge historical narrative with alternative futures that ‘might-have-been’; they might therefore usefully be added as a more experimental type to Inayatullah’s taxonomy of historical 'traces' (Inayatullah, S. 2012, 'Humanity 3000: A comparative analysis of methodological approaches to forecasting the long-term', Foresight, vol. 14, no. 5, pp. 401-417). A case study based on a life story from Aceh is used to demonstrate ways in which alternative futures can emerge from life stories and then be acted upon. The paper concludes that the experimental power of life stories as historical traces lies not only in the stories themselves but in the unique event of storytelling and its potentially transformative impact on the teller and listener, and hence the future.

Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases1, while rare variants in CDK4, BRCA2, BAP1, and the promoter of TERT, have also been linked to the disease2-5. Here we set out to identify novel high-penetrance susceptibility genes in unexplained cases by sequencing 184 melanoma patients from 105 pedigrees recruited in the United Kingdom, the Netherlands, and Australia that were negative for variants in known predisposition genes. We identify families where melanoma co-segregates with loss-of-function variants in the protection of telomeres 1 (POT1) gene, a proportion of members presenting with an early age of onset and multiple primaries. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide-/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding, leading to increased telomere length. Thus, POT1 variants predispose to melanoma formation via a direct effect on telomeres.

Urban political ecology emphasises the hybrid nature of cities and the flows of people and materials that constitute the built environment. Climate change introduces a profound dimension of uncertainty in the socio-material relations of urban life, raising questions for urban residents of how to act, what sort of actions might make a ‘difference’ and ‘matter’. For renters this uncertainty is amplified by limited access to ‘resources for adaption’ such as gardens, water efficiency and alternative energy, and exacerbated by poor communication and unresponsiveness from landlords. The built environment, and housing in particular, is recognized as both a significant site of greenhouse gas emissions and a site where adaptation to climate change will need to occur. However, the capacity of urban residents to make changes to their housing is uneven. This paper draws on a case study of rental property managers and tenants in Newcastle, NSW to explore social and cultural processes that are both shaped by and shape rental housing provision. In this paper we explore the urban political ecologies of rental housing through the lens of water, revealing a suite of practices, materials and discourses that assemble to make resources for adaptation, and simultaneously render water as useful, troubled and troublesome. The socionatural relations of tenure are shaped by regulatory practices including leases, insurance and capital investment alongside human and non-human actors. In particular the paper draws attention to the different conditions of access to ‘resources for adaptation’ in the material relations of public and private rental housing provision.

The shift towards social, government and corporate ethics which value environmental sustainability has also embraced householders in a plethora of educational guides, policies, regulations and consumer information about green home improvements, purchasing choices and household practices. In this paper, we make the claim that the rental housing sector, and in particular the private rental sector, has yet to participate, structurally, culturally and materially, in this shift to an ethics of sustainability. We argue, however, that even on such otherwise arid ground, an alternative ethic is developing, a sustainability ethic practiced by green tenants whose activities inside and outside their homes go beyond the considerable material constraints of their dwellings and incomes, and beyond the purely transactional utility of the rental contract. These activities, relational, interconnected and resilient, offer both glimpses of a greening rental housing sector, and a clearer picture of the areas where work remai...

Purpose To determine if a circulating microRNA (miRNA) panel could be used to distinguish between uveal melanoma and uveal nevi. Methods We report on a multicenter, cross-sectional study conducted between June 2012 and September 2015. The follow-up time was approximately 3 to 5 years. Blood was drawn from participants presenting with a uveal nevus (n = 10), localized uveal melanoma (n = 50), or metastatic uveal melanoma (n = 5). Levels of 17 miRNAs were measured in blood samples of study participants using a sensitive real-time PCR system. Results A panel of six miRNAs (miR-16, miR-145, miR-146a, miR-204, miR-211, and miR-363-3p) showed significant differences between participants with uveal nevi compared with patients with localized and metastatic uveal melanoma. Importantly, miR-211 was able to accurately distinguish metastatic disease from localized uveal melanoma (P < 0.0001; area under the curve = 0.96). When the six-miRNA panel was evaluated as a group it had the ability to identify uveal melanoma when four or more miRNAs (93% sensitivity and 100% specificity) reached or exceeded their cut-point. Conclusions This miRNA panel, in tandem with clinical findings, may be suited to confirm benign lesions. In addition, due to the panel's high precision in identifying malignancy, it has the potential to augment melanoma detection in subsequent clinical follow-up of lesions with atypical clinical features. Translational Relevance Uveal nevi mimic the appearance of uveal melanoma and their transformation potential cannot be definitively determined without a biopsy. This panel is most relevant at the nevus stage and in lesions with uncertain malignant potential as a companion diagnostic tool to assist in clinical decision-making.

The authors regret that the online version of this article contains an error. The MBD4 mutation in sample MM138 was given an incorrect dbSNP ID. The correct ID is rs769076971.

e13534Background: Germline mutations in the BRCA1-associated protein (BAP1) gene are linked to a large spectrum of cancers, defined as the BAP1 tumour predisposition syndrome (BAP1-TPDS). The cance...

Germline mutations in the exonuclease domain of POLE have been shown to predispose to colorectal cancers and adenomas. POLE is an enzyme involved in DNA repair and chromosomal DNA replication. In order to assess whether such mutations might also predispose to cutaneous melanoma, we interrogated whole-genome and exome data from probands of 34 melanoma families lacking pathogenic mutations in known high penetrance melanoma susceptibility genes: CDKN2A, CDK4, BAP1, TERT, POT1, ACD and TERF2IP. We found a novel germline mutation, POLE p.(Trp347Cys), in a 7-case cutaneous melanoma family. Functional assays in S. pombe showed that this mutation led to an increased DNA mutation rate comparable to that seen with a Pol e mutant with no exonuclease activity. We then performed targeted sequencing of POLE in 1243 cutaneous melanoma cases and found that a further ten probands had novel or rare variants in the exonuclease domain of POLE. Although this frequency is not significantly higher than that in unselected Caucasian controls, we observed multiple cancer types in the melanoma families, suggesting that some germline POLE mutations may predispose to a broad spectrum of cancers, including melanoma. In addition, we found the first mutation outside the exonuclease domain, p.(Gln520Arg), in a family with an extensive history of colorectal cancer.

The shelterin complex protects chromosomal ends by regulating how the telomerase complex interacts with telomeres. Following the recent finding in familial melanoma of inactivating germline mutations in POT1, encoding a member of the shelterin complex, we searched for mutations in the other five components of the shelterin complex in melanoma families.Next-generation sequencing techniques were used to screen 510 melanoma families (with unknown genetic etiology) and control cohorts for mutations in shelterin complex encoding genes: ACD, TERF2IP, TERF1, TERF2, and TINF 2. Maximum likelihood and LOD [logarithm (base 10) of odds] analyses were used. Mutation clustering was assessed with χ(2) and Fisher's exact tests. P values under .05 were considered statistically significant (one-tailed with Yates' correction).Six families had mutations in ACD and four families carried TERF2IP variants, which included nonsense mutations in both genes (p.Q320X and p.R364X, respectively) and point mutations that cosegregated with melanoma. Of five distinct mutations in ACD, four clustered in the POT1 binding domain, including p.Q320X. This clustering of novel mutations in the POT1 binding domain of ACD was statistically higher (P = .005) in melanoma probands compared with population control individuals (n = 6785), as were all novel and rare variants in both ACD (P = .040) and TERF2IP (P = .022). Families carrying ACD and TERF2IP mutations were also enriched with other cancer types, suggesting that these variants also predispose to a broader spectrum of cancers than just melanoma. Novel mutations were also observed in TERF1, TERF2, and TINF2, but these were not convincingly associated with melanoma.Our findings add to the growing support for telomere dysregulation as a key process associated with melanoma susceptibility.

Over the past 20 years, the incidence of cutaneous malignant melanoma (CMM) has increased dramatically worldwide. A positive family history of the disease is among the most established risk factors for CMM; it is estimated that 10% of CMM cases result from an inherited predisposition. Although mutations in two genes, CDKN2A and CDK4, have been shown to confer an increased risk of CMM, they account for only 20%-25% of families with multiple cases of CMM. Therefore, to localize additional loci involved in melanoma susceptibility, we have performed a genomewide scan for linkage in 49 Australian pedigrees containing at least three CMM cases, in which CDKN2A and CDK4 involvement has been excluded. The highest two-point parametric LOD score (1.82; recombination fraction [theta] 0.2) was obtained at D1S2726, which maps to the short arm of chromosome 1 (1p22). A parametric LOD score of 4.65 (theta=0) and a nonparametric LOD score of 4.19 were found at D1S2779 in nine families selected for early age at onset. Additional typing yielded seven adjacent markers with LOD scores3 in this subset, with the highest parametric LOD score, 4.95 (theta=0) (nonparametric LOD score 5.37), at D1S2776. Analysis of 33 additional multiplex families with CMM from several continents provided further evidence for linkage to the 1p22 region, again strongest in families with the earliest mean age at diagnosis. A nonparametric ordered sequential analysis was used, based on the average age at diagnosis in each family. The highest LOD score, 6.43, was obtained at D1S2779 and occurred when the 15 families with the earliest ages at onset were included. These data provide significant evidence of a novel susceptibility gene for CMM located within chromosome band 1p22.

Research involving fieldwork can present the researcher with ethical dilemmas not anticipated in institutional ethics approval processes. Ethical dilemmas can present both profound personal and methodological challenges. Decisions made in response to these dilemmas have the potential to affect both the validity of data collected and its analysis at later stages of the research project. They may also generate feelings such as discomfort, uncertainty and guilt for the researcher. The authors’ experiences of conducting qualitative fieldwork in four distinctly different contexts illustrate some of these unexpected consequences and ethical dilemmas. Issues encountered included: compromised relationships with informants which develop in unforeseen ways; engagement with traumatized informants which lead to unexpected roles for the researcher such as confidante, dealing with new information that is critical to informants’ futures but could undermine the research project, and the implications of ethical decisions for research design and analysis. Through joint reflection on the researchers’ experiences and decisions, the four case studies in this paper provide a basis for examining anticipatory rather than reactive ways of dealing with ethical dilemmas. In acknowledging that one needs to expect the unexpected during field work, preparation and critical reflection were found to be key tools in relating to field informants, dealing with the personal challenges of undertaking field work and developing useful research outcomes after returning home. This paper concludes with some suggestions for field researchers regarding ethical and fieldwork design issues to consider in addition to the concerns addressed in a standard university ethics approval process.

A substantial number of melanoma patients will develop multiple primary melanomas (MPM). Currently, little is known about the impact of MPM on survival.We aimed to determine whether melanoma survival is worse for patients with MPM compared to those with a single invasive primary melanoma (SPM).A cohort study was conducted. Patients were sourced from an Australian population, with follow-up information collected retrospectively from registry data. Melanoma-specific survival analysis was performed to find associated variables after adjustment for known prognostic factors, using four different models, each selecting a different index melanoma lesion.1068 stage I and II melanoma patients were followed up for a median of 24.4 years. MPM was found in 17.8% of the cohort (190 patients), more likely among males and older age groups. Other clinicopathological parameters were similar between the MPM and SPM (878 patients) cohorts. After adjustment for age, sex and Breslow thickness, MPM was a hazard for death from melanoma, across all models, reaching significance when considering the last invasive lesion as the index melanoma (HR = 2.76, P = 0.017).Patients with multiple invasive lesions seem more at risk of death from melanoma, independent of known prognostic factors.

This chapter examines both assets and barriers for climate adaptation in the rental housing sector through a case study of renters and housing managers in regional Australia. The study included in-depth semi-structured interviews with 22 tenants and 17 housing managers in the public and private housing sectors. A wide range of secondary sources including media articles, sustainable renting guides and legislative and policy documents. Private sector tenants believed that negative social and political attitudes to renters in Australia were an obstacle to changing tenancy conditions and improving housing. There was a wide range of views among property managers about the importance or reality of climate change, from belief to some scepticism. Amending tenancy conditions to enhance the active contribution of tenants to climate change adaptation may require innovative legislative frameworks that reflect climate change and equity imperatives as well as protection for landlords and tenants.

Partner and localizer of BRCA2 (PALB2) interacts with BRCA2 to enable double strand break repair through homologous recombination. Similar to BRCA2, germline mutations in PALB2 have been shown to predispose to Fanconi anaemia as well as pancreatic and breast cancer. The PALB2/BRCA2 protein interaction, as well as the increased melanoma risk observed in families harbouring BRCA2 mutations, makes PALB2 a candidate for melanoma susceptibility. In order to assess PALB2 as a melanoma predisposition gene, we sequenced the entire protein-coding sequence of PALB2 in probands from 182 melanoma families lacking pathogenic mutations in known high penetrance melanoma susceptibility genes: CDKN2A, CDK4, and BAP1. In addition, we interrogated whole-genome and exome data from another 19 kindreds with a strong family history of melanoma for deleterious mutations in PALB2. Here we report a rare known deleterious PALB2 mutation (rs118203998) causing a premature truncation of the protein (p.Y1183X) in an individual who had developed four different cancer types, including melanoma. Three other family members affected with melanoma did not carry the variant. Overall our data do not support a case for PALB2 being associated with melanoma predisposition.

Endocrine tumours of the pancreas, anterior pituitary or parathyroids arise either sporadically in the general population, or as a part of inherited syndromes such as multiple endocrine neoplasia type 1 (MEN 1). The mechanisms responsible for the development of sporadic endocrine lesions are not well understood, although loss of heterozygosity (LOH) of the MEN1 locus on chromosome 11q13 and somatic mutation of the MEN1 gene have been frequently associated with the development of MEN 1-type sporadic endocrine lesions. To further investigate the role of the MEN1 gene in sporadic endocrine tumorigenesis, we analysed DNA from 14 primary parathyroid lesions, 8 anterior pituitary tumours and 3 pancreatic tumours for the presence of somatic MEN1 gene mutations and LOH of seven microsatellite markers flanking the MEN1 locus. In addition, we similarly analysed 8 secondary parathyroid lesions which arose in patients with chronic renal failure. None of the patients studied had a family history of MEN 1. Three primary parathyroid lesions and one pancreatic tumour (glucagonoma) were found to have lost one allele at the MEN1 locus. Somatic mutations were identified by SSCP and sequence analysis in one of these parathyroid lesions (P320L) and in the glucagonoma (E179V). These results support previous findings that inactivation of the MEN1 tumour suppressor gene contributes to the development of sporadic MEN 1-type endocrine lesions but is not associated with the development of parathyroid hyperplasia seen in some renal failure patients. © 2000 Cancer Research Campaign