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

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

Risk prediction models, which include a combination of risk factors, have been developed as a more accurate way of estimating risk and personalising preventive interventions. Many melanoma risk prediction models have been published but few have been independently validated.1 We aimed to externally validate 12 melanoma risk prediction models using the Australian Melanoma Family Study (AMFS), a population-based, case-control-family study comprising 629 incident first-primary melanoma cases, 240 population-based controls ascertained using the electoral roll (voting is compulsory) and 295 spouse or friend controls.2 Recruitment took place from 2001 to 2005 in the states of New South Wales, Queensland and Victoria.

Background/objectives In melanoma management, sentinel lymph node biopsy (SLNB) is used to stage patients and to indicate prognosis. More recently, it has been used to select patients for adjuvant therapy. This study aimed to report knowledge of and attitudes towards SLNB for patients with melanoma among Australian dermatologists. Methods Mixed methods study using cross-sectional questionnaires (n = 88) and semi-structured interviews (n = 13), May-September 2019. Results Of the dermatologists surveyed, 56% thought SLNB had an important role in melanoma management, 26% were unsure and 18% thought SLNB unimportant. Of the 92% who would discuss SLNB with their patients, the main stated value of SLNB was for assessing eligibility for adjuvant therapies (79%); only 60% indicated SLNB was of value for providing prognostic information, and just over half (53%) thought it could improve staging. Interview data indicated that attitudes towards SLNB are shifting among dermatologists, driven by data from landmark clinical trials and the influence of professional networks. Accordingly, interviewees adopted one of three positions in relation to SLNB: (a) believed in utility of SLNB and adhered to the guidelines; (b) were unconvinced about utility of SLNB but adhered to the guidelines; and (c) were unconvinced about utility of SLNB and did not adhere to the guidelines. Conclusion Although most of the dermatologists surveyed were familiar with and follow the SLNB recommendations, some disagreement with and distrust of the recommendations was evident. Greater acceptance of the SLNB recommendations appeared to be driven by the improved outcomes demonstrated in stage III patients receiving adjuvant systemic therapy.

In Australia, the uptake of the sentinel lymph node biopsy (SLNB) appears low despite clinical practice guideline recommendations. The aim of this study was to describe the knowledge and attitudes of general practitioners (GPs) to SLNB.GPs were recruited at an annual conference and a skin cancer skills workshop, and using GP professional communications. A mixed methods approach comprised a cross-sectional questionnaire and, for a subset of participants, semi-structured interviews.Overall, 231 GPs completed the questionnaire, of whom 23 were interviewed. One-third (32%) described themselves as quite or very familiar with the guidelines, and two-thirds (68%) thought that SLNB had an important role in the management of patients with melanoma. Of GPs who would discuss SLNB with eligible patients,40% correctly identified that SLNB is recommended for patients with an invasive melanoma1 mm thick.GPs were generally supportive of SLNB. Familiarity with the guidelines was low, particularly regarding which patients should be considered for SLNB.

IntroductionFear of cancer recurrence (FCR) is commonly reported by patients diagnosed with early-stage (0–II) melanoma and can have a significant impact on daily functioning. This study will pilot the implementation of the Melanoma Care Program, an evidence-based, psychological intervention to reduce FCR, into routine practice, using a stepped-care model.Methods and analysisIntervention effectiveness and level of implementation will be investigated using a hybrid type I design. Between 4 weeks before and 1 week after their next dermatological appointment, patients with melanoma will be invited to complete the Fear of Cancer Recurrence Inventory Short-Form, measuring self-reported FCR severity. Using a stepped-care model, clinical cut-off points will guide the level of support offered to patients. This includes: (1) usual care, (2) Melanoma: Questions and Answers psychoeducational booklet, and (3) three or five psychotherapeutic telehealth sessions. This longitudinal, mixed-methods pilot implementation study aims to recruit 108 patients previously diagnosed with stage 0–II melanoma. The primary effectiveness outcome is change in FCR severity over time. Secondary effectiveness outcomes include change in anxiety, depression, stress, health-related quality of life and melanoma-related knowledge over time. All outcomes are measured at baseline, within 1 week of the final telehealth session, and 6 and 12 months post-intervention. Implementation stakeholders at each study site and interested patients will provide feedback on intervention acceptability and appropriateness. Implementation stakeholders will also provide feedback on intervention cost, feasibility, fidelity and sustainability. These outcomes will be measured throughout implementation, using questionnaires and semistructured interviews/expert group discussions. Descriptive statistics, linear mixed-effects regression and thematic analysis will be used to analyse study data.Ethics and disseminationEthics approval was granted by the Sydney Local Health District–Royal Prince Alfred Zone (2020/ETH02518), protocol number: X20-0495. Results will be disseminated through peer-reviewed journals, conference presentations, social media and result summaries distributed to interested participants.Trial registration details(ACTRN12621000145808).

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.

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.

Funder: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior; doi: http://dx.doi.org/10.13039/501100002322, Funder: Radiumhemmets Forskningsfonder; doi: http://dx.doi.org/10.13039/501100007232, Funder: Swedish Cancer Society, Funder: Lunds Universitet Paulsson Trust, Funder: CIBER de Enfermedades Raras of the Instituto de Salud Carlos III, Funder: European Regional Development Fund; doi: http://dx.doi.org/10.13039/501100008530, Funder: Diagnoptics, Funder: CERCA Programme Generalitat de Catalunya, Funder: Esther Koplowitz Center, Barcelona, Spain, Funder: Comision Honoraria de Lucha Contra el Cancer, CSIC, Fundacion Manuel Perez, Montevideo, Uruguay, BACKGROUND: Individuals from melanoma-prone families have similar or reduced sun-protective behaviors compared to the general population. Studies on trends in sun-related behaviors have been temporally and geographically limited. METHODS: Individuals from an international consortium of melanoma-prone families (GenoMEL) were retrospectively asked about sunscreen use, sun exposure (time spent outside), sunburns, and sunbed use at several timepoints over their lifetime. Generalized linear mixed models were used to examine the association between these outcomes and birth cohort defined by decade spans, after adjusting for covariates. RESULTS: A total of 2407 participants from 547 families across 17 centers were analyzed. Sunscreen use increased across subsequent birth cohorts, and although the likelihood of sunburns increased until the 1950s birth cohort, it decreased thereafter. Average sun exposure did not change across the birth cohorts, and the likelihood of sunbed use increased in more recent birth cohorts. We generally did not find any differences in sun-related behavior when comparing melanoma cases to non-cases. Melanoma cases had increased sunscreen use, decreased sun exposure, and decreased odds of sunburn and sunbed use after melanoma diagnosis compared to before diagnosis. CONCLUSIONS: Although sunscreen use has increased and the likelihood of sunburns has decreased in more recent birth cohorts, individuals in melanoma-prone families have not reduced their overall sun exposure and had an increased likelihood of sunbed use in more recent birth cohorts. These observations demonstrate partial improvements in melanoma prevention and suggest that additional intervention strategies may be needed to achieve optimal sun-protective behavior in melanoma-prone families.

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 .

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.

Importance A previous single-center study observed fewer excisions, lower health care costs, thinner melanomas, and better quality of life when surveillance of high-risk patients was conducted in a melanoma dermatology clinic with a structured surveillance protocol involving full-body examinations every 6 months aided by total-body photography (TBP) and sequential digital dermoscopy imaging (SDDI). Objective To examine longer-term sustainability and expansion of the surveillance program to numerous practices, including a primary care skin cancer clinic setting. Design, Setting, and Participants This prospective cohort study recruited 593 participants assessed from 2012 to 2018 as having very high risk of melanoma, with a median of 2.9 years of follow-up (interquartile range, 1.9-3.3 years), from 4 melanoma high-risk clinics (3 dermatology clinics and 1 primary care skin cancer clinic) in New South Wales, Australia. Data analyses were conducted from February to September 2020. Exposures Six-month full-body examination with the aid of TBP and SDDI. For equivocal lesions, the clinician performed SDDI at 3 or 6 months. Main Outcomes and Measures All suspect monitored or excised lesions were recorded, and pathology reports obtained. Outcomes included the incidence and characteristics of new lesions and the association of diagnostic aids with rates of new melanoma detection. Results Among 593 participants, 340 (57.3%) were men, and the median age at baseline was 58 years (interquartile range, 47-66 years). There were 1513 lesions excised during follow-up, including 171 primary melanomas. The overall benign to malignant excision ratio, including keratinocyte carcinomas, was 0.8:1.0; the benign melanocytic to melanoma excision ratio was 2.4:1.0; and the melanoma in situ to invasive melanoma ratio was 2.2:1.0. The excision ratios were similar across the 4 centers. The risk of developing a new melanoma was 9.0% annually in the first 2 years and increased with time, particularly for those with multiple primary melanomas. The thicker melanomas (>1-mm Breslow thickness; 7 of 171 melanomas [4.1%]) were mostly desmoplastic or nodular (4 of 7), self-detected (2 of 7), or clinician detected without the aid of TBP (3 of 7). Overall, new melanomas were most likely to be detected by a clinician with the aid of TBP (54 of 171 [31.6%]) followed by digital dermoscopy monitoring (50 of 171 [29.2%]). Conclusions and Relevance The structured surveillance program for high-risk patients may be implemented at a larger scale given the present cohort study findings suggesting the sustainability and replication of results in numerous settings, including a primary care skin cancer clinic.

The contribution of melanocortin-1 receptor (MC1R) gene variants to the development of early-onset melanoma is unknown. Using an Australian population-based, case-control-family study, we sequenced MC1R for 565 cases with invasive cutaneous melanoma diagnosed between ages 18 and 39 years, 409 unrelated controls and 518 sibling controls. Variants were classified a priori into "R" variants (D84E, R142H, R151C, I155T, R160W, D294H) and "r" variants (all other nonsynonymous variants). We estimated odds ratios (OR) for melanoma using unconditional (unrelated controls) and conditional (sibling controls) logistic regression. The prevalence of having at least one R or r variant was 86% for cases, 73% for unrelated controls and 81% for sibling controls. R151C conferred the highest risk (per allele OR 2.57, 95% confidence interval 1.86-3.56 for the case-unrelated-control analysis and 1.70 (1.12-2.60) for the case-sibling-control analysis). When mutually adjusted, the ORs per R allele were 2.23 (1.77-2.80) and 2.06 (1.47-2.88), respectively, from the two types of analysis, and the ORs per r allele were 1.69 (1.33-2.13) and 1.25 (0.88-1.79), respectively. The associations were stronger for men and those with none or few nevi or with high childhood sun exposure. Adjustment for phenotype, nevi and sun exposure attenuated the overall log OR for R variants by approximately 18% but had lesser influence on r variant risk estimates. MC1R variants explained about 21% of the familial aggregation of melanoma. Some MC1R variants are important determinants of early-onset melanoma. The strength of association with melanoma differs according to the type and number of variants.

To examine associations between early-life sun exposure and risk of invasive cutaneous melanoma diagnosed between ages 18 and 39 years. Data were analysed from 606 cases and 481 controls from the Australian Melanoma Family Study, a population-based, case–control-family study. Self- and parent-reported sun exposure was collected by interview. Odds ratios (OR) were estimated using unconditional logistic regression, adjusted for potential confounders. Self-reported childhood total sun exposure was not associated with melanoma overall, but was positively associated with melanoma diagnosed at 18–29 years of age (OR for highest vs. lowest quartile: 3.21, 95% confidence intervals (CI) 1.38–7.44; P trend 0.02; P interaction by age group 0.09). Analyses restricted to participants whose self-reported sun exposure was concordant with that recalled by their parents gave an OR for the highest versus lowest tertile of childhood total sun exposure of 2.28 (95% CI 1.03–5.04; P trend 0.05), and for any versus no severe childhood sunburn of 2.36 (95% CI 1.05–5.31). The association of self-reported severe sunburn with melanoma was evident only in people who tended to tan rather than burn and in people who had few nevi. The association of early-life sun exposure with early-onset melanoma is influenced by host factors.

Importance There are limited data among young adults on sunscreen use during childhood and adulthood and on the association of sunscreen use with melanoma risk. Objective To assess correlates of early-life sunscreen use and the association between sunscreen use and risk of cutaneous melanoma before age 40 years. Design, Setting, and Participants This population-based, case-control family study analyzed Australian Melanoma Family Study data for persons with questionnaire data on sunscreen use collected by interview from 2001 to 2005 across 3 states in Australia, representing two-thirds of the country’s population. Case participants (aged 18-39 years) had confirmed first primary melanoma. Siblings of case participants were included, and case participants without a sibling control were excluded. Unrelated controls (aged 18-44 years) were recruited from the electoral roll or were a spouse, partner, or friend nominated by case participants. Data analyses were conducted from October 2017 to February 2018. Exposures Self- and parent-reported sunscreen use, sun exposure, and other candidate risk factors during childhood and adulthood. Main Outcomes and Measures Logistic regression analyses adjusted for potential confounders were used to estimate odds ratios (ORs) for melanoma and for correlates of sunscreen use. Results Participation was 629 of 830 contactable cases (76%) (629 of 1197 overall [53%]), 240 of 570 contactable controls (42%) from the electoral roll (240 of 1068 overall [23%]), and 295 of 371 nominated spouse or friend controls (80%); analysis incuded 603 cases and 1088 controls. The median (interquartile range) age was 32 (28-36) years for 603 cases, 35 (30-38) years for 478 unrelated controls, and 34 (29-38) years for 610 sibling controls. There were more women than men (range, 57%-62%) in all groups, approximately 40% (range, 39%-43%) of participants had a university education, and most participants (range, 58%-73%) had British/northern European ethnicity. Risk of melanoma was less with higher use of sunscreen in childhood (OR for highest vs lowest tertiles, 0.60; 95% CI, 0.42-0.87; P = .02 for trend) and across the lifetime (OR, 0.65; 95% CI, 0.45-0.93; P = .07 for trend). Subgroup analyses suggested that the protective association of sunscreen with melanoma was stronger for people reporting blistering sunburn, receiving a diagnosis of melanoma at a younger age, or having some or many nevi. Total lifetime sun exposure was unrelated to melanoma risk (OR for highest vs lowest tertile, 0.97; 95% CI, 0.66-1.43; P = .94 for trend). By contrast, total sun exposure inversely weighted by sunscreen use (as a measure of sun exposure unprotected by sunscreen) was significantly associated with melanoma risk (OR, 1.80; 95% CI, 1.22-2.65; P = .007 for trend) and appeared stronger for people having lighter pigmentation or some or many nevi or using sunscreen to stay longer in the sun. Regular users of sunscreen were more likely to be female, younger, and of British or northern European ancestry and to have higher educational levels, lighter skin pigmentation, and a stronger history of blistering sunburn. Conclusions and Relevance Our findings provided evidence that regular sunscreen use is significantly associated with reduced risk of cutaneous melanoma among young adults and identified several characteristics associated with less sunscreen use.

Discovering and understanding genetic risk factors for melanoma and their interactions with phenotype, sun exposure, and other risk factors could lead to new strategies for melanoma control. This paper describes the Australian Melanoma Family Study, which uses a multicenter, population-based, case-control-family design. From 2001 to 2005, the authors recruited 1,164 probands including 629 cases with histopathologically confirmed, first-primary cutaneous melanoma diagnosed before age 40 years, 240 population-based controls frequency matched for age, and 295 spouse/friend controls. Information on lifetime sun exposure, phenotype, and residence history was collected for probands and nearly 4,000 living relatives. More than 3,000 subjects donated a blood sample. Proxy-reported information was collected for childhood sun exposure and deceased relatives. Important features of this study include the population-based, family-based design; a focus on early onset disease; probands from 3 major cities differing substantially in solar ultraviolet exposure and melanoma incidence; a population at high risk because of high ultraviolet exposure and susceptible pigmentation phenotypes; population-based, spouse/friend, and sibling controls; systematic recruitment of relatives of case and control probands; self and parent reports of childhood sun exposure; and objective clinical skin examinations. The authors discuss methodological and analytical issues related to the study design and conduct, as well as the potentially novel insights the study can deliver.

Peter Brugger spricht uber die von ihm seit Jahren erforschte Beziehung zwischen dem Glauben an paranormale Phanomene (Hellsehen, Telepathie etc.) und Gehirnfunktionen. Es werden Experimente (zur semantischen Bahnung) dargestellt, anhand deren eine neuropsychologische Leistung, z. B. assoziatives Verhalten, als Funktion der Glaubigkeit studiert wird. Die Experimente zeigen, dass glaubige Probanden uber eine bessere Bahnung in der rechten Hirnhalfte verfugen, d. h., es ist die rechte Hirnhalfte, die metaphorisch denkt. Das magische Denken hat ein Janusgesicht: Einerseits brauchen wir eine Prise Magie, wenn wir die Grenzen der Wissenschaft uberschreiten wollen. Nimmt das magische Denken aber ein pathologisches Ausmas an, wie z. B. in der Schizophrenie, so erschwert es die Anpassung an die Realitat.

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.

In Interviews mit der leitenden Arztin der Schmerzklinik des Universitatsspitals Zurich und den beiden Psychologinnen der Rheumaklinik werden zwei Modelle der interdisziplinaren Behandlung chronischer Schmerzerkrankungen dargestellt. Alle Beteiligten gehen von einem biopsychosozialen Schmerzverstandnis aus, und es werden die moglichen Ursachen diskutiert, die zur Entwicklung einer chronischen Schmerzkrankheit beitragen. An der Schmerzklinik spielt die Therapie mit Medikamenten (Opioide, Antidepressiva) eine grose Rolle. Die Psychologinnen der Rheumaklinik versuchen mit einer Kombination verschiedener Methoden (Gruppenpsychotherapie, Medizinische Trainingstherapie etc.), die Patienten zu aktivieren.

Background Mutations in the CDKN2A and CDK4 genes predispose to melanoma. From three case-control studies of cutaneous melanoma, we estimated the prevalence and predictors of these mutations for people from regions with widely differing latitudes and melanoma incidence. Methods Population-based cases and controls from the United Kingdom (1586 cases, 499 controls) and Australia (596 early-onset cases, 476 controls), and a hospital-based series from Spain (747 cases, 109 controls), were screened for variants in all exons of CDKN2A and the p16INK4A binding domain of CDK4. Results The prevalence of mutations for people with melanoma was similar across regions: 2.3%, 2.5% and 2.0% for Australia, Spain and the United Kingdom respectively. The strongest predictors of carrying a mutation were having multiple primaries (odds ratio (OR) = 5.4, 95% confidence interval (CI: 2.5, 11.6) for 2 primaries and OR = 32.4 (95% CI: 14.7, 71.2) for 3 or more compared with 1 primary only); and family history (OR = 3.8; 95% CI:1.89, 7.5) for 1 affected first- or second-degree relative and OR = 23.2 (95% CI: 11.3, 47.6) for 2 or more compared with no affected relatives). Only 1.1% of melanoma cases with neither a family history nor multiple primaries had mutations. Conclusions There is a low probability (

Background: Awareness of individual risk may encourage improved prevention and early detection of melanoma. Methods: We evaluated the accuracy of self-reported pigmentation and nevus phenotype compared with clinical assessment, and examined agreement between nevus counts from selected anatomical regions. The sample included 456 cases with invasive cutaneous melanoma diagnosed between ages 18 to 39 years and 538 controls from the population-based Australian Melanoma Family Study. Participants completed a questionnaire about their pigmentation and nevus phenotype, and attended a dermatologic skin examination. Results: There was strong agreement between self-reported and clinical assessment of eye color [κ, = 0.78; 95% confidence interval (CI), 0.74–0.81]; and moderate agreement for hair color (κ = 0.46; 95% CI, 0.42–0.50). Agreement between self-reported skin color and spectrophotometer-derived measurements was poor (κ = 0.12; 95% CI, 0.08–0.16) to moderate (Spearman correlation rs = −0.37; 95% CI, −0.32 to −0.42). Participants tended to underestimate their nevus counts and pigmentation; men were more likely to underreport their skin color. The rs was 0.43 (95% CI, 0.38–0.49) comparing clinical total body nevus counts with self-reported nevus categories. There was good agreement between total body nevus counts and site-specific nevus counts, particularly on both arms. Conclusions: Young adults have suboptimal accuracy when assessing important risk characteristics including nevus numbers and pigmentation. Measuring nevus count on the arms is a good predictor of full body nevus count. Impact: These results have implications for the likely success of targeted public health programs that rely on self-assessment of these factors. Cancer Epidemiol Biomarkers Prev; 24(4); 736–43. ©2015 AACR.

Importance The clinical phenotype and certain predisposing genetic mutations that confer increased melanoma risk are established; however, no consensus exists regarding optimal screening for such individuals. Early identification remains the most important intervention in reducing melanoma mortality. Objective To evaluate the impact of full-body examinations every 6 months supported by dermoscopy and total-body photography (TBP) on all patients and sequential digital dermoscopy imaging (SDDI), when indicated, on detecting primary melanoma in an extreme-risk population. Design, Setting, and Participants Prospective observational study from February 2006 to February 2011, with patients recruited from Sydney Melanoma Diagnostic Centre and Melanoma Institute Australia who had a history of invasive melanoma and dysplastic nevus syndrome, history of invasive melanoma and at least 3 first-degree or second-degree relatives with prior melanoma, history of at least 2 primary invasive melanomas, or a CDKN2A or CDK4 gene mutation. Exposures Six-month full-body examination compared with TBP. For equivocal lesions, SDDI short term (approximately 3 months) or long term (≥6 months), following established criteria, was performed. Atypical lesions were excised. Main Outcomes and Measures New primary melanoma numbers, characteristics, and cumulative incidence in each patient subgroup; effect of diagnostic aids on new melanoma identification. Results In 311 patients with a median (interquartile range [IQR]) follow-up of 3.5 (2.4-4.2) years, 75 primary melanomas were detected, 14 at baseline visit. Median (IQR) Breslow thickness of postbaseline incident melanomas was in situ (in situ to 0.60 mm). Thirty-eight percent were detected using TBP and 39% with SDDI. Five melanomas were greater than 1 mm Breslow thickness, 3 of which were histologically desmoplastic; the other 2 had nodular components. The benign to malignant excision ratio was 1.6:1 for all lesions excised and 4.4:1 for melanocytic lesions. Cumulative risk of developing a novel primary melanoma was 12.7% by year 2, with new primary melanoma incidence during the final 3 years of follow-up half of that observed during the first 2 years (incidence density ratio, 0.43 [95% CI, 0.25-0.74]; P = .002). Conclusions and Relevance Monitoring patients at extreme risk with TBP and SDDI assisted with early diagnosis of primary melanoma. Hypervigilance for difficult-to-detect thick melanoma subtypes is crucial.

Mutation analysis of two genes involved in melanoma susceptibility (CDKN2A/p16INK4a and CDK4) was undertaken in 131 probands with a family history of melanoma. Screening of all three exons of CDKN2A and exon 2 of CDK4 by single-strand conformation polymorphism (SSCP) analysis and/or direct sequencing identified a total of 10 different CDKN2A germline mutations, including 6 not previously described in the germline. All but one has been previously proven to, or is likely to, affect the structure and function of p16INK4a. The incidence of CDKN2A mutation was 8.4% (11/131), but was significantly higher in families with three or more cases of melanoma (10/66, 15.1%) than in those in which only two relatives were affected (1/65, 1.5%). The incidence of CDKN2A mutation was also higher in families with three or more cases of melanoma and at least one member with multiple primary melanomas (6/19, 31.6%) than in similar families without multiple primary melanomas (4/47, 8.5%). One novel CDK4 variant of uncertain significance was found in a kindred that also carries a CDKN2A mutation. Genes Chromosomes Cancer 25:339–348, 1999. © 1999 Wiley-Liss, Inc.

Family and twin studies indicate that melanoma susceptibility has a strong genetic component. Very rarely, melanoma runs in families in which there is an inherited mutation in a single ‘high penetrance’ gene, but in the general population melanoma susceptibility is thought to be governed by variation in a series of ‘low penetrance’ genes. We sought to identify new melanoma risk genes of both classes by conducting an Australian genome-wide association study (GWAS) of ~2200 melanoma cases and ~4300 matched controls (from the AMFS and Q-MEGA studies), in parallel with whole-genome sequencing of cases from densely affected melanoma families with follow up genotyping of interesting variants in the GWAS sample and other highly case-loaded melanoma families. Genotyping of the GWAS sample was carried out using Illumina Hap610K or OMNI 1M arrays. All 25 SNPs that reached genome-wide statistical significance (i.e. p

We performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian individuals with melanoma and 4,387 control individuals. In this discovery phase, we confirm several previously characterized melanoma-associated loci at MC1R, ASIP and MTAP-CDKN2A. We selected variants at nine loci for replication in three independent case-control studies (Europe: 2,804 subjects with melanoma, 7,618 control subjects; United States 1: 1,804 subjects with melanoma, 1,026 control subjects; United States 2: 585 subjects with melanoma, 6,500 control subjects). The combined meta-analysis of all case-control studies identified a new susceptibility locus at 1q21.3 (rs7412746, P = 9.0 x 10(-11), OR in combined replication cohorts of 0.89 (95% CI 0.85-0.95)). We also show evidence suggesting that melanoma associates with 1q42.12 (rs3219090, P = 9.3 x 10(-8)). The associated variants at the 1q21.3 locus span a region with ten genes, and plausible candidate genes for melanoma susceptibility include ARNT and SETDB1. Variants at the 1q21.3 locus do not seem to be associated with human pigmentation or measures of nevus density.

So far, two genes associated with familial melanoma have been identified, accounting for a minority of genetic risk in families. Mutations in CDKN2A account for approximately 40% of familial cases, and predisposing mutations in CDK4 have been reported in a very small number of melanoma kindreds. Here we report the whole-genome sequencing of probands from several melanoma families, which we performed in order to identify other genes associated with familial melanoma. We identify one individual carrying a novel germline variant (coding DNA sequence c.G1075A; protein sequence p.E318K; rs149617956) in the melanoma-lineage-specific oncogene microphthalmia-associated transcription factor (MITF). Although the variant co-segregated with melanoma in some but not all cases in the family, linkage analysis of 31 families subsequently identified to carry the variant generated a log of odds (lod) score of 2.7 under a dominant model, indicating E318K as a possible intermediate risk variant. Consistent with this, the E318K variant was significantly associated with melanoma in a large Australian case-control sample. Likewise, it was similarly associated in an independent case-control sample from the United Kingdom. In the Australian sample, the variant allele was significantly over-represented in cases with a family history of melanoma, multiple primary melanomas, or both. The variant allele was also associated with increased naevus count and non-blue eye colour. Functional analysis of E318K showed that MITF encoded by the variant allele had impaired sumoylation and differentially regulated several MITF targets. These data indicate that MITF is a melanoma-predisposition gene and highlight the utility of whole-genome sequencing to identify novel rare variants associated with disease susceptibility.

Background CDKN2A mutations confer a substantial risk of cutaneous melanoma; however, the magnitude of risk is uncertain. Methods The study estimated the hazard ratio (HR) and the average age specific cumulative risk (ie, penetrance) of reported melanoma for CDKN2A mutation carriers in case families using a modified segregation analysis of the first and higher degree relatives of 35 population-based cases. The study sample included 223 relatives of 13 melanoma cases diagnosed when aged 18–39 years from Melbourne, Sydney and Brisbane, Australia, and 322 relatives of 22 melanoma cases diagnosed at any age from Yorkshire, UK. Results The estimated HR for melanoma for mutation carriers relative to the general population decreased with regions of increasing ambient ultraviolet (UV) irradiance, being higher for the UK than Australia (87, 95% CI 50 to 153 vs 31, 95% CI 20 to 50, p=0.008), and across Australia, 49 (95% CI 24 to 98) for Melbourne, 44 (95% CI 22 to 88) for Sydney, and 9 (95% CI 2 to 33) for Brisbane (p=0.02). Penetrance did not differ by geographic region. It is estimated that 16% (95% CI 10% to 27%) of UK and 20% (95% CI 13% to 30%) of Australian CDKN2A mutation carriers would be diagnosed with melanoma by age 50 years, and 45% (95% CI 29% to 65%) and 52% (95% CI 37% to 69%), respectively, by age 80 years. Conclusions Contrary to the strong association between UV radiation exposure and melanoma risk for the general population, CDKN2A mutation carriers appear to have the same cumulative risk of melanoma irrespective of the ambient UV irradiance of the region in which they live.

We conducted a genome-wide association pooling study for cutaneous melanoma and performed validation in samples totaling 2,019 cases and 2,105 controls. Using pooling, we identified a new melanoma risk locus on chromosome 20 (rs910873 and rs1885120), with replication in two further samples (combined P < 1 x 10(-15)). The per allele odds ratio was 1.75 (1.53, 2.01), with evidence for stronger association in early-onset cases.

CDKN2A is the major melanoma susceptibility gene so far identified, but only 40% of three or more case families have identified mutations. A comparison of mutation detection rates was carried out by "blind" exchange of samples across GenoMEL, the Melanoma Genetics Consortium, to establish the false negative detection rates. Denaturing high performance liquid chromatography (DHPLC) screening results from 451 samples were compared to screening data from nine research groups in which the initial mutation screen had been done predominantly by sequencing. Three samples with mutations identified at the local centres were not detected by the DHPLC screen. No additional mutations were detected by DHPLC. Mutation detection across groups within GenoMEL is carried out to a consistently high standard. The relatively low rate of CDKN2A mutation detection is not due to failure to detect mutations and implies the existence of other high penetrance melanoma susceptibility genes.

GenoMEL, comprising major familial melanoma research groups from North America, Europe, Asia, and Australia has created the largest familial melanoma sample yet available to characterize mutations in the high-risk melanoma susceptibility genes CDKN2A/alternate reading frames (ARF), which encodes p16 and p14ARF, and CDK4 and to evaluate their relationship with pancreatic cancer (PC), neural system tumors (NST), and uveal melanoma (UM). This study included 466 families (2,137 patients) with at least three melanoma patients from 17 GenoMEL centers. Overall, 41% (n = 190) of families had mutations; most involved p16 (n = 178). Mutations in CDK4 (n = 5) and ARF (n = 7) occurred at similar frequencies (2-3%). There were striking differences in mutations across geographic locales. The proportion of families with the most frequent founder mutation(s) of each locale differed significantly across the seven regions (P = 0.0009). Single founder CDKN2A mutations were predominant in Sweden (p.R112_L113insR, 92% of family's mutations) and the Netherlands (c.225_243del19, 90% of family's mutations). France, Spain, and Italy had the same most frequent mutation (p.G101W). Similarly, Australia and United Kingdom had the same most common mutations (p.M53I, c.IVS2-105A>G, p.R24P, and p.L32P). As reported previously, there was a strong association between PC and CDKN2A mutations (P < 0.0001). This relationship differed by mutation. In contrast, there was little evidence for an association between CDKN2A mutations and NST (P = 0.52) or UM (P = 0.25). There was a marginally significant association between NST and ARF (P = 0.05). However, this particular evaluation had low power and requires confirmation. This GenoMEL study provides the most extensive characterization of mutations in high-risk melanoma susceptibility genes in families with three or more melanoma patients yet available. (Cancer Res 2006; 66(20): 9818-28)

BACKGROUND: The major factors individually reported to be associated with an increased frequency of CDKN2A mutations are increased number of patients with melanoma in a family, early age at melanoma diagnosis, and family members with multiple primary melanomas (MPM) or pancreatic cancer. METHODS: These four features were examined in 385 families with > or =3 patients with melanoma pooled by 17 GenoMEL groups, and these attributes were compared across continents. RESULTS: Overall, 39% of families had CDKN2A mutations ranging from 20% (32/162) in Australia to 45% (29/65) in North America to 57% (89/157) in Europe. All four features in each group, except pancreatic cancer in Australia (p = 0.38), individually showed significant associations with CDKN2A mutations, but the effects varied widely across continents. Multivariate examination also showed different predictors of mutation risk across continents. In Australian families, > or =2 patients with MPM, median age at melanoma diagnosis or =6 patients with melanoma in a family jointly predicted the mutation risk. In European families, all four factors concurrently predicted the risk, but with less stringent criteria than in Australia. In North American families, only > or =1 patient with MPM and age at diagnosis < or =40 years simultaneously predicted the mutation risk. CONCLUSIONS: The variation in CDKN2A mutations for the four features across continents is consistent with the lower melanoma incidence rates in Europe and higher rates of sporadic melanoma in Australia. The lack of a pancreatic cancer-CDKN2A mutation relationship in Australia probably reflects the divergent spectrum of mutations in families from Australia versus those from North America and Europe. GenoMEL is exploring candidate host, genetic and/or environmental risk factors to better understand the variation observed.

Background Melanocortin-1 receptor (MC1R) gene variants are very common and are associated with melanoma risk, but their contribution to melanoma risk prediction compared with traditional risk factors is unknown. We aimed to 1) evaluate the separate and incremental contribution of MC1R genotype to prediction of early-onset melanoma, and compare this with the contributions of physician-measured and self-reported traditional risk factors, and 2) develop risk prediction models that include MC1R, and externally validate these models using an independent dataset from a genetically similar melanoma population. Methods Using data from an Australian population-based, case-control-family study, we included 413 case and 263 control participants with sequenced MC1R genotype, clinical skin examination and detailed questionnaire. We used unconditional logistic regression to estimate predicted probabilities of melanoma. Results were externally validated using data from a similar study in England. Results When added to a base multivariate model containing only demographic factors, MC1R genotype improved the area under the receiver operating characteristic curve (AUC) by 6% (from 0.67 to 0.73; P

We transplanted pole cells betweenDrosophila melanogaster, D. mauritiana andD. ananassae to investigate the ability of germ cells to develop in the gonad of a heterospecific host, and to study the interaction between somatic follicle cells and the cells of the germ line in producing the species-specific chorion. FemaleD. mauritiana germ cells in aD. melanogaster ovary produced functional eggs with normal development potential. The same is true for the reciprocal combination. FemaleD. ananassae pole cells in aD. melanogaster host only developed to a very early stage and degenerated afterwards. None of the interspecific combinations of male pole cells led to functional sperm. We could not determine at what stage the transplanted male pole cells were arrested. The cooperation of follicle cells and the oocyte-nurse cell complex in producing the chorion was studied using the germ-line-dependent mutationfs(1) K10 ofD. melanogaster, which causes fused respiratory appendages and an abnormal chorion morphology. Wild-type femaleD. mauritiana germ cells in a mutantfs(1) K10 D. melanogaster ovary led to the production of wild-type eggs withD. melanogaster-specific, short respiratory appendages. On the other hand,D. melanogaster fs(1) K10 germ cells in aD. mauritiana ovary induced the formation of eggs with mutant fused appendages which were, however, typicallyD. mauritiana in length. When.D. mauritiana pole cells developed in aD. melanogaster ovary, the chorion exhibited a new imprint pattern that differs from both species-specific patterns.

SummarySex determination inDrosophiladepends on the ratio ofXchromosomes to sets of autosomes (X:A). This chromosomal signal is used to regulate a few control genes whose state of activity selects either the male or the female sexual pathway. We have studied the structure and function ofdsx(double sex) which appears to be the last regulatory gene on whose function the sexual pathway eventually depends. We have mutagenized the locus, varied the doses of dominantdsx-mutations and wildtype alleles, and combined differentdsx-alleles with recessive mutations in other sex-determining genes, such asix,tra-2andtra.The locusdsxharbours two genetic functions,dsxmto implement the male program,dsxfto implement the female program. We found thatdsxmanddsxfcan mutate independently although most mutations abolish both functions. We conclude thatdsxmanddsxfeach have their specific domain, but also share a large region of DNA that is essential for both functions. We present evidence that the dominant mutations correspond to a constitutive expression of the male-determining functiondsxm, with the simultaneous abolishment of the female-determining functiondsxf. This effect can be counteracted by two doses of expresseddsxfso that a female phenotype results. The products of one dose of expresseddsxmand one dose of expresseddsxfin the same cell appear to neutralize each other which leads to a null phenotype. The mutant combinations suggest that the product ofdsxfrequires the products ofix+,tra-2+andtra+to become functional.

To investigate the mechanism of sex determination in the germ line, we analyzed the fate of XY germ cells in ovaries, and the fate of XX germ cells in testes. In ovaries, germ cells developed according to their X:A ratio, i.e., XX cells underwent oogenesis, XY cells formed spermatocytes. In testes, however, XY and XX germ cells entered the spermatogenic pathway. Thus, to determine their sex, the germ cells of Drosophila have cell-autonomous genetic information, and XX cells respond to inductive signals of the soma. Results obtained with amorphic and constitutive mutations of Sxl show that both the genetic and the somatic signals act through Sxl to achieve sex determination in germ cells.