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1.
Nat Commun ; 10(1): 3163, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31320640

RESUMO

Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors. Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2. Significantly mutated genes are NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8. SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas. TERT aberrations and ATRX mutations are associated with alterations in telomere length. Mutation profiles of the majority of mucosal melanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.

2.
J Invest Dermatol ; 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31254517

RESUMO

Actinic keratosis (AK), Bowen's disease (BD) and cutaneous squamous cell carcinoma (cSCC) are heterogeneous keratinocytic skin lesions (KSL). Biomarkers that can accurately stratify these lesion types are needed to support a new paradigm of personalised, precise management of skin neoplasia. In this paper, we used the data independent acquisition (DIA) proteomics workflow, SWATH-MS, to analyse formalin-fixed paraffin embedded (FFPE) samples of normal skin and KSL including well differentiated (WD), moderately differentiated (MD) and poorly differentiated (PD) cSCC. We quantified 3574 proteins across 93 samples studied. Differential abundance analysis identified 19, five and six protein markers exclusive to AK, BD and cSCC lesions, respectively. Among cSCC lesions of various levels of tumour differentiation, 118, 230 and 17 proteins showed potential as biomarkers of WD-, MD- and PD-cSCC lesions, respectively. Bioinformatics analysis revealed that AK and cSCC lesions were associated with decreased apoptosis, and BD lesions with over-representation of DNA damage repair pathway. Differential expression of FGFR2 alternative splicing, Rho GTPase signalling, and RNA metabolism proteins were associated with the level of cSCC tumour differentiation. Proteome profiles also separated KSL subtypes on principal components analysis. Overall, protein markers have excellent potential to discriminate KSL subtypes and facilitate new diagnostic and therapeutic strategies.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31228015

RESUMO

OBJECTIVE: This study aimed to evaluate the cost effectiveness of a newly developed psycho-educational intervention to reduce fear of cancer recurrence (FCR) in early-stage melanoma patients. METHODS: A within-trial cost-effectiveness and cost-utility analysis was conducted from the Australian health system perspective using data from linked Medicare records. Outcomes included FCR, measured with the severity subscale of the FCR Inventory; quality-adjusted life years (QALYs) measured using the preference-based instrument, Assessment of Quality of Life-8 Dimensions (AQoL-8D) and 12-month survival. An incremental cost-effectiveness ratio (ICER) was calculated for two economic outcomes: (1) cost per additional case of 'high' FCR avoided and (2) cost per QALY gained. Means and 95% CIs around the ICER were generated from non-parametric bootstrapping with 1000 replications. RESULTS: A total of 151 trial participants were included in the economic evaluation. The mean cost of the psycho-educational intervention was AU$1614 per participant, including intervention development costs. The ICER per case of high FCR avoided was AU$12,903. The cost-effectiveness acceptability curve demonstrated a 78% probability of the intervention being cost effective relative to the control at a threshold of AU$50,000 per extra person avoiding FCR. The ICER per QALY gained was AU$116,126 and the probability of the intervention being cost effective for this outcome was 36% at a willingness to pay of AU$50,000 per QALY. CONCLUSION: The psycho-educational intervention reduced FCR at 12 months for people at high risk of developing another melanoma and may represent good value for money. For the QALY outcome, the psycho-educational intervention is unlikely to be cost effective at standard government willingness-to-pay levels. The trial was prospectively registered in the Australian and New Zealand Clinical Trials Registry (CTRN12613000304730).

4.
Melanoma Res ; 29(3): 342-344, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31026248

RESUMO

Validating newly discovered biomarkers in large, publicly available data sets is often difficult and requires specialized computer programming skills. Melanoma Explorer is a web application that enables easy interrogation of melanoma omics data sets that are freely available in online data repositories with a point-and-click interface. Two use cases are demonstrated. First, the relationship of lysozyme mRNA expression is shown to be prognostic in two independent gene expression microarray data sets. Second, a figure from a journal article showing the relationship of tumour thickness and miR-382 abundance is reproduced. Melanoma Explorer is demonstrated to be a useful tool for reproducing results of published studies and providing additional evidence for biomarkers in independent data sets.


Assuntos
Biomarcadores Tumorais/genética , Biologia Computacional/métodos , Internet , Melanoma/genética , Recidiva Local de Neoplasia/genética , Neoplasias Cutâneas/genética , Software , Metilação de DNA , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma/mortalidade , Melanoma/patologia , Melanoma/terapia , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Prognóstico , Linguagens de Programação , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/secundário , Neoplasias Cutâneas/terapia , Taxa de Sobrevida
5.
J Am Acad Dermatol ; 81(2): 386-394, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30731170

RESUMO

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.

6.
J Invest Dermatol ; 139(8): 1762-1768, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30772300

RESUMO

The benign melanocytic nevus is the most common tumor in humans and rarely transforms into cutaneous melanoma. Elucidation of the nevus genome is required to better understand the molecular steps of progression to melanoma. We performed whole genome sequencing on a series of 14 benign melanocytic nevi consisting of both congenital and acquired types. All nevi had driver mutations in the MAPK signaling pathway, either BRAF V600E or NRAS Q61R/L. No additional definite driver mutations were identified. Somatic mutations in nevi with higher mutation loads showed a predominance of mutational signatures 7a and 7b, consistent with UVR exposure, whereas nevi with lower mutation loads (including all three congenital nevi) had a predominance of the ubiquitous signatures 1 and 5. Two nevi had mutations in promoter regions predicted to bind E26 transformation-specific family transcription factors, as well as subclonal mutations in the TERT promoter. This paper presents whole genome data from melanocytic nevi. We confirm that UVR is involved in the etiology of a subset of nevi. This study also establishes that TERT promoter mutations are present in morphologically benign skin nevi in subclonal populations, which has implications regarding the interpretation of this emerging biomarker in sensitive assays.

7.
Int J Cancer ; 144(12): 3070-3085, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-30556600

RESUMO

Despite recent advances in targeted and immune-based therapies, advanced stage melanoma remains a clinical challenge with a poor prognosis. Understanding the genes and cellular processes that drive progression and metastasis is critical for identifying new therapeutic strategies. Here, we found that the GTPase RAB27A was overexpressed in a subset of melanomas, which correlated with poor patient survival. Loss of RAB27A expression in melanoma cell lines inhibited 3D spheroid invasion and cell motility in vitro, and spontaneous metastasis in vivo. The reduced invasion phenotype was rescued by RAB27A-replete exosomes, but not RAB27A-knockdown exosomes, indicating that RAB27A is responsible for the generation of pro-invasive exosomes. Furthermore, while RAB27A loss did not alter the number of exosomes secreted, it did change exosome size and altered the composition and abundance of exosomal proteins, some of which are known to regulate cancer cell movement. Our data suggest that RAB27A promotes the biogenesis of a distinct pro-invasive exosome population. These findings support RAB27A as a key cancer regulator, as well as a potential prognostic marker and therapeutic target in melanoma.

8.
Australas J Dermatol ; 2018 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-30302753

RESUMO

BACKGROUND/OBJECTIVES: There are limited population-based data documenting the incidence and management of lentigo maligna (LM) and invasive lentigo maligna melanoma (LMM). We report the data on occurrence and management of LM and LMM in an Australian population. METHODS: Prospective collection of incidence and clinician-reported management of melanoma in situ (MIS; n = 450, capped) and localised invasive melanoma (n = 3251) notified to the New South Wales Cancer Registry over 12-months in 2006-2007. RESULTS: The estimated annual incidence of all MIS was 27.0 per 100 000 (LM 12.2, non-LM MIS 5.9 and unclassified MIS 9.0). Patients with LM or LMM were on average approximately 10 years older than those with other melanoma subtypes (P < 0.001). The head and neck was the location of 59% of LM, 44% of LMM and <20% of other melanoma subtypes (P < 0.001). The majority of LM and LMM were treated only by specialists. Diagnostic partial biopsies were more frequent for LM and LMM than for other melanoma subtypes, and primary care physicians were more likely than specialists to do a punch partial biopsy than a shave biopsy. The reported median definitive excision margin for LM was 5.0 mm compared with 7.2 mm for non-LM MIS (P = 0.001). CONCLUSIONS: In this Australian population, LM was twice as frequent as other types of MIS. Improved strategies for diagnosis and management are required.

9.
Proteomics Clin Appl ; : e1800084, 2018 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-30247810

RESUMO

PURPOSE: Actinic keratoses (AK) are premalignant tumors that can be clinically difficult to differentiate from skin cancer. An easy, quick, and reliable noninvasive alternative to biopsy is needed to definitively confirm the clinical diagnoses. This study evaluates Tape Stripping (TS) of stratum corneum (SC) for noninvasive biomarker analysis of AK. METHOD: Lesional and nonlesional human SC samples are obtained by application of stripping tapes on the skin of five AK patients. Following sample preparation, protein digests are analyzed by LC-MS/MS. Bioinformatics analyses are performed using Funrich, Ingenuity Pathway Analysis (IPA), and Oncomine bioinformatics and analytical tools. RESULTS: Of the total 613 unique proteins identified, 477 overlap with proteins identified in the proteomic analysis of formalin-fixed and paraffin-embedded (FFPE) AK samples. Additionally, 32 proteins are significantly increased and four proteins decreased in AK samples compared to the normal skin (p < 0.05). In line with proteomic analysis of FFPE samples, IPA and Funrich analysis show that differentially abundant proteins in the TS AK samples are implicated in PI3K/AKT and EGF signaling pathways. These findings are confirmed at the transcript level. CONCLUSION: Tape stripped AK sample is suitable for biomarker analysis. The application of this technique further could revolutionize management of keratinocytic skin tumors by reducing the need for traditional invasive biopsy.

10.
Int J Cancer ; 2018 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-30178487

RESUMO

Cutaneous melanoma accounts for at least >10% of all cancers in adolescents and young adults (AYA, 15-30 years of age) in Western countries. To date, little is known about the correlations between germline variants and somatic mutations and mutation signatures in AYA melanoma patients that might explain why they have developed a cancer predominantly affecting those over 65 years of age. We performed genomic analysis of 50 AYA melanoma patients (onset 10-30 years, median 20); 25 underwent whole genome sequencing (WGS) of both tumor and germline DNA, exome data were retrieved from 12 TCGA AYA cases, and targeted DNA sequencing was conducted on 13 cases. The AYA cases were compared with WGS data from 121 adult cutaneous melanomas. Similar to mature adult cutaneous melanomas, AYA melanomas showed a high mutation burden and mutation signatures of ultraviolet radiation (UVR) damage. The frequencies of somatic mutations in BRAF (96%) and PTEN (36%) in the AYA WGS cohort were double the rates observed in adult melanomas (Q < 6.0 × 10-6 and 0.028, respectively). Furthermore, AYA melanomas contained a higher proportion of non-UVR-related mutation signatures than mature adult melanomas as a proportion of total mutation burden (p = 2.0 × 10-4 ). Interestingly, these non-UVR mutation signatures relate to APOBEC or mismatch repair pathways, and germline variants in related genes were observed in some of these cases. We conclude that AYA melanomas harbor some of the same molecular aberrations and mutagenic insults occurring in older adults, but in different proportions. Germline variants that may have conferred disease susceptibility correlated with somatic mutation signatures in a subset of AYA melanomas.

11.
Br J Cancer ; 119(6): 713-723, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30116025

RESUMO

BACKGROUND: Genotyping of melanomas is used to identify patients for treatment with BRAF and MEK inhibitors, but clinical responses are highly variable. This study investigated the utility of protein expression phenotyping to provide an integrated assessment of gene expression programs in BRAF/NRAS melanoma which would be useful for prognosis and may predict response to MEK inhibition. METHODS: Mass spectrometry profiling of early passage cell lines established from Stage III cutaneous melanomas was conducted. Basal protein expression was correlated with in vitro response to the MEK inhibitor, selumetinib. Protein expression in a cohort of 32 drug naïve BRAF/NRAS metastatic melanoma specimens was examined. The prognostic utility of a subset of these proteins and mRNA transcripts from a separate cohort was determined. RESULTS: Unsupervised analysis of basal cell line protein abundances delineated response to selumetinib, but BRAF/NRAS genotype did not. Resistance was associated with functions including cell motility, cell adhesion and cytoskeletal organization. Several of these response biomarkers were observed in lymph node biospecimens and correlated with melanoma-specific survival. Loss of ICAM-1 protein and mRNA expression was a strong prognosticator of diminished survival in BRAF/NRAS mutant melanoma. CONCLUSIONS: These results demonstrate the utility of proteomic phenotyping to identify both putative biomarkers of response to MEK inhibition and prognostication associated with metastatic melanoma.

12.
JAMA Dermatol ; 154(9): 1001-1009, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30027280

RESUMO

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.

13.
J Invest Dermatol ; 138(12): 2617-2624, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29890168

RESUMO

It is unclear to what degree genomic and traditional (phenotypic and environmental) risk factors overlap in their prediction of melanoma risk. We evaluated the incremental contribution of common genomic variants (in pigmentation, nevus, and other pathways) and their overlap with traditional risk factors, using data from two population-based case-control studies from Australia (n = 1,035) and the United Kingdom (n = 1,460) that used the same questionnaires. Polygenic risk scores were derived from 21 gene regions associated with melanoma and odds ratios from published meta-analyses. Logistic regression models were adjusted for age, sex, center, and ancestry. Adding the polygenic risk score to a model with traditional risk factors increased the area under the receiver operating characteristic curve (AUC) by 2.3% (P = 0.003) for Australia and by 2.8% (P = 0.002) for Leeds. Gene variants in the pigmentation pathway, particularly MC1R, were responsible for most of the incremental improvement. In a cross-tabulation of polygenic by traditional tertile risk scores, 59% (Australia) and 49% (Leeds) of participants were categorized in the same (concordant) tertile. Of participants with low traditional risk, 9% (Australia) and 21% (Leeds) had high polygenic risk. Testing of genomic variants can identify people who are susceptible to melanoma despite not having a traditional phenotypic risk profile.

14.
Nucleic Acids Res ; 46(10): 4903-4918, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29718321

RESUMO

The replicative immortality of human cancer cells is achieved by activation of a telomere maintenance mechanism (TMM). To achieve this, cancer cells utilise either the enzyme telomerase, or the Alternative Lengthening of Telomeres (ALT) pathway. These distinct molecular pathways are incompletely understood with respect to activation and propagation, as well as their associations with clinical outcomes. We have identified significant differences in the telomere repeat composition of tumours that use ALT compared to tumours that do not. We then employed a machine learning approach to stratify tumours according to telomere repeat content with an accuracy of 91.6%. Importantly, this classification approach is applicable across all tumour types. Analysis of pathway mutations that were under-represented in ALT tumours, across 1,075 tumour samples, revealed that the autophagy, cell cycle control of chromosomal replication, and transcriptional regulatory network in embryonic stem cells pathways are involved in the survival of ALT tumours. Overall, our approach demonstrates that telomere sequence content can be used to stratify ALT activity in cancers, and begin to define the molecular pathways involved in ALT activation.

15.
Contemp Clin Trials ; 70: 106-116, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29802966

RESUMO

BACKGROUND: Reducing ultraviolet radiation (UV) exposure and improving early detection may reduce melanoma incidence, mortality and health system costs. This study aims to evaluate the efficacy and cost-effectiveness of providing information on personal genomic risk of melanoma in reducing UV exposure at 12 months, according to low and high traditional risk. METHODS: In this randomized controlled trial, participants (target sample = 892) will be recruited from the general population, and randomized (1:1 ratio, intervention versus control). Intervention arm participants provide a saliva sample, receive personalized melanoma genomic risk information, a genetic counselor phone call, and an educational booklet on melanoma prevention. Control arm participants receive only the educational booklet. Eligible participants are aged 18-69 years, have European ancestry and no personal history of melanoma. All participants will complete a questionnaire and wear a UV dosimeter to objectively measure their sun exposure at baseline, 1- and 12-month time-points, except 1-month UV dosimetry will be limited to ~250 participants. The primary outcome is total daily Standard Erythemal Doses at 12 months. Secondary outcomes include objectively measured UV exposure for specific time periods (e.g. midday hours), self-reported sun protection and skin-examination behaviors, psycho-social outcomes, and ethical considerations surrounding offering genomic testing at a population level. A within-trial and modelled economic evaluation will be undertaken from an Australian health system perspective to assess the intervention costs and outcomes. DISCUSSION: This trial will inform the clinical and personal utility of introducing genomic testing into the health system for melanoma prevention and early detection at a population-level. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12617000691347.

16.
Int J Cancer ; 143(3): 508-514, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-29473154

RESUMO

Melanoma is the deadliest form of skin cancer, mainly affecting populations of European ancestry. Some observational studies suggest that particular diets reduce melanoma risk, putatively through an increase in polyunsaturated fatty acid (PUFA) consumption. However, interpretation of these observational findings is difficult due to residual confounding or reverse causality. To date, a randomized controlled trial has not been carried out to examine the relationship between PUFAs and melanoma. Hence, we performed a Mendelian randomisation (MR) study to evaluate the link between PUFAs and melanoma. To perform MR, we used summary results from the largest risk genome-wide association study (GWAS) meta-analysis of melanoma, consisting of 12,874 cases and 23,203 controls. As instrumental variables we selected SNPs associated with PUFA levels from a GWAS meta-analysis of PUFA levels, from the CHARGE consortium. We used the inverse variance weighted method to estimate a causal odds ratio. To aid interpretation, we established a benchmark "large" predicted change in PUFAs in which, for example, an increase in docosahexaenoic acid (DPA) of 0.17 units (equal to 1 standard deviation) moves a person from the 17th percentile to the median. Raising PUFA levels by a large amount (increasing DPA by 0.17 units) only negligibly changed melanoma risk: odds ratio [OR] = 1.03 (95% confidence interval [CI] = 0.96-1.10). Other PUFAs yielded similar results as DPA. Our MR analysis suggests that the effect of PUFA levels on melanoma risk is either zero or very small.

17.
Appl Health Econ Health Policy ; 16(2): 235-242, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29305821

RESUMO

BACKGROUND: Specialised surveillance using total body photography and digital dermoscopy to monitor people at very high risk of developing a second or subsequent melanoma has been reported as cost effective. OBJECTIVES: We aimed to estimate the 5-year healthcare budget impact of providing specialised surveillance for people at very high risk of subsequent melanoma from the perspective of the Australian healthcare system. METHODS: A budget impact model was constructed to assess the costs of monitoring and potential savings compared with current routine care based on identification of patients at the time of a melanoma diagnosis. We used data from a published cost-effectiveness analysis of specialised surveillance, and Cancer Registry data, to estimate the patient population and healthcare costs for 2017-2021. RESULTS: When all eligible patients, estimated at 18% of patients with melanoma diagnosed annually in Australia, received specialised surveillance rather than routine care, the cumulative 5-year cost was estimated at $93.5 million Australian dollars ($AU) ($US 64 million) for specialised surveillance compared with $AU 120.7 million ($US 82.7 million) for routine care, delivering savings of $AU 27.2 million ($US 18.6 million). With a staggered introduction of 60% of eligible patients accessing surveillance in year 1, increasing to 90% in years 4 and 5, the cumulative cost over 5 years was estimated at $AU 98.1 million ($US 67.2 million), amounting to savings of $AU 22.6 million ($US 15.5 million) compared with routine care. CONCLUSIONS: Specialised melanoma surveillance is likely to provide substantial cost savings for the Australian healthcare system.

18.
Proteomics Clin Appl ; 12(3): e1700094, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29227041

RESUMO

PURPOSE: To validate differences in protein levels between good and poor prognosis American Joint Committee on Cancer (AJCC) stage III melanoma patients and compile a protein panel to stratify patient risk. EXPERIMENTAL DESIGN: Protein extracts from melanoma metastases within lymph nodes in patients with stage III disease with good (n = 16, >4 years survival) and poor survival (n = 14, <2 years survival) were analyzed by selected reaction monitoring (SRM). Diagonal Linear Discriminant Analysis (DLDA) was performed to generate a protein biomarker panel. RESULTS: SRM analysis identified ten proteins that were differentially abundant between good and poor prognosis stage III melanoma patients. The ten differential proteins were combined with 22 proteins identified in our previous work. A panel of 14 proteins was selected by DLDA that was able to accurately classify patients into prognostic groups based on levels of these proteins. CONCLUSIONS AND CLINICAL RELEVANCE: The ten differential proteins identified by SRM have biological significance in cancer progression. The final signature of 14 proteins identified by SRM could be used to identify AJCC stage III melanoma patients likely to have poor outcomes who may benefit from adjuvant systemic therapy.

19.
JAMA Dermatol ; 154(1): 52-59, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29188268

RESUMO

Importance: The diagnosis of a life-threatening disease like melanoma can affect all aspects of a person's life, including health-related quality of life (HRQOL) and psychological aspects of melanoma such as fear of cancer recurrence (FCR). Economic evaluations of psychological interventions require preference-based (utility) instruments that are sensitive to changes in well-being and HRQOL; however, very few studies have evaluated the sensitivity of these instruments when used for people with melanoma. Objective: To compare utility scores from the multiple-attribute instrument Assessment of Quality of Life-8-Dimension Scale (AQoL-8D) with the mapped utility scores of the Functional Assessment of Cancer Therapy-Melanoma (FACT-M) and to investigate the sensitivity of both instruments in identifying the influence of FCR on HRQOL. Design, Setting, and Participants: This assessment of data from a randomized clinical trial of a psychoeducational intervention to reduce FCR, conducted at 3 high-risk melanoma clinics in Australia, evaluated 164 patients with early-stage melanoma and a high risk of developing a second primary melanoma. Main Outcomes and Measures: The FACT-M and AQoL-8D were used to assess HRQOL and FCR among the study participants. Concurrent validity was assessed by comparing the total and subdomain scores of the 2 instruments, and the strength of associations was assessed using Pearson correlation coefficient. Convergent validity was assessed by comparing participants' HRQOL, demographic, and clinical characteristics using the χ2 test and F statistic. Both the FACT-M and AQoL-8D utilities were regressed on FCR Inventory (FCRI) severity scores to estimate the effect of elevated FCR on HRQOL. Results: A total of 164 participants completed the baseline questionnaires, but only 163 met all inclusion criteria and underwent the full analysis: 72 were women; 91 were men; and mean (SD) age was 58.2 (12.1) years. Both the AQoL-8D and FACT-M instruments showed good concurrent validity and could differentiate between relevant subgroups including level of FCRI severity. The AQoL-8D and FACT-M utilities were strongly correlated (r2 = 0.57). Respondents had a mean (SD) AQoL-8D utility of 0.77 (0.2), and a mean (SD) FACT-M utility score of 0.76 (0.07). High levels of FCRI severity were associated with a decrease in utility of 0.12 (95% CI, -0.19 to -0.05) as measured by AQoL-8D, and a decrease of 0.03 (95% CI, -0.05 to -0.01) as measured by the FACT-M. Conclusions and Relevance: For economic evaluations of psychological interventions in melanoma, the AQoL-8D and FACT-M are valid measures of utility; however, the AQoL-8D demonstrates greater sensitivity to FCRI severity. Our results suggest a significant association between FCR and HRQOL.

20.
J Invest Dermatol ; 137(12): 2606-2612, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28830827

RESUMO

Germline mutations in CDKN2A are frequently identified among melanoma kindreds and are associated with increased atypical nevus counts. However, a clear relationship between pathogenic CDKN2A mutation carriage and other nevus phenotypes including counts of common acquired nevi has not yet been established. Using data from GenoMEL, we investigated the relationships between CDKN2A mutation carriage and 2-mm, 5-mm, and atypical nevus counts among blood-related members of melanoma families. Compared with individuals without a pathogenic mutation, those who carried one had an overall higher prevalence of atypical (odds ratio = 1.64; 95% confidence interval = 1.18-2.28) nevi but not 2-mm nevi (odds ratio = 1.06; 95% confidence interval = 0.92-1.21) or 5-mm nevi (odds ratio = 1.26; 95% confidence interval = 0.94-1.70). Stratification by case status showed more pronounced positive associations among non-case family members, who were nearly three times (odds ratio = 2.91; 95% confidence interval = 1.75-4.82) as likely to exhibit nevus counts at or above the median in all three nevus categories simultaneously when harboring a pathogenic mutation (vs. not harboring one). Our results support the hypothesis that unidentified nevogenic genes are co-inherited with CDKN2A and may influence carcinogenesis.


Assuntos
Inibidor de Quinase Dependente de Ciclina p18/genética , Mutação em Linhagem Germinativa , Melanoma/genética , Nevo/genética , Neoplasias Cutâneas/genética , Análise Mutacional de DNA , Saúde da Família , Feminino , Genótipo , Humanos , Masculino , Nevo Pigmentado/genética , Razão de Chances , Fenótipo , Sistema de Registros
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