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1.  MC1R genotypes and risk of melanoma before age 40 years: a population-based case-control-family study 
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 18–39 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.
PMCID: PMC4330189  PMID: 22095472
MC1R; melanoma; early-onset; phenotype; nevi; sun exposure
2.  Loss-of-Function Fibroblast Growth Factor Receptor-2 Mutations in Melanoma 
We report that 10% of melanoma tumors and cell lines harbor mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. These novel mutations include three truncating mutations and 20 missense mutations occurring at evolutionary conserved residues in FGFR2 as well as among all four FGFRs. The mutation spectrum is characteristic of those induced by UV radiation. Mapping of these mutations onto the known crystal structures of FGFR2 followed by in vitro and in vivo studies show that these mutations result in receptor loss of function through several distinct mechanisms, including loss of ligand binding affinity, impaired receptor dimerization, destabilization of the extracellular domains, and reduced kinase activity. To our knowledge, this is the first demonstration of loss-of-function mutations in a class IV receptor tyrosine kinase in cancer. Taken into account with our recent discovery of activating FGFR2 mutations in endometrial cancer, we suggest that FGFR2 may join the list of genes that play context-dependent opposing roles in cancer.
PMCID: PMC4233648  PMID: 19147536
3.  TRIM16 inhibits proliferation and migration through regulation of interferon beta 1 in melanoma cells 
Oncotarget  2014;5(20):10127-10139.
High basal or induced expression of the tripartite motif protein, TRIM16, leads to reduce cell growth and migration of neuroblastoma and skin squamous cell carcinoma cells. However, the role of TRIM16 in melanoma is currently unknown. TRIM16 protein levels were markedly reduced in human melanoma cell lines, compared with normal human epidermal melanocytes due to both DNA methylation and reduced protein stability. TRIM16 knockdown strongly increased cell migration in normal human epidermal melanocytes, while TRIM16 overexpression reduced cell migration and proliferation of melanoma cells in an interferon beta 1 (IFNβ1)-dependent manner. Chromatin immunoprecipitation assays revealed TRIM16 directly bound the IFNβ1 gene promoter. Low level TRIM16 expression in 91 melanoma patient samples, strongly correlated with lymph node metastasis, and, predicted poor patient prognosis in a separate cohort of 170 melanoma patients with lymph node metastasis. The BRAF inhibitor, vemurafenib, increased TRIM16 protein levels in melanoma cells in vitro, and induced growth arrest in BRAF-mutant melanoma cells in a TRIM16-dependent manner. High levels of TRIM16 in melanoma tissues from patients treated with Vemurafenib correlated with clinical response. Our data, for the first time, demonstrates TRIM16 is a marker of cell migration and metastasis, and a novel treatment target in melanoma.
PMCID: PMC4259410  PMID: 25333256
Melanoma; TRIM16; BRAF inhibitor; cell migration; IFNβ1
4.  The Effect on Melanoma Risk of Genes Previously Associated With Telomere Length 
Telomere length has been associated with risk of many cancers, but results are inconsistent. Seven single nucleotide polymorphisms (SNPs) previously associated with mean leukocyte telomere length were either genotyped or well-imputed in 11108 case patients and 13933 control patients from Europe, Israel, the United States and Australia, four of the seven SNPs reached a P value under .05 (two-sided). A genetic score that predicts telomere length, derived from these seven SNPs, is strongly associated (P = 8.92x10-9, two-sided) with melanoma risk. This demonstrates that the previously observed association between longer telomere length and increased melanoma risk is not attributable to confounding via shared environmental effects (such as ultraviolet exposure) or reverse causality. We provide the first proof that multiple germline genetic determinants of telomere length influence cancer risk.
PMCID: PMC4196080  PMID: 25231748
5.  Association between putative functional variants in the PSMB9 gene and risk of melanoma - re-analysis of published melanoma genome-wide association studies 
Pigment cell & melanoma research  2013;26(3):10.1111/pcmr.12069.
To mine possibly hidden causal single nucleotide polymorphisms (SNPs) in the etiology of melanoma, we investigated the association of SNPs in 76 M/G1 transition genes with melanoma risk using our published genome-wide association study (GWAS) dataset with 1804 melanoma cases and 1,026 cancer-free controls. We found multiple SNPs with P < 0.01 and performed validation studies for 18 putative functional SNPs in PSMB9 in other two GWAS datasets. Two SNPs (rs1351383 and rs2127675) were associated with melanoma risk in the GenoMEL dataset (P = 0.013 and 0.004, respectively), but failed validation in the Australia dataset. Genotype-phenotype analysis revealed these two SNPs were significantly correlated with mRNA expression levels of PSMB9. Further experiments revealed that the promoter SNP rs2071480, which is in high LD with rs1351383 and rs2127675, involved in influencing transcription factor binding and gene expression. Taken together, our data suggested that functional variants in PSMB9 may contribute to melanoma susceptibility.
PMCID: PMC3721546  PMID: 23360169
GWAS; Cell cycle; PSMB9; Polymorphism; melanoma
6.  A highly recurrent RPS27 5'UTR mutation in melanoma 
Oncotarget  2014;5(10):2912-2917.
The incidence of melanoma continues to rise globally and is increasing at a rate greater than any other cancer. To systematically search for new genes involved in melanomagenesis, we collated exome sequencing data from independent melanoma cohort datasets, including those in the public domain. We identified recurrent mutations that may drive melanoma growth, survival or metastasis, and which may hold promise for the design of novel therapies to treat melanoma. These included a frequent recurrent (i.e. hotspot) mutation in the 5' untranslated region of RPS27 in ~10% of samples. We show that the mutation expands the 5'TOP element, a motif known to regulate the expression of most of the ribosomal protein family, to which RPS27 belongs, and thus might sensitize the mutated transcript to growth-mediated regulation. This finding highlights not only the important role of non-protein coding genetic aberrations in cancer development but also their potential as novel therapeutic targets.
PMCID: PMC4102779  PMID: 24913145
Melanoma; somatic mutation; RPS27; exome sequencing; 5' untranslated region
7.  Association between functional polymorphisms in genes involved in the MAPK signaling pathways and cutaneous melanoma risk 
Carcinogenesis  2013;34(4):885-892.
Genome-wide association studies (GWASs) have mainly focused on top significant single nucleotide polymorphisms (SNPs), most of which did not have clear biological functions but were just surrogates for unknown causal variants. Studying SNPs with modest association and putative functions in biologically plausible pathways has become one complementary approach to GWASs. To unravel the key roles of mitogen-activated protein kinase (MAPK) pathways in cutaneous melanoma (CM) risk, we re-evaluated the associations between 47 818 SNPs in 280 MAPK genes and CM risk using our published GWAS dataset with 1804 CM cases and 1026 controls. We initially found 105 SNPs with P ≤ 0.001, more than expected by chance, 26 of which were predicted to be putatively functional SNPs. The risk associations with 16 SNPs around DUSP14 (rs1051849) and a previous reported melanoma locus MAFF/PLA2G6 (proxy SNP rs4608623) were replicated in the GenoMEL dataset (P < 0.01) but failed in the Australian dataset. Meta-analysis showed that rs1051849 in the 3ʹ untranslated regions of DUSP14 was associated with a reduced risk of melanoma (odds ratio = 0.89, 95% confidence interval: 0.82–0.96, P = 0.003, false discovery rate = 0.056). Further genotype–phenotype correlation analysis using the 90 HapMap lymphoblastoid cell lines from Caucasians showed significant correlations between two SNPs (rs1051849 and rs4608623) and messenger RNA expression levels of DUSP14 and MAFF (P = 0.025 and P = 0.010, respectively). Gene-based tests also revealed significant SNPs were over-represented in MAFF, PLA2G6, DUSP14 and other 16 genes. Our results suggest that functional SNPs in MAPK pathways may contribute to CM risk. Further studies are warranted to validate our findings.
PMCID: PMC3616673  PMID: 23291271
8.  Surface antigen profiles of leukocytes and melanoma cells in lymph node metastases are associated with survival in AJCC stage III melanoma patients 
There is an urgent need to identify more accurate prognostic biomarkers in melanoma patients, particularly in those with metastatic disease. This study aimed to identify melanoma and leukocyte surface antigens predictive of survival in a prospective series of AJCC stage IIIb/c melanoma patients (n = 29). Live cell suspensions were prepared from melanoma metastases within lymph nodes (LN). The suspensions were immuno-magnetically separated into CD45+ (leukocyte) and CD45− (non-hematopoietic, enriched melanoma cell) fractions. Surface antigens on CD45− and CD45+ cell populations were profiled using DotScan™ microarrays (Medsaic Pty. Ltd.) and showed differential abundance levels for 52 and 78 antigens respectively. Associations of the surface profiles with clinicopathologic and outcome data (median follow-up 35.4 months post LN resection) were sought using univariate (log-rank test) and multivariate (Wald’s test; modelled with patient’s age, gender and AJCC staging at LN recurrence) survival models. CD9 (p = 0.036), CD39 (p = 0.004) and CD55 (p = 0.005) on CD45+ leukocytes were independently associated with distant metastasis-free survival using multivariate analysis. Leukocytes with high CD39 levels were also significantly associated with increased overall survival (OS) in multivariate analysis (p = 0.016). LNs containing leukocytes expressing CD11b (p = 0.025), CD49d (p = 0.043) and CD79b (p = 0.044) were associated with reduced OS on univariate analysis. For enriched melanoma cells (CD45− cell populations), 11 surface antigens were significantly correlated with the disease-free interval (DFI) between diagnosis of culprit primary melanoma and LN metastasis resection. Nine antigens on CD45+ leukocytes also correlated with DFI. Following validation in independent datasets, surface markers identified here should enable more accurate determination of prognosis in stage III melanoma patients and provide better risk stratification of patients entering clinical trials.
Electronic supplementary material
The online version of this article (doi:10.1007/s10585-014-9636-7) contains supplementary material, which is available to authorized users.
PMCID: PMC3973954  PMID: 24435119
Antibody microarray; Metastatic melanoma; CD antigen; Survival; Prognosis
9.  Oncogenic B-RAFV600E signaling induces the T-box3 transcriptional repressor to repress E-cadherin and enhance melanoma cell invasion 
Approximately 50% of melanomas require oncogenic B-RAFV600E signaling for proliferation, survival and metastasis, and the use of highly selective B-RAF inhibitors has yielded remarkable, albeit short term, clinical responses. Re-activation of signaling downstream of B-RAF is frequently associated with acquired resistance to B-RAF inhibitors, and the identification of B-RAF targets may therefore provide new strategies for managing melanoma. In this report, we applied whole genome expression analyses to reveal that oncogenic B-RAFV600E regulates genes associated with epithelial-mesenchymal transition in normal cutaneous human melanocytes. Most prominent was the B-RAF-mediated transcriptional repression of E-cadherin, a keratinocyte-melanoma adhesion molecule whose loss is intimately associated with melanoma invasion and metastasis. Here we identify a link between oncogenic B-RAF, the transcriptional repressor Tbx3 and E-cadherin. We show that B-RAFV600E induces the expression of Tbx3, which potently represses E-cadherin expression in melanocytes and melanoma cells. Tbx3 expression is normally restricted to developmental embryonic tissues, promoting cell motility but is also aberrantly increased in various cancers and has been linked to tumor cell invasion and metastasis. We propose that this B-RAF/Tbx3/E-cadherin pathway plays a critical role in promoting the metastasis of B-RAF mutant melanomas.
PMCID: PMC3788590  PMID: 23190890
10.  VAN: an R package for identifying biologically perturbed networks via differential variability analysis 
BMC Research Notes  2013;6:430.
Large-scale molecular interaction networks are dynamic in nature and are of special interest in the analysis of complex diseases, which are characterized by network-level perturbations rather than changes in individual genes/proteins. The methods developed for the identification of differentially expressed genes or gene sets are not suitable for network-level analyses. Consequently, bioinformatics approaches that enable a joint analysis of high-throughput transcriptomics datasets and large-scale molecular interaction networks for identifying perturbed networks are gaining popularity. Typically, these approaches require the sequential application of multiple bioinformatics techniques – ID mapping, network analysis, and network visualization. Here, we present the Variability Analysis in Networks (VAN) software package: a collection of R functions to streamline this bioinformatics analysis.
VAN determines whether there are network-level perturbations across biological states of interest. It first identifies hubs (densely connected proteins/microRNAs) in a network and then uses them to extract network modules (comprising of a hub and all its interaction partners). The function identifySignificantHubs identifies dysregulated modules (i.e. modules with changes in expression correlation between a hub and its interaction partners) using a single expression and network dataset. The function summarizeHubData identifies dysregulated modules based on a meta-analysis of multiple expression and/or network datasets. VAN also converts protein identifiers present in a MITAB-formatted interaction network to gene identifiers (UniProt identifier to Entrez identifier or gene symbol using the function generatePpiMap) and generates microRNA-gene interaction networks using TargetScan and Microcosm databases (generateMicroRnaMap). The function obtainCancerInfo is used to identify hubs (corresponding to significantly perturbed modules) that are already causally associated with cancer(s) in the Cancer Gene Census database. Additionally, VAN supports the visualization of changes to network modules in R and Cytoscape (visualizeNetwork and obtainPairSubset, respectively). We demonstrate the utility of VAN using a gene expression data from metastatic melanoma and a protein-protein interaction network from the Human Protein Reference Database.
Our package provides a comprehensive and user-friendly platform for the integrative analysis of -omics data to identify disease-associated network modules. This bioinformatics approach, which is essentially focused on the question of explaining phenotype with a 'network type’ and in particular, how regulation is changing among different states of interest, is relevant to many questions including those related to network perturbations across developmental timelines.
PMCID: PMC4015612  PMID: 24156242
Protein-protein interaction networks; Network modules; Melanoma
11.  A variant in FTO shows association with melanoma risk not due to BMI 
Iles, Mark M | Law, Matthew H | Stacey, Simon N | Han, Jiali | Fang, Shenying | Pfeiffer, Ruth | Harland, Mark | MacGregor, Stuart | Taylor, John C | Aben, Katja K | Akslen, Lars A | Avril, Marie-Françoise | Azizi, Esther | Bakker, Bert | Benediktsdottir, Kristrun R | Bergman, Wilma | Scarrà, Giovanna Bianchi | Brown, Kevin M | Calista, Donato | Chaudru, Valerié | Fargnoli, Maria Concetta | Cust, Anne E | Demenais, Florence | de Waal, Anne C | Dębniak, Tadeusz | Elder, David E | Friedman, Eitan | Galan, Pilar | Ghiorzo, Paola | Gillanders, Elizabeth M | Goldstein, Alisa M | Gruis, Nelleke A | Hansson, Johan | Helsing, Per | Hočevar, Marko | Höiom, Veronica | Hopper, John L | Ingvar, Christian | Janssen, Marjolein | Jenkins, Mark A | Kanetsky, Peter A | Kiemeney, Lambertus A | Lang, Julie | Lathrop, G Mark | Leachman, Sancy | Lee, Jeffrey E | Lubiński, Jan | Mackie, Rona M | Mann, Graham J | Mayordomo, Jose I | Molven, Anders | Mulder, Suzanne | Nagore, Eduardo | Novaković, Srdjan | Okamoto, Ichiro | Olafsson, Jon H | Olsson, Håkan | Pehamberger, Hubert | Peris, Ketty | Grasa, Maria Pilar | Planelles, Dolores | Puig, Susana | Puig-Butille, Joan Anton | Randerson-Moor, Juliette | Requena, Celia | Rivoltini, Licia | Rodolfo, Monica | Santinami, Mario | Sigurgeirsson, Bardur | Snowden, Helen | Song, Fengju | Sulem, Patrick | Thorisdottir, Kristin | Tuominen, Rainer | Van Belle, Patricia | van der Stoep, Nienke | van Rossum, Michelle M | Wei, Qingyi | Wendt, Judith | Zelenika, Diana | Zhang, Mingfeng | Landi, Maria Teresa | Thorleifsson, Gudmar | Bishop, D Timothy | Amos, Christopher I | Hayward, Nicholas K | Stefansson, Kari | Bishop, Julia A Newton | Barrett, Jennifer H
Nature genetics  2013;45(4):428-432.
We report the results of an association study of melanoma based on the genome-wide imputation of the genotypes of 1,353 cases and 3,566 controls of European origin conducted by the GenoMEL consortium. This revealed a novel association between several single nucleotide polymorphisms (SNPs) in intron 8 of the FTO gene, including rs16953002, which replicated using 12,313 cases and 55,667 controls of European ancestry from Europe, the USA and Australia (combined p=3.6×10−12, per-allele OR for A=1.16). As well as identifying a novel melanoma susceptibility locus, this is the first study to identify and replicate an association with SNPs in FTO not related to body mass index (BMI). These SNPs are not in intron 1 (the BMI-related region) and show no association with BMI. This suggests FTO’s function may be broader than the existing paradigm that FTO variants influence multiple traits only through their associations with BMI and obesity.
PMCID: PMC3640814  PMID: 23455637
12.  MC1R genotype as a predictor of early-onset melanoma, compared with self-reported and physician-measured traditional risk factors: an Australian case-control-family study 
BMC Cancer  2013;13:406.
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.
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.
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 < 0.001) and improved the quartile classification by a net 26% of participants. In a more extensive multivariate model, the factors that contributed significantly to the AUC were MC1R genotype, number of nevi and previous non-melanoma skin cancer; the AUC was 0.78 (95% CI 0.75-0.82) for the model with self-reported nevi and 0.83 (95% CI 0.80-0.86) for the model with physician-counted nevi. Factors that did not further contribute were sun and sunbed exposure and pigmentation characteristics. Adding MC1R to a model containing pigmentation characteristics and other self-reported risk factors increased the AUC by 2.1% (P = 0.01) and improved the quartile classification by a net 10% (95% CI 1-18%, P = 0.03).
Although MC1R genotype is strongly associated with skin and hair phenotype, it was a better predictor of early-onset melanoma than was pigmentation characteristics. Physician-measured nevi and previous non-melanoma skin cancer were also strong predictors. There might be modest benefit to measuring MC1R genotype for risk prediction even if information about traditional self-reported or clinically measured pigmentation characteristics and nevi is already available.
PMCID: PMC3766240  PMID: 24134749
MC1R; Risk prediction; Accuracy; Melanoma; Sun exposure; Early-onset; Pigmentation; Nevi
13.  Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma‐prone families from three continents 
Journal of Medical Genetics  2006;44(2):99-106.
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.
These four features were examined in 385 families with ⩾3 patients with melanoma pooled by 17 GenoMEL groups, and these attributes were compared across continents.
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, ⩾2 patients with MPM, median age at melanoma diagnosis ⩽40 years and ⩾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 ⩾1 patient with MPM and age at diagnosis ⩽40 years simultaneously predicted the mutation risk.
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.
PMCID: PMC2598064  PMID: 16905682
melanoma;  CDKN2A ; multiple primary melanomas; pancreatic cancer
14.  Identification of new prognostic biomarkers for Stage III metastatic melanoma patients 
Oncoimmunology  2013;2(9):e25564.
Accurately predicting disease outcome among patients bearing Stage III metastatic melanoma is complex. However, current advances in personalized medicine call for ever more precise prognostic assessments, as these have a significant impact not only on the design and analysis of clinical trials, but also on therapeutic decision-making.
PMCID: PMC3820811  PMID: 24228228
BRAF; expression profile; melanoma; metastasis; mutation; NRAS; pathology; prognosis; outcome; treatment
15.  Genome-wide association study identifies novel loci predisposing to cutaneous melanoma† 
Human Molecular Genetics  2011;20(24):5012-5023.
We performed a multistage genome-wide association study of melanoma. In a discovery cohort of 1804 melanoma cases and 1026 controls, we identified loci at chromosomes 15q13.1 (HERC2/OCA2 region) and 16q24.3 (MC1R) regions that reached genome-wide significance within this study and also found strong evidence for genetic effects on susceptibility to melanoma from markers on chromosome 9p21.3 in the p16/ARF region and on chromosome 1q21.3 (ARNT/LASS2/ANXA9 region). The most significant single-nucleotide polymorphisms (SNPs) in the 15q13.1 locus (rs1129038 and rs12913832) lie within a genomic region that has profound effects on eye and skin color; notably, 50% of variability in eye color is associated with variation in the SNP rs12913832. Because eye and skin colors vary across European populations, we further evaluated the associations of the significant SNPs after carefully adjusting for European substructure. We also evaluated the top 10 most significant SNPs by using data from three other genome-wide scans. Additional in silico data provided replication of the findings from the most significant region on chromosome 1q21.3 rs7412746 (P = 6 × 10−10). Together, these data identified several candidate genes for additional studies to identify causal variants predisposing to increased risk for developing melanoma.
PMCID: PMC3298855  PMID: 21926416
17.  Sunbed use during adolescence and early adulthood is associated with increased risk of early-onset melanoma 
Sunbed use is associated with increased risk of melanoma. Younger people might be more susceptible to the carcinogenic effects of ultraviolet radiation. We investigated the association between sunbed use and risk of early-onset cutaneous malignant melanoma. From the Australian Melanoma Family Study, a multi-centre, population-based, case-control-family study, we analysed data for 604 cases diagnosed between ages 18 and 39 years and 479 controls. Data were collected by interview. Associations were estimated as odds ratios (ORs) using unconditional logistic regression, adjusting for age, sex, city, education, family history, skin colour, usual skin response to sunlight, and sun exposure. Compared with having never used a sunbed, the OR for melanoma associated with ever-use was 1.41 (95% confidence interval (CI) 1.01-1.96), and 2.01 (95% CI 1.22-3.31) for more than 10 lifetime sessions (Ptrend 0.01 with cumulative use). The association was stronger for earlier age at first use (Ptrend 0.02). The association was also stronger for melanoma diagnosed when aged 18-29 years (OR for more than 10 lifetime sessions = 6.57, 95% CI 1.41-30.49) than for melanoma diagnosed when 30-39 years (OR 1.60, 95% CI 0.92-2.77; Pinteraction 0.01). Among those who had ever used a sunbed and were diagnosed between 18-29 years of age, three quarters (76%) of melanomas were attributable to sunbed use. Sunbed use is associated with increased risk of early-onset melanoma, with risk increasing with greater use, an earlier age at first use and for earlier onset disease.
PMCID: PMC2993823  PMID: 20669232
sunbed; artificial tanning; melanoma; risk factor; early-onset
19.  Genome-wide association study identifies three new melanoma susceptibility loci 
Barrett, Jennifer H | Iles, Mark M | Harland, Mark | Taylor, John C | Aitken, Joanne F | Andresen, Per Arne | Akslen, Lars A | Armstrong, Bruce K | Avril, Marie-Francoise | Azizi, Esther | Bakker, Bert | Bergman, Wilma | Bianchi-Scarrà, Giovanna | Paillerets, Brigitte Bressac-de | Calista, Donato | Cannon-Albright, Lisa A | Corda, Eve | Cust, Anne E | Dębniak, Tadeusz | Duffy, David | Dunning, Alison | Easton, Douglas F | Friedman, Eitan | Galan, Pilar | Ghiorzo, Paola | Giles, Graham G | Hansson, Johan | Hocevar, Marko | Höiom, Veronica | Hopper, John L | Ingvar, Christian | Janssen, Bart | Jenkins, Mark A | Jönsson, Göran | Kefford, Richard F | Landi, Giorgio | Landi, Maria Teresa | Lang, Julie | Lubiński, Jan | Mackie, Rona | Malvehy, Josep | Martin, Nicholas G | Molven, Anders | Montgomery, Grant W | van Nieuwpoort, Frans A | Novakovic, Srdjan | Olsson, Håkan | Pastorino, Lorenza | Puig, Susana | Puig-Butille, Joan Anton | Randerson-Moor, Juliette | Snowden, Helen | Tuominen, Rainer | Van Belle, Patricia | van der Stoep, Nienke | Whiteman, David C | Zelenika, Diana | Han, Jiali | Fang, Shenying | Lee, Jeffrey E | Wei, Qingyi | Lathrop, G Mark | Gillanders, Elizabeth M | Brown, Kevin M | Goldstein, Alisa M | Kanetsky, Peter A | Mann, Graham J | MacGregor, Stuart | Elder, David E | Amos, Christopher I | Hayward, Nicholas K | Gruis, Nelleke A | Demenais, Florence | Newton Bishop, Julia A | Bishop, D Timothy
Nature Genetics  2011;43(11):1108-1113.
We report a genome-wide association study of melanoma, conducted by GenoMEL, of 2,981 cases, of European ancestry, and 1,982 study-specific controls, plus a further 6,426 French and UK population controls, all genotyped for 317,000 or 610,000 SNPs. The analysis confirmed previously known melanoma susceptibility loci. The 7 novel regions with at least one SNP with p<10−5 and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Houston, Texas). Additional replication came from UK and Dutch case-control series. Three of the 7 regions replicated at p<10−3: an ATM missense polymorphism (rs1801516, overall p=3.4×10−9); a polymorphism within MX2 (rs45430, p=2.9×10−9) and a SNP adjacent to CASP8 (rs13016963, p=8.6×10−10). A fourth region near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication. Unlike the previously known regions, the novel loci showed no association with nevus or pigmentation phenotypes in a large UK case-control series.
PMCID: PMC3251256  PMID: 21983787
20.  Selection criteria for genetic assessment of patients with familial melanoma 
Approximately 5% to 10% of melanoma may be hereditary in nature, and about 2% of melanoma can be specifically attributed to pathogenic germline mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A). To appropriately identify the small proportion of patients who benefit most from referral to a genetics specialist for consideration of genetic testing for CDKN2A, we have reviewed available published studies of CDKN2A mutation analysis in cohorts with invasive, cutaneous melanoma and found variability in the rate of CDKN2A mutations based on geography, ethnicity, and the type of study and eligibility criteria used. Except in regions of high melanoma incidence, such as Australia, we found higher rates of CDKN2A positivity in individuals with 3 or more primary invasive melanomas and/or families with at least one invasive melanoma and two or more other diagnoses of invasive melanoma and/or pancreatic cancer among first- or second-degree relatives on the same side of the family. The work summarized in this review should help identify individuals who are appropriate candidates for referral for genetic consultation and possible testing.
PMCID: PMC3307795  PMID: 19751883
CDKN2A; familial; genetic counseling; genetic testing; hereditary; melanoma; p16
21.  A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma 
Nature  2011;480(7375):99-103.
So far, two familial melanoma genes have been identified, accounting for a minority of genetic risk in families. Mutations in CDKN2A account for approximately 40% of familial cases1, and predisposing mutations in CDK4 have been reported in a very small number of melanoma kindreds2. To identify other familial melanoma genes, here we conducted whole-genome sequencing of probands from several melanoma families, identifying 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 odds ratio (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.
PMCID: PMC3266855  PMID: 22080950
22.  The COMPASs Study: Community Preferences for Prostate cAncer Screening. Protocol for a quantitative preference study 
BMJ Open  2012;2(1):e000587.
Prostate cancer screening using prostate-specific antigen (PSA) testing remains controversial. Trade-offs between the potential benefits and downsides of screening must be weighed by men deciding whether to participate in prostate cancer screening; little is known about benefit:harm trade-offs men are willing to accept.
The Community Preferences for Prostate Cancer Screening (COMPASs) Study examines Australian men's preferences for prostate cancer screening using PSA testing. The aims are to (1) determine which factors influence men's decision to participate in prostate cancer screening or not and (2) determine the extent of trade-offs between benefits and harms that men are willing to accept in making these decisions. Quantitative methods will be used to assess men's preferences for PSA screening. Using data on the quantitative outcomes of PSA testing from the published literature, a discrete choice study will be designed to quantitatively assess men's preferences. A web-based survey will be conducted in approximately 1000 community respondents aged 40–69 years, stratified by family history of prostate cancer, to assess men's preferences for PSA testing. A mixed logit model will be used; model results will be expressed as parameter estimates (β) and the odds of choosing screening over no screening. Trade-offs between attributes will also be calculated.
Ethics and Dissemination
The COMPASs study has been approved by the University of Sydney, Human Research Ethics committee (Protocol number 13186). The results will be published in internal reports, in peer-reviewed scientific journals as well as via conference presentations.
Article summary
Article focus
To assess men's preferences for prostate cancer screening and determine the relative importance of various factors that influence men's decision to participate in prostate cancer screening or not.
To determine the extent of trade-offs between benefits and harms that men are willing to accept in making decisions about participation in screening.
Key messages
Prostate cancer screening may offer some benefit in terms of a reduction in prostate cancer-specific mortality. However, there is also evidence of substantial harms: screened men have a higher likelihood of being diagnosed as having prostate cancer, including the diagnosis of cancers that would not have become clinically apparent within the man's lifetime, meaning more men experiencing the attendant harms of diagnosis and treatment such as unnecessary biopsies from false-positive prostate-specific antigen tests or impotence and/or incontinence from treatments.
Trade-offs between the potential benefits and downsides of screening must be weighed by men deciding whether to participate in prostate cancer screening; little is known about benefit:harm trade-offs men are willing to make.
This study will use best practice quantitative methods for preference elicitation (discrete choice experiments) to assess men's preferences for prostate-specific antigen screening and the trade-offs they are willing to make decision whether to participate in screening.
Strengths and limitations of this study
The strengths of the study are that it is the first study to use discrete choice methods to examine men's preferences for prostate cancer screening, and the benefit:harm trade-offs men may be willing to make; it will consider the influence of age and family history on preferences in a large cohort of men, broadly representative of the Australian population aged 40 to 69 years.
The limitation is that it is conducted in one country, Australia, and thus its generalisability may be limited by the prevailing screening environment.
PMCID: PMC3253419  PMID: 22226686
23.  Population-based, Case-Control-Family Design to Investigate Genetic and Environmental Influences on Melanoma Risk 
American Journal of Epidemiology  2009;170(12):1541-1554.
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.
PMCID: PMC2800270  PMID: 19887461
case-control studies; environmental exposure; family; genetic predisposition to disease; melanoma; risk factors
24.  Genome-wide association study identifies three loci associated with melanoma risk 
Nature genetics  2009;41(8):920-925.
We report a genome-wide association study of melanoma conducted by the GenoMEL consortium based on 317k tagging SNPs for 1650 genetically-enriched cases (from Europe and Australia) and 4336 controls and subsequent replication in 1149 genetically-enriched cases and 964 controls and a population-based case-control study of 1163 cases and 903 controls. The genome-wide screen identified five regions with genotyped or imputed SNPs reaching p < 5×10−7; three regions were replicated: 16q24 encompassing MC1R (overall p=2.54×10−27 for rs258322), 11q14-q21 encompassing TYR (p=2.41×10−14 for rs1393350) and 9p21 adjacent to MTAP and flanking CDKN2A (p=4.03×10−7 for rs7023329). MC1R and TYR are associated with pigmentation, freckling and cutaneous sun sensitivity, well-recognised melanoma risk factors, while the 9p21 locus is novel for common variants associated with melanoma. Despite wide variation in allele frequency, these genetic variants show notable homogeneity of effect across populations of European ancestry living at different latitudes and contribute independently to melanoma risk.
PMCID: PMC2741419  PMID: 19578364
25.  Common sequence variants on 20q11.22 confer melanoma susceptibility 
Nature genetics  2008;40(7):838-840.
We conducted a genome-wide association pooling study for cutaneous melanoma and performed validation in samples totalling 2019 cases and 2105 controls. Using pooling we identified a novel melanoma risk locus on chromosome 20 (rs910873, rs1885120), with replication in two further samples (combined P <1 × 10-15). The odds ratio is 1.75 (1.53, 2.01), with evidence for stronger association in early onset cases.
PMCID: PMC2755512  PMID: 18488026

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