Publications by authors named "Nelleke A Gruis"

79 Publications

Birth cohort-specific trends of sun-related behaviors among individuals from an international consortium of melanoma-prone families.

BMC Public Health 2021 04 23;21(1):692. Epub 2021 Apr 23.

Department of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands.

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.
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http://dx.doi.org/10.1186/s12889-021-10424-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063451PMC
April 2021

Association of HERV-K and LINE-1 hypomethylation with reduced disease-free survival in melanoma patients.

Epigenomics 2020 10 30;12(19):1689-1706. Epub 2020 Oct 30.

Division of Molecular Genetic Epidemiology, German Cancer Research Center, 69120 Heidelberg, Germany.

To evaluate CpG methylation of long interspersed nuclear elements 1 (LINE-1) and human endogenous retrovirus K (HERV-K) retroelements as potential prognostic biomarkers in cutaneous melanoma. Methylation of HERV-K and LINE-1 retroelements was assessed in resected melanoma tissues from 82 patients ranging in age from 14 to 88 years. In addition, nevi from eight patients were included for comparison with nonmalignant melanocytic lesions. Methylation levels were lower in melanomas than in nevi. HERV-K and LINE-1 methylation were decreased in melanoma patients with clinical parameters associated with adverse prognosis, while they were independent of age and gender. Hypomethylation of HERV-K (but not LINE-1) was an independent predictor of reduced disease-free survival. : HERV-K hypomethylation can be a potential independent biomarker of melanoma recurrence.
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http://dx.doi.org/10.2217/epi-2020-0127DOI Listing
October 2020

Association between a 46-SNP Polygenic Risk Score and melanoma risk in Dutch patients with familial melanoma.

J Med Genet 2020 Sep 29. Epub 2020 Sep 29.

Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Background: Familial clustering of melanoma suggests a shared genetic predisposition among family members, but only 10%-40% of familial cases carry a pathogenic variant in a known high-risk melanoma susceptibility gene. We investigated whether a melanoma-specific Polygenic Risk Score (PRS) is associated with melanoma risk in patients with genetically unexplained familial melanoma.

Methods: Dutch familial melanoma cases (n=418) were genotyped for 46 SNPs previously identified as independently associated with melanoma risk. The 46-SNP PRS was calculated and standardised to 3423 healthy controls (sPRS) and the association between PRS and melanoma risk was modelled using logistic regression. Within the case series, possible differences were further explored by investigating the PRS in relation to (1) the number of primary melanomas in a patient and (2) the extent of familial clustering of melanoma.

Results: The PRS was significantly associated with melanoma risk, with a per-SD OR of 2.12 (95% CI 1.90 to 2.35, p<0.001), corresponding to a 5.70-fold increased risk (95% CI 3.93 to 8.28) when comparing the top 90th to the middle 40-60th PRS percentiles. The mean PRS was significantly higher in cases with multiple primary melanomas than in cases with a single melanoma (sPRS 1.17 vs 0.71, p=0.001). Conversely, cases from high-density melanoma families had a lower (but non-significant) mean PRS than cases from low-density families (sPRS 0.60 vs 0.94, p=0.204).

Conclusion: Our work underlines the significance of a PRS in determining melanoma susceptibility and encourages further exploration of the diagnostic value of a PRS in genetically unexplained melanoma families.
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http://dx.doi.org/10.1136/jmedgenet-2020-107251DOI Listing
September 2020

The role of MC1R gene variants and phenotypical features in predicting high nevus count.

Melanoma Res 2020 10;30(5):511-514

Department of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands.

Variants in the Melanocortin 1 Receptor (MC1R) gene have been associated with an increased risk of melanoma, but the role in nevus count is unclear. We investigated if specific MC1R gene variants or the number of MC1R gene variants and phenotypical features were associated with nevus count. A total of 494 participants of the 'Leiden skin cancer study' were included and the MC1R gene coding sequence was analysed by single-strand conformation polymorphism analysis followed by sequencing of unknown variants. The association between MC1R gene variants and nevus count and the association between age, gender and phenotypical features and nevus count were studied using the Chi-square test. Study of nine frequently occurring MC1R gene variants in participants without skin cancer (n = 203) showed that the 'r' Val60Leu variant was significantly associated with high nevus count (>50 nevi) (P = 0.017). This association was very strong among women (P < 0.001), but not present among men. Having one or two MC1R variants in general did not show a significant difference in the nevus count. Hair colour, skin type, eye colour and age were not significantly associated with nevus count, whereas gender showed a significant association (P = 0.008), with the highest nevus counts in female. The Val60Leu variant of the MC1R gene could be a promising candidate as an independent predictor of high nevus count, particularly in women. This information about the genetic makeup could promote personalized follow-up strategies and might help to prevent skin cancer in the future.
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http://dx.doi.org/10.1097/CMR.0000000000000687DOI Listing
October 2020

Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility.

Nat Genet 2020 05 27;52(5):494-504. Epub 2020 Apr 27.

Department of Dermatology, Instituto Valenciano de Oncología, Valencia, Spain.

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.
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http://dx.doi.org/10.1038/s41588-020-0611-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255059PMC
May 2020

Loss of Wild-Type CDKN2A Is an Early Event in the Development of Melanoma in FAMMM Syndrome.

J Invest Dermatol 2020 11 28;140(11):2298-2301.e3. Epub 2020 Mar 28.

Department of Dermatology, LUMC, Leiden, the Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2020.03.938DOI Listing
November 2020

Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT.

J Am Acad Dermatol 2019 Aug 5;81(2):386-394. Epub 2019 Feb 5.

Department of Clinical Sciences, Lund University Hospital Lund, Sweden; Department of Surgery, Lund University Hospital, Lund, Sweden.

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.
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http://dx.doi.org/10.1016/j.jaad.2019.01.079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6634996PMC
August 2019

Multigene panel sequencing of established and candidate melanoma susceptibility genes in a large cohort of Dutch non-CDKN2A/CDK4 melanoma families.

Int J Cancer 2019 05 21;144(10):2453-2464. Epub 2019 Jan 21.

Department of Clinical Genetics, Leiden University Medical Centre, Leiden, the Netherlands.

Germline mutations in the major melanoma susceptibility gene CDKN2A explain genetic predisposition in only 10-40% of melanoma-prone families. In our study we comprehensively characterized 488 melanoma cases from 451 non-CDKN2A/CDK4 families for mutations in 30 established and candidate melanoma susceptibility genes using a custom-designed targeted gene panel approach. We identified (likely) pathogenic variants in established melanoma susceptibility genes in 18 families (n = 3 BAP1, n = 15 MITF p.E318K; diagnostic yield 4.0%). Among the three identified BAP1-families, there were no reported diagnoses of uveal melanoma or malignant mesothelioma. We additionally identified two potentially deleterious missense variants in the telomere maintenance genes ACD and TERF2IP, but none in the POT1 gene. MC1R risk variants were strongly enriched in our familial melanoma cohort compared to healthy controls (R variants: OR 3.67, 95% CI 2.88-4.68, p <0.001). Several variants of interest were also identified in candidate melanoma susceptibility genes, in particular rare (pathogenic) variants in the albinism gene OCA2 were repeatedly found. We conclude that multigene panel testing for familial melanoma is appropriate considering the additional 4% diagnostic yield in non-CDKN2A/CDK4 families. Our study shows that BAP1 and MITF are important genes to be included in such a diagnostic test.
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http://dx.doi.org/10.1002/ijc.31984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590189PMC
May 2019

High Growth Rate of Pancreatic Ductal Adenocarcinoma in Mutation Carriers.

Cancer Prev Res (Phila) 2018 09 10;11(9):551-556. Epub 2018 Jul 10.

Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, the Netherlands.

- mutation carriers have a 20% to 25% risk of developing pancreatic ductal adenocarcinoma (PDAC). Better understanding of the natural course of PDAC might allow the surveillance protocol to be improved. The aims of the study were to evaluate the role of cystic precursor lesions in the development of PDAC and to assess the growth rate. In 2000, a surveillance program was initiated, consisting of annual MRI in carriers of a mutation. The study cohort included 204 (42% male) patients. Cystic precursor lesions were found in 52 (25%) of 204 mutation carriers. Five (9.7%) of 52 mutation carriers with cystic lesions and 8 (7.0%) of 114 mutation carriers without cystic lesions developed PDAC ( = 0.56). Three of 6 patients with a cystic lesion of ≥10 mm developed PDAC. The median size of all incident PDAC detected between 9 and 12 months since the previous normal MRI was 15 mm, suggesting an annual growth rate of about 15 mm/year. In conclusion, our findings show that patients with and without a cystic lesions have a similar risk of PDAC. However, cystic precursor lesions between 10 and 20 mm increase the risk of PDAC substantially. In view of the large size of the screen-detected tumors, a shorter interval of screening might be recommended for all patients. .
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http://dx.doi.org/10.1158/1940-6207.CAPR-18-0035DOI Listing
September 2018

variants as melanoma risk factors independent of at-risk phenotypic characteristics: a pooled analysis from the M-SKIP project.

Cancer Manag Res 2018 14;10:1143-1154. Epub 2018 May 14.

Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy.

Purpose: Melanoma represents an important public health problem, due to its high case-fatality rate. Identification of individuals at high risk would be of major interest to improve early diagnosis and ultimately survival. The aim of this study was to evaluate whether variants predicted melanoma risk independently of at-risk phenotypic characteristics.

Materials And Methods: Data were collected within an international collaboration - the M-SKIP project. The present pooled analysis included data on 3,830 single, primary, sporadic, cutaneous melanoma cases and 2,619 controls from seven previously published case-control studies. All the studies had information on gene variants by sequencing analysis and on hair color, skin phototype, and freckles, ie, the phenotypic characteristics used to define the red hair phenotype.

Results: The presence of any variant was associated with melanoma risk independently of phenotypic characteristics (OR 1.60; 95% CI 1.36-1.88). Inclusion of variants in a risk prediction model increased melanoma predictive accuracy (area under the receiver-operating characteristic curve) by 0.7% over a base clinical model (=0.002), and 24% of participants were better assessed (net reclassification index 95% CI 20%-30%). Subgroup analysis suggested a possibly stronger role of in melanoma prediction for participants without the red hair phenotype (net reclassification index: 28%) compared to paler skinned participants (15%).

Conclusion: The authors suggest that measuring the genotype might result in a benefit for melanoma prediction. The results could be a valid starting point to guide the development of scientific protocols assessing melanoma risk prediction tools incorporating the genotype.
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http://dx.doi.org/10.2147/CMAR.S155283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958947PMC
May 2018

CM-Score: a validated scoring system to predict germline mutations in melanoma families from Northern Europe.

J Med Genet 2018 10 16;55(10):661-668. Epub 2018 Apr 16.

Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.

Background: Several factors have been reported that influence the probability of a germline mutation in a melanoma family. Our goal was to create a scoring system to estimate this probability, based on a set of clinical features present in the patient and his or her family.

Methods: Five clinical features and their association with mutations were investigated in a training cohort of 1227 Dutch melanoma families (13.7% with mutation) using multivariate logistic regression. Predefined features included number of family members with melanoma and with multiple primary melanomas, median age at diagnosis and presence of pancreatic cancer or upper airway cancer in a family member. Based on these five features, a scoring system (()) was developed and subsequently validated in a combined Swedish and Dutch familial melanoma cohort (n=421 families; 9.0% with mutation).

Results: All five features were significantly associated (p<0.05) with a mutation. At a CM-Score of 16 out of 49 possible points, the threshold of 10% mutation probability is approximated (9.9%; 95% CI 9.8 to 10.1). This probability further increased to >90% for families with ≥36 points. A CM-Score under 16 points was associated with a low mutation probability (≤4%). CM-Score performed well in both the training cohort (area under the curve (AUC) 0.89; 95% CI 0.86 to 0.92) and the external validation cohort (AUC 0.94; 95% CI 0.90 to 0.98).

Conclusion: We developed a practical scoring system to predict mutation status among melanoma-prone families. We suggest that analysis should be recommended to families with a CM-Score of ≥16 points.
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http://dx.doi.org/10.1136/jmedgenet-2017-105205DOI Listing
October 2018

Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families.

J Invest Dermatol 2017 12 19;137(12):2606-2612. Epub 2017 Aug 19.

Melanoma Institute Australia, Westmead, New South Wales, Australia; Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, New South Wales, Australia.

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.
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http://dx.doi.org/10.1016/j.jid.2017.07.829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701856PMC
December 2017

Genomic analysis and clinical management of adolescent cutaneous melanoma.

Pigment Cell Melanoma Res 2017 05 19;30(3):307-316. Epub 2017 Apr 19.

Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK.

Melanoma in young children is rare; however, its incidence in adolescents and young adults is rising. We describe the clinical course of a 15-year-old female diagnosed with AJCC stage IB non-ulcerated primary melanoma, who died from metastatic disease 4 years after diagnosis despite three lines of modern systemic therapy. We also present the complete genomic profile of her tumour and compare this to a further series of 13 adolescent melanomas and 275 adult cutaneous melanomas. A somatic BRAF mutation and a high mutational load equivalent to that found in adult melanoma and composed primarily of C>T mutations were observed. A germline genomic analysis alongside a series of 23 children and adolescents with melanoma revealed no mutations in known germline melanoma-predisposing genes. Adolescent melanomas appear to have genomes that are as complex as those arising in adulthood and their clinical course can, as with adults, be unpredictable.
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http://dx.doi.org/10.1111/pcmr.12574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435926PMC
May 2017

Germline TERT promoter mutations are rare in familial melanoma.

Fam Cancer 2016 Jan;15(1):139-44

Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, LS9 7TF, UK.

Germline CDKN2A mutations occur in 40 % of 3-or-more case melanoma families while mutations of CDK4, BAP1, and genes involved in telomere function (ACD, TERF2IP, POT1), have also been implicated in melanomagenesis. Mutation of the promoter of the telomerase reverse transcriptase (TERT) gene (c.-57 T>G variant) has been reported in one family. We tested for the TERT promoter variant in 675 multicase families wild-type for the known high penetrance familial melanoma genes, 1863 UK population-based melanoma cases and 529 controls. Germline lymphocyte telomere length was estimated in carriers. The c.-57 T>G TERT promoter variant was identified in one 7-case family with multiple primaries and early age of onset (earliest, 15 years) but not among population cases or controls. One family member had multiple primary melanomas, basal cell carcinomas and a bladder tumour. The blood leukocyte telomere length of a carrier was similar to wild-type cases. We provide evidence confirming that a rare promoter variant of TERT (c.-57 T>G) is associated with high penetrance, early onset melanoma and potentially other cancers, and explains <1 % of UK melanoma multicase families. The identification of POT1 and TERT germline mutations highlights the importance of telomere integrity in melanoma biology.
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http://dx.doi.org/10.1007/s10689-015-9841-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4698275PMC
January 2016

Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma.

Nat Genet 2015 Sep 3;47(9):987-995. Epub 2015 Aug 3.

Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland, USA.

Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10(-8)), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology.
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http://dx.doi.org/10.1038/ng.3373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4557485PMC
September 2015

Development and validation of a melanoma risk score based on pooled data from 16 case-control studies.

Cancer Epidemiol Biomarkers Prev 2015 May 24;24(5):817-24. Epub 2015 Feb 24.

B.C. Cancer Research Centre, Vancouver, British Columbia, Canada.

Background: We report the development of a cutaneous melanoma risk algorithm based upon seven factors; hair color, skin type, family history, freckling, nevus count, number of large nevi, and history of sunburn, intended to form the basis of a self-assessment Web tool for the general public.

Methods: Predicted odds of melanoma were estimated by analyzing a pooled dataset from 16 case-control studies using logistic random coefficients models. Risk categories were defined based on the distribution of the predicted odds in the controls from these studies. Imputation was used to estimate missing data in the pooled datasets. The 30th, 60th, and 90th centiles were used to distribute individuals into four risk groups for their age, sex, and geographic location. Cross-validation was used to test the robustness of the thresholds for each group by leaving out each study one by one. Performance of the model was assessed in an independent UK case-control study dataset.

Results: Cross-validation confirmed the robustness of the threshold estimates. Cases and controls were well discriminated in the independent dataset [area under the curve, 0.75; 95% confidence interval (CI), 0.73-0.78]. Twenty-nine percent of cases were in the highest risk group compared with 7% of controls, and 43% of controls were in the lowest risk group compared with 13% of cases.

Conclusion: We have identified a composite score representing an estimate of relative risk and successfully validated this score in an independent dataset.

Impact: This score may be a useful tool to inform members of the public about their melanoma risk.
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http://dx.doi.org/10.1158/1055-9965.EPI-14-1062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4487528PMC
May 2015

Histologic features of melanoma associated with CDKN2A genotype.

J Am Acad Dermatol 2015 Mar 13;72(3):496-507.e7. Epub 2015 Jan 13.

Department of Pathology and Laboratory Medicine at the Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.

Background: Inherited susceptibility genes have been associated with histopathologic characteristics of tumors.

Objective: We sought to identify associations between histology of melanomas and CDKN2A genotype.

Methods: This was a case-control study design comparing 28 histopathologic tumor features among individuals with sporadic melanomas (N = 81) and cases from melanoma families with (N = 123) and without (N = 120) CDKN2A germline mutations.

Results: Compared with CDKN2A(-) cases, mutation carriers tended to have histologic features of superficial spreading melanoma subtype including higher pigmentation (Ptrend = .02) and increased pagetoid scatter (Ptrend = .07) after adjusting for age at diagnosis, sex, and American Joint Committee on Cancer thickness category. Similar associations were observed when comparing mutation carriers with a combined group of CDKN2A(-) (wild type) and sporadic melanomas. The presence of spindle cell morphology in the vertical growth phase was also an important predictor of genotype. Of the 15 cases with this phenotype, none were observed to harbor a CDKN2A mutation.

Limitations: Our study examined rare mutations and may have been underpowered to detect small, but biologically significant associations between histology and genotype.

Conclusion: Familial melanomas with CDKN2A mutations preferentially express a histologic phenotype of dense pigmentation, high pagetoid scatter, and a non-spindle cell morphology in the vertical growth phase.
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http://dx.doi.org/10.1016/j.jaad.2014.11.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4333073PMC
March 2015

Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma.

J Natl Cancer Inst 2015 Feb 13;107(2). Epub 2014 Dec 13.

Affiliations of authors: QIMR Berghofer Medical Research Institute, Brisbane, Australia (LGA, ALP, MG, PJ, JMP, JS, VB, SW, KDR, MSS, GWM, NGM, NKH); Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK (CDRE, TMK, DJA); Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark (KW, AMG); Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK (MH, HSn, DTB, JANB); Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD (JC, KMB); Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias (IUOPA) Universidad de Oviedo, Oviedo, Spain (VQ, AJR, CLO); Cancer Genomics Research Laboratory, NCI Frederick, SAIC-Frederick Inc., Frederick MD (XZ, KJ); Department of Dermatology, Leiden University Medical Centre, Leiden, the Netherlands (RvD, NAG); Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden (HO, CI, ÅB, GJ); Translational Genomics Institute, Phoenix, AZ (JMT); University of Sydney at Westmead Millennium Institute, Westmead, Sydney, NSW, Australia (EAH, HSc, GJM); Melanoma Institute Australia, North Sydney, NSW, Australia (EAH, HSc, GJM).

Background: 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.

Methods: 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).

Results: 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.

Conclusions: Our findings add to the growing support for telomere dysregulation as a key process associated with melanoma susceptibility.
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http://dx.doi.org/10.1093/jnci/dju408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334787PMC
February 2015

The effect on melanoma risk of genes previously associated with telomere length.

J Natl Cancer Inst 2014 Oct 17;106(10). Epub 2014 Sep 17.

Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, Leeds Cancer Research UK Centre, University of Leeds, Leeds, UK (MMI, DTB, JCT, MHa, JRM, JANB, JHB); Oncogenomics (NKH), Genetic Epidemiology (NGM), Inflammatory Bowel Diseases Laboratory (GLRS), Cancer Control Group (DCW), Statistical Genetics (SM, MHL), and Molecular Epidemiology (GWM), QIMR Berghofer Medical Research Institute, Brisbane, Australia; INSERM, UMR-946, Genetic Variation and Human Diseases Unit, Paris, France (MB, FD); Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France (MB, FD); Cancer Epidemiology and Services Research, Sydney School of Public Health, University of Sydney, Australia (AEC); Department of Oncology, University of Cambridge, Cambridge, UK (AMD, PDPP); Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX (JEL); Centre for Genetic Origins of Health and Disease, Faculty of Medicine, Dentistry and Health Sciences, University of Western Australia, Crawley, Australia (EKM, SVW); Centre for Cancer Biomarkers CCBIO (LAA) and Gade Laboratory for Pathology (AM), Department of Clinical Medicine, University of Bergen, Bergen, Norway; Department of Pathology, Haukeland University Hospital, Bergen, Norway (LAA); Department of Pathology, Molecular Pathology (PAA) and Department of Dermatology (PH), Oslo University Hospital, Rikshospitalet, Oslo, Norway; Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Service de Dermatologie, Université Paris Descartes, Paris, France (MFA); Department of Dermatology (EA) and Oncogenics Unit (EA, EF), Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv, Israel (EA); Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy (GBS, EFPG); Laboratory of Genetics of Rare Hereditary Cancers, San Martino-IST Research Hospital, Genoa, Italy (GBS, EFPG); Division of Cancer Epidemiology and Gene

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.
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http://dx.doi.org/10.1093/jnci/dju267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4196080PMC
October 2014

Fine mapping of genetic susceptibility loci for melanoma reveals a mixture of single variant and multiple variant regions.

Int J Cancer 2015 Mar 14;136(6):1351-60. Epub 2014 Aug 14.

Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.

At least 17 genomic regions are established as harboring melanoma susceptibility variants, in most instances with genome-wide levels of significance and replication in independent samples. Based on genome-wide single nucleotide polymorphism (SNP) data augmented by imputation to the 1,000 Genomes reference panel, we have fine mapped these regions in over 5,000 individuals with melanoma (mainly from the GenoMEL consortium) and over 7,000 ethnically matched controls. A penalized regression approach was used to discover those SNP markers that most parsimoniously explain the observed association in each genomic region. For the majority of the regions, the signal is best explained by a single SNP, which sometimes, as in the tyrosinase region, is a known functional variant. However in five regions the explanation is more complex. At the CDKN2A locus, for example, there is strong evidence that not only multiple SNPs but also multiple genes are involved. Our results illustrate the variability in the biology underlying genome-wide susceptibility loci and make steps toward accounting for some of the "missing heritability."
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http://dx.doi.org/10.1002/ijc.29099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4328144PMC
March 2015

Promoter CpG island hypermethylation in dysplastic nevus and melanoma: CLDN11 as an epigenetic biomarker for malignancy.

J Invest Dermatol 2014 Dec 7;134(12):2957-2966. Epub 2014 Jul 7.

Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands; The first two and last three authors contributed equally to this work. Electronic address:

Dysplastic nevi are melanocytic lesions that represent an intermediate stage between common nevus and melanoma. Histopathological distinction of dysplastic nevus from melanoma can be challenging and there is a requirement for molecular diagnostic markers. In this study, we examined promoter CpG island methylation of a selected panel of genes, identified in a genome-wide methylation screen, across a spectrum of 405 melanocytic neoplasms. Promoter methylation analysis in common nevi, dysplastic nevi, primary melanomas, and metastatic melanomas demonstrated progressive epigenetic deregulation. Dysplastic nevi were affected by promoter methylation of genes that are frequently methylated in melanoma but not in common nevi. We assessed the diagnostic value of the methylation status of five genes in distinguishing primary melanoma from dysplastic nevus. In particular, CLDN11 promoter methylation was specific for melanoma, as it occurred in 50% of primary melanomas but in only 3% of dysplastic nevi. A diagnostic algorithm that incorporates methylation of the CLDN11, CDH11, PPP1R3C, MAPK13, and GNMT genes was validated in an independent sample set and helped distinguish melanoma from dysplastic nevus (area under the curve 0.81). Melanoma-specific methylation of these genes supports the utility as epigenetic biomarkers and could point to their significance in melanoma development.
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http://dx.doi.org/10.1038/jid.2014.270DOI Listing
December 2014

MC1R variants increased the risk of sporadic cutaneous melanoma in darker-pigmented Caucasians: a pooled-analysis from the M-SKIP project.

Int J Cancer 2015 Feb 18;136(3):618-31. Epub 2014 Jun 18.

Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy.

The MC1R gene is a key regulator of skin pigmentation. We aimed to evaluate the association between MC1R variants and the risk of sporadic cutaneous melanoma (CM) within the M-SKIP project, an international pooled-analysis on MC1R, skin cancer and phenotypic characteristics. Data included 5,160 cases and 12,119 controls from 17 studies. We calculated a summary odds ratio (SOR) for the association of each of the nine most studied MC1R variants and of variants combined with CM by using random-effects models. Stratified analysis by phenotypic characteristics were also performed. Melanoma risk increased with presence of any of the main MC1R variants: the SOR for each variant ranged from 1.47 (95%CI: 1.17-1.84) for V60L to 2.74 (1.53-4.89) for D84E. Carriers of any MC1R variant had a 66% higher risk of developing melanoma compared with wild-type subjects (SOR; 95%CI: 1.66; 1.41-1.96) and the risk attributable to MC1R variants was 28%. When taking into account phenotypic characteristics, we found that MC1R-associated melanoma risk increased only for darker-pigmented Caucasians: SOR (95%CI) was 3.14 (2.06-4.80) for subjects with no freckles, no red hair and skin Type III/IV. Our study documents the important role of all the main MC1R variants in sporadic CM and suggests that they have a direct effect on melanoma risk, independently on the phenotypic characteristics of carriers. This is of particular importance for assessing preventive strategies, which may be directed to darker-pigmented Caucasians with MC1R variants as well as to lightly pigmented, fair-skinned subjects.
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http://dx.doi.org/10.1002/ijc.29018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378685PMC
February 2015

In-vitro melanoma models: invasive growth is determined by dermal matrix and basement membrane.

Melanoma Res 2014 Aug;24(4):305-14

Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands.

A critical first step in the metastatic progression of cutaneous melanoma, invasive growth into the dermal compartment, would ideally be studied in the proper three-dimensional tissue microenvironment. In this study, we compared the growth and behavior of four melanoma cell lines originating from primary and metastatic human cutaneous melanomas (AN, RU, M14, and WK) in in-vitro human skin equivalents (HSEs) generated with four different dermal matrices: human fibroblast-seeded rat tail collagen, human fibroblast-derived matrix (FDM), noncellular human de-epidermized dermis (DED), and a novel fully cellular human DED with an intact pre-existent basement membrane. Melanoma cells showed proliferation in all HSEs, indicating that the microenvironment formed in all HSEs studied here allows the growth of melanoma cells in concert with epidermal keratinocytes for multiple weeks in vitro. Melanoma cells did not affect epidermal proliferation and terminal differentiation. Growth of melanoma cells in the dermal compartment, as a measure of invasive potential, differs markedly between the four types of in-vitro human melanoma models. Notably, the growth of melanoma cells in the dermal matrix was observed in all HSEs cultured with cell lines originating from metastatic melanoma, except for cDED-based HSEs, and the growth of melanoma cells of nonmetastatic origin was observed in the dermal compartment of FDM-based HSEs. Our results show that the type of dermal equivalent and the presence of an intact basement membrane should be taken into consideration when studying melanoma invasion using in-vitro HSEs.
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http://dx.doi.org/10.1097/CMR.0000000000000079DOI Listing
August 2014

POT1 loss-of-function variants predispose to familial melanoma.

Nat Genet 2014 May 30;46(5):478-481. Epub 2014 Mar 30.

Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA. UK.

Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases, and rare variants in CDK4, BRCA2, BAP1 and the promoter of TERT have also been linked to the disease. Here we set out to identify new high-penetrance susceptibility genes by sequencing 184 melanoma cases from 105 pedigrees recruited in the UK, The Netherlands and Australia that were negative for variants in known predisposition genes. We identified families where melanoma cosegregates with loss-of-function variants in the protection of telomeres 1 gene (POT1), with a proportion of family members presenting with an early age of onset and multiple primary tumors. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding and leading to increased telomere length. These findings suggest that POT1 variants predispose to melanoma formation via a direct effect on telomeres.
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http://dx.doi.org/10.1038/ng.2947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266105PMC
May 2014

An inherited variant in the gene coding for vitamin D-binding protein and survival from cutaneous melanoma: a BioGenoMEL study.

Pigment Cell Melanoma Res 2014 Mar 11;27(2):234-43. Epub 2013 Dec 11.

Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.

An association between low serum vitamin D levels and poorer melanoma survival has been reported. We have studied inheritance of a polymorphism of the GC gene, rs2282679, coding for the vitamin D-binding protein, which is associated with lower serum levels of vitamin D, in a meta-analysis of 3137 melanoma patients. The aim was to investigate evidence for a causal relationship between vitamin D and outcome (Mendelian randomization). The variant was not associated with reduced overall survival (OS) in the UK cohort, per-allele hazard ratio (HR) for death 1.23 (95% confidence interval (CI) 0.93, 1.64). In the smaller cohorts, HR in OS analysis was 1.07 (95% CI 0.88, 1.3) and for all cohorts combined, HR for OS was 1.09 (95% CI 0.93, 1.29). There was evidence of increased melanoma-specific deaths in the seven cohorts for which these data were available. The lack of unequivocal findings despite the large sample size illustrates the difficulties of implementing Mendelian randomization.
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http://dx.doi.org/10.1111/pcmr.12193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4065372PMC
March 2014

Acquired melanocytic nevi in childhood and familial melanoma.

JAMA Dermatol 2014 Jan;150(1):35-40

Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands.

Importance: In the surveillance of familial melanoma, the identification of children at greater risk of developing melanoma later in life would serve as a helpful tool.

Objective: To determine whether acquired melanocytic nevi in childhood are an indicator of risk of melanoma in children from families with familial melanoma.

Design, Setting, And Participants: A 20-year follow-up study of a cohort of children from families with familial melanoma. Phenotypical data on melanocytic nevi were collected from a random sample of 133 members of families with familial melanoma 2 to 18 years of age with variable risks of being a mutation carrier. More than 20 years of follow-up data (gene-carrier status, diagnosis of melanoma, and excisions of nevi) were collected. In a subgroup of 40 people, childhood phenotypical data were compared with data on nevus numbers in adulthood. Survival analyses, correlation analyses, and t tests were calculated to examine associations.

Main Outcomes And Measures: Nevus count and distribution in childhood were correlated with the occurrence of melanoma and mutation carrier status.

Results: Significant risk factors for melanoma were found, specifically in the group with the highest risk of being a mutation carrier: total number of atypical nevi in childhood (hazard ratio [HR], 1.21; 95% CI, 1.02-1.44; P = .03), the nevus count of atypical nevi on the buttocks (HR, 14.00; 95% CI, 2.94-66.55; P = .001), and the number of excisions during follow-up (HR, 1.27; 95% CI, 1.23-1.31; P < .001). The analysis also found a correlation between the distribution of nevi in childhood and adulthood and the distribution of melanomas (correlation, 0.89; 95% CI, 0.67-0.96; and correlation, 0.99; 95% CI, 0.98-1.00; P < .001, respectively for both).

Conclusions And Relevance: Numbers and distribution of melanocytic nevi in childhood are major indicators of the risk of melanoma in patients from families with familial melanoma.
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http://dx.doi.org/10.1001/jamadermatol.2013.5588DOI Listing
January 2014
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