Publications by authors named "Wilma Bergman"

51 Publications

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

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

Unscheduled Visits of Patients with Familial Melanoma to a Pigmented Lesion Clinic: Evaluation of Patients' Characteristics and Suspicious Lesions.

Acta Derm Venereol 2018 Jul;98(7):667-670

Department of Dermatology B-1-Q,, Leiden University Medical Center, PO-box 9600, 2300 ZA Leiden, The Netherlands.

Approximately 10% of all melanomas occur in subjects with a family history of melanoma. This retrospective follow-up study investigated the characteristics of patients with familial melanoma who made unscheduled visits to our pigmented lesions clinic, and the diagnosis of excised lesions. A total of 110 (9%) out of 1,267 patients made at least one unscheduled visit between May 2011 and February 2016. Histopathology was taken from 59 patients. Thirty-four naevi, 7 melanomas and 3 basal cell carcinomas were detected. All patients with melanoma were CDKN2A carriers and all melanomas were discovered at a very early stage. In this patient population it appears to be safe to limit visits to once or twice yearly, provided patients are easily able to make an unscheduled extra visit if they have a worrisome lesion. We recommend supporting patients' self-reliance by stimulating them to carry out self-examination of their skin.
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http://dx.doi.org/10.2340/00015555-2922DOI Listing
July 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

Risks of unregulated use of alpha-melanocyte-stimulating hormone analogues: a review.

Int J Dermatol 2017 Oct 7;56(10):975-980. Epub 2017 Mar 7.

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

Recently, the unregulated use of untested synthetic alpha-melanocyte-stimulating hormone (α-MSH) analogues, commonly known as melanotan I and II, appears to have increased. These analogues are primarily used for their tan-stimulating effects. Dermatologists see many patients in their clinic who tan. This review provides an overview of the risks of the unregulated use of these substances. Other topics discussed here include the history and safety of afamelanotide, which is the only α-MSH analogue that is approved for use in a limited number of medical indications. Although afamelanotide has been thoroughly tested and deemed safe, illegal melanotans are likely risky for several reasons. There are questions regarding the preparation, administration, and dosage of these substances. In addition to these general risks, increasing numbers of case reports indicate that the unregulated use of both melanotan I and II is associated with cutaneous complications, particularly melanocytic changes in existing moles and newly emerging (dysplastic) nevi. Four case reports have described melanomas emerging from existing moles either during or shortly after the use of melanotan. Although conclusive evidence linking these phenomena is lacking, publications have stressed the importance of awareness that melanotan is a part of a 'tanning culture' in certain subpopulations. Multiple national health organizations have issued safety warnings regarding the use of melanotan I and II.
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http://dx.doi.org/10.1111/ijd.13585DOI Listing
October 2017

Effect of a Dermoscopy Training Course on the Accuracy of Primary Care Physicians in Diagnosing Pigmented Lesions.

Acta Derm Venereol 2017 02;97(2):263-265

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

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http://dx.doi.org/10.2340/00015555-2526DOI Listing
February 2017

A Female with Hereditary Angioedema Developing Wheals: A Case Report.

Acta Derm Venereol 2017 02;97(2):285-286

Department of Dermatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.

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http://dx.doi.org/10.2340/00015555-2490DOI Listing
February 2017

Benefit of Surveillance for Pancreatic Cancer in High-Risk Individuals: Outcome of Long-Term Prospective Follow-Up Studies From Three European Expert Centers.

J Clin Oncol 2016 06 25;34(17):2010-9. Epub 2016 Apr 25.

Hans Vasen, Isaura Ibrahim, Kristin Robbers, Anneke M. van Mil, Thomas Potjer, Bert A. Bonsing, Wilma Bergman, Martin Wasser, and Hans Morreau, Leiden University Medical Center, Leiden; Wouter H. de Vos tot Nederveen Cappel, Isala Clinics, Zwolle, the Netherlands; Carmen Guillen Ponce, Alfredo Carrato, Julie Earl, Evelina Mocci, Enrique Vazquez-Sequeiros, Alfonso Sanjuanbenito, Maria Muñoz-Beltran, and José Montans, Ramón y Cajal University Hospital, Ramón y Cajal Health Research Institute, Madrid, Spain; Emily P. Slater, Elvira Matthäi, Volker Fendrich, and Detlef K. Bartsch, University Hospital Marburg; Christoph Schicker, Martin Steinkamp, and Jens Figiel, Philipps University Marburg, Marburg; Günter Klöppel, Consultation Centre for Pancreatic and Endocrine Tumors, Technical University Munich; Peter Langer, Klinikum Hanau, Hanau, Germany; and Irene Esposito, Innsbruck University Hospital, Innsbruck, Austria.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. Hereditary factors play a role in the development of PDAC in 3% to 5% of all patients. Surveillance of high-risk groups, may facilitate detection of PDAC at an early stage. The aim of this study was to assess whether surveillance aids detection of early-stage PDAC or precursor lesions (PRLs) and improves the prognosis.

Patients And Methods: Screening outcomes were collected from three European centers that conduct prospective screening in high-risk groups including families with clustering of PDAC (familial pancreatic cancer [FPC]) or families with a gene defect that predisposes to PDAC. The surveillance program consisted of annual magnetic resonance imaging, magnetic resonance cholangiopancreatography, and/or endoscopic ultrasound.

Results: Four hundred eleven asymptomatic individuals participated in the surveillance programs, including 178 CDKN2A mutation carriers, 214 individuals with FPC, and 19 BRCA1/2 or PALB2 mutation carriers. PDAC was detected in 13 (7.3%) of 178 CDKN2A mutation carriers. The resection rate was 75%, and the 5-year survival rate was 24%. Two CDKN2A mutation carriers (1%) underwent surgical resection for low-risk PRL. Two individuals (0.9%) in the FPC cohort had a pancreatic tumor, including one advanced PDAC and one early grade 2 neuroendocrine tumor. Thirteen individuals with FPC (6.1%) underwent surgical resection for a suspected PRL, but only four (1.9%) had high-risk lesions (ie, high-grade intraductal papillary mucinous neoplasms or grade 3 pancreatic intraepithelial neoplasms). One BRCA2 mutation carrier was found to have PDAC, and another BRCA2 mutation carrier and a PALB2 mutation carrier underwent surgery and were found to have low-risk PRL. No serious complications occurred as consequence of the program.

Conclusion: Surveillance of CDNK2A mutation carriers is relatively successful, detecting most PDACs at a resectable stage. The benefit of surveillance in families with FPC is less evident.
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http://dx.doi.org/10.1200/JCO.2015.64.0730DOI Listing
June 2016

Total Body Photography as an Aid to Skin Self-examination: A Patient's Perspective.

Acta Derm Venereol 2016 Feb;96(2):186-90

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

Skin self-examination can help patients who are at high risk for developing melanoma to become more involved in their own surveillance and treatment. This study examined the use of total body photography as an aid to skin self-examination from the patients' perspective. A total of 179 individuals at high risk for developing melanoma who had undergone total body photography (60.5% response rate) completed a self-reported questionnaire assessing the frequency of skin self-examination, perceived usefulness of total body photography, and a variety of potential demographic, clinical and psychological factors. Only approximately half of the participants indicated skin self-examination as useful and 78.9% preferred clinical skin examination by a specialist. Finding total body photography useful was associated with having received instructions on how to perform skin self-examination, the use of a (hand)mirror, and confidence to detect changing moles. These findings allow us to develop strategies to further improve patients' self-screening behaviours.
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http://dx.doi.org/10.2340/00015555-2228DOI Listing
February 2016

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

Prospective risk of cancer and the influence of tobacco use in carriers of the p16-Leiden germline variant.

Eur J Hum Genet 2015 May 17;23(5):711-4. Epub 2014 Sep 17.

Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.

The p16-Leiden germline variant in the CDKN2A gene is associated with a high risk of melanoma and pancreatic cancer. The aims of this study were to assess the risk of developing other cancers and to determine whether tobacco use would alter cancer risk in carriers of such a variant. We therefore prospectively evaluated individuals with a p16-Leiden germline variant, participating in a pancreatic surveillance programme, for the occurrence of cancer (n=150). Tobacco use was assessed at the start of the surveillance programme. We found a significantly increased risk for melanoma (relative risk (RR) 41.3; 95% confidence interval (CI) 22.9-74.6) and pancreatic cancer (RR 80.8; 95% CI 44.7-146). In addition, increased risks were found for cancers of the lip, mouth and pharynx (RR 18.8; 95% CI 6.05-58.2) and respiratory tumours (RR 4.56; 95% CI 1.71-12.1). Current smokers developed significantly more cancers of the lip, mouth and pharynx, respiratory system and pancreas compared with former and never-smokers. In conclusion, this study shows that carriers of a p16-Leiden variant have an increased risk of developing various types of cancer, and smoking significantly increases the risk of frequently occurring cancers. Smoking cessation should be an integral part of the management of p16-Leiden variant carriers.
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http://dx.doi.org/10.1038/ejhg.2014.187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402641PMC
May 2015

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

Surveillance of second-degree relatives from melanoma families with a CDKN2A germline mutation.

Cancer Epidemiol Biomarkers Prev 2013 Oct 29;22(10):1771-7. Epub 2013 Jul 29.

Authors' Affiliations: Department of Dermatology, Medical Statistics and Clinical Epidemiology, Clinical Genetics, Leiden University Medical Center, Leiden; Medical Affairs, Agendia, Amsterdam; Department of Pathology, VU University Medical Center, Amsterdam; The Netherlands Foundation for the Detection of Hereditary Tumors, Leiden; and Department of Gastroenterology, Leiden University Medical Center, Leiden, the Netherlands.

Background: Lifetime melanoma risk of mutation carriers from families with a germline mutation in the CDKN2A gene is estimated to be 67%. The necessity to include family members in a melanoma surveillance program is widely endorsed, but there is no consensus on which family members should be invited.

Methods: In a retrospective follow-up study, we investigated the yield of surveillance of first- and second-degree relatives of melanoma and pancreatic cancer patients from 21 families with the "p16-Leiden" CDKN2A mutation. Melanoma incidence rates were compared with the general population.

Results: Three-hundred and fifty-four first-degree relatives and 391 second-degree relatives were included. Forty-five first-degree relatives and 11 second-degree relatives were diagnosed with melanoma. Most (72%) of second-degree relatives diagnosed with melanoma had become a first-degree relative before diagnosis, due to the occurrence of a melanoma in a parent or sibling. Overall, melanoma incidence rate was 2.1 per 1,000 person years [95% confidence interval (CI), 1.2-3.8] in family members still being second-degree relatives at diagnosis, compared with 9.9 per 1,000 person years (95% CI, 7.4-13.3) in first-degree relatives. The standardized morbidity ratio for melanoma of second-degree relatives compared with the general population was 12.9 (95% CI, 7.2-23.4).

Conclusion: Second-degree relatives from families with the p16-Leiden mutation in CDKN2A have a considerably increased melanoma risk compared with the general population.

Impact: This study provides justification for the surveillance of second-degree relatives from families with a CDKN2A germline mutation.
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http://dx.doi.org/10.1158/1055-9965.EPI-13-0130DOI Listing
October 2013

[Revision of the national guideline 'Melanoma'].

Ned Tijdschr Geneeskd 2013 ;157(12):A6136

Integraal Kankercentrum Nederland, afd. Richtlijnen, Groningen, the Netherlands.

Melanoma is in the top ten of the most common types of cancer in the Netherlands. Incidence is increasing steadily by about 4% every year. The relative 5-year survival rate for patients with a melanoma with Breslow thickness < 1mm is about 98%. The national guideline 'Melanoma version 2.0' is the result of an evidence based revision focussed on the most important bottlenecks encountered in clinical practice. The most important changes concern indications for sentinel node procedures (in patients with tumours stage 1b and higher) and multidisciplinary consultation (patients with stage 3 and 4 tumours). The guideline is intended for all professionals involved in diagnosis, treatment and support of patients with melanoma of the skin.- Guideline summary cards and the 'Melanoma Pathway' ('Zorgpad Melanoom') are available at www.iknl.nl.- An English translation of the quideline will be available in April 2013 at www.oncoline.nl.
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May 2013

A variant in FTO shows association with melanoma risk not due to BMI.

Nat Genet 2013 Apr 3;45(4):428-32, 432e1. Epub 2013 Mar 3.

Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, Leeds Cancer Research UK Centre, St. James's University Hospital, Leeds, UK.

We report the results of an association study of melanoma that is 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 an association between several 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 odds ratio for allele A = 1.16). In addition to identifying a new melanoma-susceptibility locus, this is to our knowledge 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 exhibit 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.
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http://dx.doi.org/10.1038/ng.2571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640814PMC
April 2013

Genome-wide analysis of gene and protein expression of dysplastic naevus cells.

J Skin Cancer 2012 28;2012:981308. Epub 2012 Nov 28.

Department of Dermatology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands.

Cutaneous melanoma, a type of skin tumor originating from melanocytes, often develops from premalignant naevoid lesions via a gradual transformation process driven by an accumulation of (epi)genetic lesions. These dysplastic naevi display altered morphology and often proliferation of melanocytes. Additionally, melanocytes in dysplastic naevi show structural mitochondrial and melanosomal alterations and have elevated reactive oxygen species (ROS) levels. For this study we performed genome-wide expression and proteomic analysis of melanocytes from dysplastic naevus (DNMC) and adjacent normal skin (MC) from 18 patients. Whole genome expression profiles of the DNMC and MC of each individual patient subjected to GO-based comparative statistical analysis yielded significantly differentially expressed GO classes including "organellar ribosome," "mitochondrial ribosome," "hydrogen ion transporter activity," and "prefoldin complex." Validation of 5 genes from these top GO classes revealed a heterogeneous differential expression pattern. Proteomic analysis demonstrated differentially expressed proteins in DNMC that are involved in cellular metabolism, detoxification, and cytoskeletal organization processes, such as GTP-binding Rho-like protein CDC42, glutathione-S-transferase omega-1 and prolyl 4-hydroxylase. Collectively these results point to deregulation of cellular processes, such as metabolism and protein synthesis, consistent with the observed elevated oxidative stress levels in DNMC potentially resulting in oxidative DNA damage in these cells.
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http://dx.doi.org/10.1155/2012/981308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3515917PMC
December 2012

Commentary II: The void of congenital naevi.

Acta Derm Venereol 2012 Nov;92(6):586

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http://dx.doi.org/10.2340/00015555-1491DOI Listing
November 2012

Melanocortin 1 receptor (MC1R) variants in high melanoma risk patients are associated with specific dermoscopic ABCD features.

Acta Derm Venereol 2012 Nov;92(6):587-92

Department of Dermatology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.

Individuals with two red hair colour (RHC)-MC1R genetic variants have light skin and blond/reddish hair and, in comparison with those without such alleles, are at an increased risk of developing melanoma. Our study investigated the association of RHC variants and the Total Dermo-scopy Score (TDS), and the items that make up the TDS, in those with atypical naevi and melanomas from high risk melanoma patients. Eight hundred and seventy-six atypical naevi and 21 melanomas were scored according to the TDS system and MC1R polymorphisms were determined. Analyses revealed that several TDS items including pigment network, dark-brown colour and streaks were more frequently observed in atypical naevi from individuals without RHC variants, while structureless areas were more often observed in individuals with two RHC variants. Finally, no significant difference in TDS was detected in atypical naevi from individuals with two RHC variants compared to those without RHC. Clinicians should be aware of a different dermoscopic naevus pheno-type in patients with light blond or RHC MC1R variants.
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http://dx.doi.org/10.2340/00015555-1457DOI Listing
November 2012

Skin examination behavior: the role of melanoma history, skin type, psychosocial factors, and region of residence in determining clinical and self-conducted skin examination.

Arch Dermatol 2012 Oct;148(10):1142-51

School of Women’s and Children’s Health, Faculty of Medicine, University of New South Wales, Kensington, NSW, Australia.

Objective: To examine the frequency and correlates of skin examination behaviors in an international sample of individuals at varying risk of developing melanoma.

Design: A cross-sectional, web-based survey.

Setting: Data were collected from the general population over a 20-month period on behalf of the Melanoma Genetics Consortium (GenoMEL).

Participants: A total of 8178 adults from Northern (32%), Central (33%), and Southern (14%) Europe, Australia (13%), and the United States (8%).

Main Outcome Measures: Self-reported frequency of skin self-examination (SSE) and clinical skin examination (CSE).

Results: After adjustment for age and sex, frequency of skin examination was higher in both Australia (odds ratio [OR]SSE=1.80 [99% CI, 1.49-2.18]; ORCSE=2.68 [99% CI, 2.23-3.23]) and the United States (ORSSE=2.28 [99% CI, 1.76-2.94]; ORCSE=3.39 [99% CI, 2.60-4.18]) than in the 3 European regions combined. Within Europe, participants from Southern Europe reported higher rates of SSE than those in Northern Europe (ORSSE=1.61 [99% CI, 1.31-1.97]), and frequency of CSE was higher in both Central (ORCSE=1.47 [99% CI, 1.22-1.78]) and Southern Europe (ORCSE=3.46 [99% CI, 2.78, 4.31]) than in Northern Europe. Skin examination behavior also varied according to melanoma history: participants with no history of melanoma reported the lowest levels of skin examination, while participants with a previous melanoma diagnosis reported the highest levels. After adjustment for region, and taking into account the role of age, sex, skin type, and mole count, engagement in SSE and CSE was associated with a range of psychosocial factors, including perceived risk of developing melanoma; perceived benefits of, and barriers to, skin examination; perceived confidence in one's ability to engage in screening; and social norms. In addition, among those with no history of melanoma, higher cancer-related worry was associated with greater frequency of SSE.

Conclusions: Given the strong association between psychosocial factors and skin examination behaviors, particularly among people with no history of melanoma, we recommend that greater attempts be made to integrate psycho-education into the fabric of public health initiatives and clinical care, with clinicians, researchers, and advocacy groups playing a key role in guiding individuals to appropriate tools and resources.
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http://dx.doi.org/10.1001/archdermatol.2012.1817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965805PMC
October 2012

Perceptions of genetic research and testing among members of families with an increased risk of malignant melanoma.

Eur J Cancer 2012 Nov 21;48(16):3052-62. Epub 2012 Jun 21.

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

Background: Several melanoma susceptibility genes have been identified. As part of the international genetic research programme of the GenoMEL consortiums research on genetic mutations in melanoma families, the aim of this study was to examine family members' views about their risk of melanoma, gene testing and genetic research.

Methods: Self-report data were gathered using online and paper-based surveys available in four languages among 312 individuals (62% from Europe, 18% from Australia, 13% from the United States of America (USA) and 7% from Israel).

Results: Fifty three percent had been diagnosed with a melanoma, and 12% had a positive susceptibility gene test result. Respondents with many moles and freckles were more likely to perceive themselves at risk for developing melanoma (odds ratio [OR](Freckles)=2.24 with 95% confidence interval [CI]=1.18-4.26; OR(Many moles)=6.92, 95%CI=2.37-20.23). Respondents who had received a non-informative (negative) genetic test result were much less likely to perceive themselves at increased risk (OR=0.17, 95% CI=0.04-0.73). Safe-guards were perceived as important to protect genetic information, but there was also support for the storage and exchange of such information. Overall, respondents were in favour of genetic testing, even if current knowledge about melanoma risk genes is still limited. Contrary to previous studies, participants reported that a non-informative (negative) genetic test result, although not necessarily indicative of lower risk of melanoma, would be likely to reduce their practise of preventive behaviours.

Conclusions: Participants were influenced by their phenotype and test results in risk estimations. They expressed positive views on genetic research and towards genetic testing, but reported that a non-informative (negative) test result might be associated with an (erroneous) perception of reduced risk and fewer preventive behaviours. These results highlight the urgency of improving the quality of genetic counselling and increasing the effectiveness of communication regarding genetic test results.
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http://dx.doi.org/10.1016/j.ejca.2012.05.017DOI Listing
November 2012

Genome-wide association study identifies three new melanoma susceptibility loci.

Nat Genet 2011 Oct 9;43(11):1108-13. Epub 2011 Oct 9.

Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, Leeds Cancer Research UK Centre, St James’s University Hospital, Leeds, UK.

We report a genome-wide association study for melanoma that was conducted by the GenoMEL Consortium. Our discovery phase included 2,981 individuals with melanoma and 1,982 study-specific control individuals of European ancestry, as well as an additional 6,426 control subjects from French or British populations, all of whom were genotyped for 317,000 or 610,000 single-nucleotide polymorphisms (SNPs). Our analysis replicated previously known melanoma susceptibility loci. Seven new 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 Texas, USA). Additional replication came from case-control series from the UK and The Netherlands. Variants at three of the seven loci replicated at P < 10(-3): an SNP in ATM (rs1801516, overall P = 3.4 × 10(-9)), an SNP in MX2 (rs45430, P = 2.9 × 10(-9)) and an SNP adjacent to CASP8 (rs13016963, P = 8.6 × 10(-10)). A fourth locus near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication (rs1485993, overall P = 4.6 × 10(-7) under a fixed-effects model and P = 1.2 × 10(-3) under a random-effects model). These newly associated variants showed no association with nevus or pigmentation phenotypes in a large British case-control series.
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http://dx.doi.org/10.1038/ng.959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3251256PMC
October 2011

Total body skin examination for skin cancer screening in patients with focused symptoms.

J Am Acad Dermatol 2012 Feb 14;66(2):212-9. Epub 2011 Jul 14.

Department of Dermatology, Second University of Naples, Naples, Italy.

Background: The value of total body skin examination (TBSE) for skin cancer screening is controversial.

Objective: We sought to determine whether TBSE could be helpful in patients with focused skin symptoms who would not otherwise have undergone TBSE.

Methods: In a prospective, multicenter, cross-sectional study consecutive adult patients were recruited during a period of 18 months. Physicians first inspected problem areas and uncovered areas and then performed TBSE. Equivocal lesions detected in both steps were excised or biopsied. Primary outcomes were the absolute and relative risks of missing skin cancer and the number of patients needed to examine to detect melanoma or another malignancy. A secondary outcome was the proportion of false-positive results obtained by TBSE.

Results: We examined 14,381 patients and detected 40 (0.3%) patients with melanoma and 299 (2.1%) with at least one nonmelanoma skin cancer by TBSE. In 195 (1.3%) patients equivocal lesions found by TBSE turned out to be benign. We calculated that 47 patients need to be examined by TBSE to find one skin malignancy and 400 patients to detect one melanoma. The risk of missing one malignancy if not performing TBSE was 2.17% (95% confidence interval 1.25-3.74). Factors significantly increasing the chance to find a skin cancer were age, male gender, previous nonmelanoma skin cancer, fair skin type, skin tumor as the reason for consultation, and presence of an equivocal lesion on problem/uncovered areas.

Limitations: The impact of TBSE on skin cancer mortality was not evaluated.

Conclusions: TBSE improves skin cancer detection in patients with focused skin symptoms and shows a low rate of false-positive results.
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http://dx.doi.org/10.1016/j.jaad.2010.12.039DOI Listing
February 2012

Impact of dermoscopy on the management of high-risk patients from melanoma families: a prospective study.

Acta Derm Venereol 2011 Jun;91(4):428-31

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

Few studies have investigated the impact of dermoscopy on the management of relatives from melanoma families. The objective of this study was to assess the impact of dermoscopy on clinical diagnosis and management decisions in high-risk familial melanoma patients. In a prospective study 132 consecutive patients were recruited from the pigmented lesions clinic of a tertiary reference centre for familial melanoma. Dermatologists expert in dermoscopy identified 49 suspicious pigmented lesions and recorded pre- and post-dermoscopy diagnoses and management decisions. Dermoscopy was performed in 37% of the patients. Two melanomas were identified. Dermoscopy did not influence sensitivity (1.0), but resulted in 42% fewer excisions, increasing specificity from 0.53 to 0.74 (p = 0.031). Dermoscopy resulted in a large reduction in the number of unnecessary excisions. These results suggest that the main effect of dermoscopy in clinical practice for this high risk population is a significant increase in specificity, rather than sensitivity.
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http://dx.doi.org/10.2340/00015555-1100DOI Listing
June 2011

Clinical and histologic characteristics of malignant melanoma in families with a germline mutation in CDKN2A.

J Am Acad Dermatol 2011 Aug 12;65(2):281-288. Epub 2011 May 12.

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

Background: About 10% of cutaneous malignant melanomas (CMM) occur in individuals with a family history of melanoma. In 20% to 40% of melanoma families germline mutations in CDKN2A are detected. Knowledge of the clinicohistologic characteristics of melanomas and patients from these families is important for optimization of management strategies, and may shed more light on the complex interplay of genetic and environmental factors in the pathogenesis of melanoma.

Objective: We sought to investigate the clinical and histologic characteristics of CMM in CDKN2A-mutated families.

Methods: Clinical and histologic characteristics of 182 patients with 429 CMM from families with a founder mutation in CDKN2A (p16-Leiden mutation) were compared with 7512 patients with 7842 CMM from a population-based cancer registry.

Results: Patients with p16-Leiden had their first melanoma 15.3 years younger than control patients. The 5-year cumulative incidence of second primary CMM was 23.4% for patients with p16-Leiden compared with 2.3% for control patients. The risk of a second melanoma was twice as high for patients with p16-Leiden who had their first melanoma before age 40 years, compared with older patients with p16-Leiden. Unlike control patients, there was no body site concordance of the first and second melanoma in patients with p16-Leiden and multiple primary melanomas. Patients with p16-Leiden had significantly more superficial spreading, and less nodular and lentiginous melanomas.

Limitations: Ascertainment of patients with p16-Leiden was family based. The study was performed in families with a founder mutation, the p16-Leiden mutation.

Conclusion: Our findings are consistent with a pathogenic pathway of melanoma development from nevi, starting early and ongoing throughout life, and not related to chronic sun exposure.
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http://dx.doi.org/10.1016/j.jaad.2010.06.044DOI Listing
August 2011

Effectiveness and causes for failure of surveillance of CDKN2A-mutated melanoma families.

J Am Acad Dermatol 2011 Aug 12;65(2):289-296. Epub 2011 May 12.

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

Background: For more than 25 years families with an increased susceptibility to melanoma have been under surveillance at our institution.

Objective: We sought to investigate the effectiveness of surveillance for CDKN2A-mutated families and causes for failure of the program in patients with more advanced tumors.

Methods: In a retrospective case-control study, Breslow thickness of melanomas diagnosed in relatives enrolled in the surveillance program were compared with melanomas of unscreened index patients. We investigated the influence of mode of detection and length of surveillance interval on outcome.

Results: Surveillance melanomas (n = 226, median thickness: 0.50 mm) had a significantly lower Breslow thickness (multiplication factor: 0.61 [95% confidence interval 0.47-0.80], P < .001) than index melanomas (n = 40, median thickness: 0.98 mm). Index melanomas were more likely diagnosed with a Breslow thickness greater than 1.0 mm (odds ratio: 3.1 [95% confidence interval 1.2-8.1], P = .022). In all, 53% of surveillance melanomas were diagnosed during regular screens, 7% during patients' first screen, 20% between regular screens, and 20% in patients who were noncompliant with the surveillance schedule. The majority of surveillance melanomas (58%) were detected within 6 months after the last screen. There was no correlation between tumor thickness and the length of the screening interval for tumors diagnosed within 24 months since the last screen.

Limitations: The study is retrospective.

Conclusions: Surveillance was associated with earlier detection of melanomas. Noncompliance was an important cause for failing surveillance. Shortening surveillance intervals may advance detection of tumors, but may paradoxically have little impact on prognosis.
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http://dx.doi.org/10.1016/j.jaad.2010.06.067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138884PMC
August 2011

Magnetic resonance imaging surveillance detects early-stage pancreatic cancer in carriers of a p16-Leiden mutation.

Gastroenterology 2011 Mar 1;140(3):850-6. Epub 2010 Dec 1.

Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.

Background & Aims: Surveillance of high-risk groups for pancreatic cancer might increase early detection and treatment outcomes. Individuals with germline mutations in p16-Leiden have a lifetime risk of 15% to 20% of developing pancreatic cancer. We assessed the feasibility of detecting pancreatic cancer at an early stage and investigated the outcomes of patients with neoplastic lesions.

Methods: Individuals with germline mutations in p16-Leiden (N = 79; 31 male; mean age, 56 years; range, 39-72 years) were offered annual surveillance by magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography (MRCP). Those found to have neoplastic lesions were offered options for surgery or intensive follow-up. Individuals found to have possible neoplastic lesions were examined again by MRI/MRCP within 2 to 4 months.

Results: After a median follow-up period of 4 years (range, 0-10 years), pancreatic cancer was diagnosed in 7 patients (9%). The mean age at diagnosis was 59 years (range, 49-72 years). Three of the tumors were present at the first examination, and 4 were detected after a negative result in the initial examination. All 7 patients had a resectable lesion; 5 underwent surgery, 3 had an R0 resection, and 2 had lymph node metastases. Possible precursor lesions (ie, duct ectasias, based on MRCP) were found in 9 individuals (11%).

Conclusions: MRI/MRCP detects small, solid pancreatic tumors and small duct ectasias. Although surveillance increases the rate of resectability, carriers of a p16-Leiden mutation develop aggressive tumors.
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http://dx.doi.org/10.1053/j.gastro.2010.11.048DOI Listing
March 2011

A flexible multiplex bead-based assay for detecting germline CDKN2A and CDK4 variants in melanoma-prone kindreds.

J Invest Dermatol 2011 Feb 18;131(2):480-6. Epub 2010 Nov 18.

Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

The presence of recurrent high-risk mutations in cyclin-dependent kinase inhibitor 2A/cyclin-dependent kinase 4 (CDKN2A/CDK4) among melanoma-prone families suggests that a high-throughput, multiplex assay could serve as an effective initial screening tool. To this end, we have developed a multiplex bead-based assay for high-throughput CDKN2A/CDK4 genotyping in the context of familial melanoma. Genomic DNA from 1,603 subjects (1,005 in training set and 598 in validation set) were amplified by multiplex PCR using five CDKN2A/CDK4 primer sets followed by multiplex allele-specific primer extension for 39 distinct germline variants. The products were then sorted and analyzed using the Luminex xMAP system. Genotypes were compared with previously determined sequence data. In the Toronto training cohort, all 145 samples with known variants were detected by the bead assay (100% concordance). Analysis of the 598 samples from the GenoMEL validation set led to identification of 150/155 expected variants (96.77%). Overall, the bead assay correctly genotyped 1,540/1,603 (96.07%) of all individuals in the study and 1,540/1,545 (99.68%) of individuals whose variants were represented in the probe set. Out of a total of 62,517 allelic calls, 62,512 (99.99%) were correctly assigned. The multiplex bead-based assay is an accurate method for genotyping CDKN2A/CDK4 variants and is potentially useful in genotyping low-to-moderate melanoma risk single-nucleotide polymorphisms.
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http://dx.doi.org/10.1038/jid.2010.331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3045700PMC
February 2011

[Mucocutaneous abnormalities in Chlamydia trachomatis-induced reactive arthritis].

Ned Tijdschr Geneeskd 2010 ;154:A1614

Leids Universitair Medisch Centrum, Afd. Dermatologie, Leiden, the Netherlands.

Reactive arthritis (previously known as Reiters syndrome) is an inflammatory arthritis that is a type of spondyloarthropathy. The disease consists of the classical triad of arthritis, urethritis and conjunctivitis, but mucocutaneous abnormalities also frequently appear: balanitis circinata, keratoderma blennorrhagicum, aphthous ulcers in the mouth and nail disorders. These skin lesions are mainly found in reactive arthritis induced by Chlamydia trachomatis (Ct). Reactive arthritis is often triggered by a sexually transmitted infection (Chlamydia trachomatis) or an enteric infection (such as Salmonella or Shigella). It is thought that human antibodies against the pathogen cross-react with the HLA antigen (mainly HLA-B27). To distinguish between reactive arthritis and psoriatic arthritis, screening of the urine or synovium for Ct infection should be carried out. Acute reactive arthritis is treated with NSAIDs as the first choice. In addition, patients may receive an intra-articular injection of glucocorticoids. The mucocutaneous abnormalities respond well to topical glucocorticoids. Although in the Netherlands a Ct induced reactive arthritis is not yet treated with antibiotics, a recent published clinical trial in patients with a chronic Ct induced reactive arthritis showed a significant reduction in complaints in the group treated with a combination of antibiotics for 6 months, compared to the placebo group. Active genitourinary Ct infection should be treated with antibiotics, the first choice being azithromycin 1000 mg as a single dose. It is important that the patient's partner is tested at the same time and if necessary treated simultaneously to prevent reinfection.
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September 2010
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