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

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.

High Growth Rate of Pancreatic Ductal Adenocarcinoma in CDKN2A-p16-Leiden Mutation Carriers.

CDKN2A-p16-Leiden 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 CDKN2A-p16-Leiden 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 (P = 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. Cancer Prev Res; 11(9); 551-6. ©2018 AACR.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

Acquired melanocytic nevi in childhood and familial melanoma.

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.

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

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.

[Revision of the national guideline 'Melanoma']. / Revisie van de landelijke richtlijn 'Melanoom'.

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.

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

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.

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

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.

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

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.