Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148

Genome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk, and exhibited preferred protein-binding and enhanced regulatory activity. Transcriptional gene silencing of this regulatory element repressed TERT expression in an allele-specific manner. Proteomic analysis identifies allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365-C, further supported by binding of purified recombinant ZNF148. Knockdown of ZNF148 results in reduced TERT expression, telomerase activity and telomere length. Our results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT expression via ZNF148 in a manner consistent with elevated TERT in carriers of the C allele

Pathway-Based Analysis of a Melanoma Genome-Wide Association Study: Analysis of Genes Related to Tumour-Immunosuppression

Systemic immunosuppression is a risk factor for melanoma, and sunburn-induced immunosuppression is thought to be causal. Genes in immunosuppression pathways are therefore candidate melanoma-susceptibility genes. If variants within these genes individually have a small effect on disease risk, the association may be undetected in genome-wide association (GWA) studies due to low power to reach a high significance level. Pathway-based approaches have been suggested as a method of incorporating a priori knowledge into the analysis of GWA studies. In this study, the association of 1113 single nucleotide polymorphisms (SNPs) in 43 genes (39 genomic regions) related to immunosuppression have been analysed using a gene-set approach in 1539 melanoma cases and 3917 controls from the GenoMEL consortium GWA study. The association between melanoma susceptibility and the whole set of tumour-immunosuppression genes, and also predefined functional subgroups of genes, was considered. The analysis was based on a measure formed by summing the evidence from the most significant SNP in each gene, and significance was evaluated empirically by case-control label permutation. An association was found between melanoma and the complete set of genes (pemp = 0.002), as well as the subgroups related to the generation of tolerogenic dendritic cells (pemp = 0.006) and secretion of suppressive factors (pemp = 0.0004), thus providing preliminary evidence of involvement of tumour-immunosuppression gene polymorphisms in melanoma susceptibility. The analysis was repeated on a second phase of the GenoMEL study, which showed no evidence of an association. As one of the first attempts to replicate a pathway-level association, our results suggest that low power and heterogeneity may present challenges

Particulate matter exposure during pregnancy is associated with birth weight, but not gestational age, 1962-1992: a cohort study

<p>Abstract</p> <p>Background</p> <p>Exposure to air pollutants is suggested to adversely affect fetal growth, but the evidence remains inconsistent in relation to specific outcomes and exposure windows.</p> <p>Methods</p> <p>Using birth records from the two major maternity hospitals in Newcastle upon Tyne in northern England between 1961 and 1992, we constructed a database of all births to mothers resident within the city. Weekly black smoke exposure levels from routine data recorded at 20 air pollution monitoring stations were obtained and individual exposures were estimated via a two-stage modeling strategy, incorporating temporally and spatially varying covariates. Regression analyses, including 88,679 births, assessed potential associations between exposure to black smoke and birth weight, gestational age and birth weight standardized for gestational age and sex.</p> <p>Results</p> <p>Significant associations were seen between black smoke and both standardized and unstandardized birth weight, but not for gestational age when adjusted for potential confounders. Not all associations were linear. For an increase in whole pregnancy black smoke exposure, from the 1^st(7.4 μg/m³) to the 25^th(17.2 μg/m³), 50^th(33.8 μg/m³), 75^th(108.3 μg/m³), and 90^th(180.8 μg/m³) percentiles, the adjusted estimated decreases in birth weight were 33 g (SE 1.05), 62 g (1.63), 98 g (2.26) and 109 g (2.44) respectively. A significant interaction was observed between socio-economic deprivation and black smoke on both standardized and unstandardized birth weight with increasing effects of black smoke in reducing birth weight seen with increasing socio-economic disadvantage.</p> <p>Conclusions</p> <p>The findings of this study progress the hypothesis that the association between black smoke and birth weight may be mediated through intrauterine growth restriction. The associations between black smoke and birth weight were of the same order of magnitude as those reported for passive smoking. These findings add to the growing evidence of the harmful effects of air pollution on birth outcomes.</p

The opinion of dermoscopy experts about teledermoscopy involving primary care physicians and dermatologists

Many dermatologists use teledermoscopy to seek second advice from experts for difficult lesions. Teledermoscopy by primary care physicians (PCP) is still controversial but already has been implemented in several regions. Since there are only few studies published about teledermoscopy in the hand of PCP with poor level of evidence we asked the opinion of dermoscopy experts (board members of the International Dermoscopy Society (IDS)). (1-6) Furthermore, we investigated the routing of patients with a suspicious pigmented skin lesion and the use of teledermoscopy in different countries. This article is protected by copyright. All rights reserved

Recognizing the haystack is the task of the primary care physician

In a reply to our letter Ferrandiz and colleagues wondered why dermoscopy experts did not already fully embrace teledermoscopy (TD) for suspicious pigmented skin lesions.(1) Our study showed that the structure of the health systems that were investigated differed, with countries where primary care physicians (PCP) hold a gate keeper function and others with direct access to a dermatologist. Significant differences in waiting time and travel distance were observed.(2) Since we believe that there is enough evidence that the addition of high quality dermoscopic pictures to a teleconsultation leads to higher accuracy of the diagnosis we did not investigate this question in our survey

Prevalence and indicators of fear of melanoma in patients with familial melanoma during surveillance

Dermatology-oncolog

The daily use of dermoscopy in the Netherlands

Background: Dermoscopy is a well-established tool for the diagnosis of skin diseases and skin cancer. Data on the use of dermoscopy by Dutch dermatologists is lacking. Objectives: To identify factors influencing the use of dermoscopy in daily dermatology practice and compare the results with those from other European countries. Materials &amp; Methods: As a part of a pan-European study, all registered dermatologists in the Netherlands were asked to complete an online survey regarding questions about training and attitude towards dermoscopy. Results: Valid answers were collected from 213 respondents (out of 475 registered dermatologists), of whom 99% reported using dermoscopy. Of those, 41% reported dermoscopy training during residency. A high level of dermoscopy use for different types of skin diseases was reported by 28.9%. Users considered dermoscopy useful for pigmented lesions, especially for the early diagnosis of melanoma, but less advantageous for inflammatory diagnoses. Seventy-three percent reported that dermoscopy increased the number of melanomas detected compared to naked eye diagnosis, and two-thirds reported a decrease in unnecessary biopsies of benign lesions. Almost one third reported that on at least one occasion, a lesion that appeared benign on dermoscopy proved to be a melanoma after excision. Conclusion: This study reveals that nearly all Dutch dermatologists use dermoscopy, particularly for melanocytic lesions, but less so for inflammatory diagnoses. Most believe that they detected more melanomas as a result of using dermoscopy compared to the naked eye. A high level of dermoscopy use was significantly associated with seeing more skin cancer patients each month compared to infrequent use

Poor agreement between the automated risk assessment of a smartphone application for skin cancer detection and the rating by dermatologists

Background: Several smartphone applications (app) with an automated risk assessment claim to be able to detect skin cancer at an early stage. Various studies that have evaluated these apps showed mainly poor performance. However, all studies were done in patients and lesions were mainly selected by a specialist. Objectives: To investigate the performance of the automated risk assessment of an app by comparing its assessment to that of a dermatologist in lesions selected by the participants. Methods: Participants of a National Skin Cancer Day were enrolled in a multicentre study. Skin lesions indicated by the participants were analysed by the automated risk assessment of the app prior to blinded rating by the dermatologist. The ratings of the automated risk assessment were compared to the assessment and diagnosis of the dermatologist. Due to the setting of the Skin Cancer Day, lesions were not verified by histopathology. Results: We included 125 participants (199 lesions). The app was not able to analyse 90 cases (45%) of which nine BCC, four atypical naevi and one lentigo maligna. Thirty lesions (67%) with a high and 21 with a medium risk (70%) rating by the app were diagnosed as benign naevi or seborrhoeic keratoses. The interobserver agreement between the ratings of the automated risk assessment and the dermatologist was poor (weighted kappa = 0.02; 95% CI −0.08-0.12; P = 0.74). Conclusions: The rating of the automated risk assessment was poor. Further investigations about the diagnostic accuracy in real-life situations are needed to provide consumers with reliable information about this healthcare application