The incidence of cutaneous melanoma is rising rapidly in a number of countries. The key environmental risk factor is exposure to the ultraviolet (UV) component in sunlight. The nucleotide excision repair (NER) pathway deals with the main forms of UV-induced DNA damage. We have investigated the hypothesis that polymorphisms in NER genes constitute genetic susceptibility factors for melanoma. However, not all melanomas arise on sun-exposed sites and so we investigated the hypothesis that genes involved in other pathways for the repair of oxidative DNA damage may also be involved in susceptibility to melanoma. Scotland, with its high incidence of melanoma and stable homogeneous population, was ideal for this case-control study, involving 596 Scottish melanoma patients and 441 population-based controls. Significant associations were found for the NER genes ERCC1 and XPF, with the strongest associations for melanoma cases aged 50 and under [ERCC1 odds ratio (OR) 1.59, P = 0.008; XPF OR 1.69, P = 0.003]. Although an XPD haplotype was associated with melanoma, it did not contain the variant 751 Gln allele, which has been associated with melanoma in some previous studies. No associations were found for the base excision repair and DNA damage response genes investigated. An association was also found for a polymorphism in the promoter of the vitamin D receptor gene, VDR (OR 1.88, P = 0.005). The products of the two NER genes, ERCC1 and XPF, where associations with melanoma were found, act together in a rate-limiting step in the repair pathway.
Two methods of estimating stratum corneum thickness using reflectance confocal microscopy were examined, and epidermal thickness measurements at multiple body sites were compared. Measurements of stratum corneum thickness were made using the derivative method, which is based on the rate of change of image intensity as a proxy for keratin concentration, and simple visual analysis of confocal images. To compare epidermal thickness we collected 1491 z-axis stacks of confocal images from 10 body sites in 39 subjects. An artefact associated with the imaging process interfered with the derivative method for stratum corneum thickness, and simple visual analysis is to be preferred. Although some epidermal properties varied by site, the most striking finding was the degree of within-site variation, which accounted for between 50% and 74% of the total variation observed. The majority of this variation was not due to measurement error, and represents genuine topographical irregularity. This finescale variation limits the ease of use of reflectance confocal microscopy for quantitative studies of the epidermis and stratum corneum.There is a scale to skin structure and hence skin biology that is not served well by techniques such as conventional transmission microscopy and subcellular analyses on the one hand, and macroscopic examination with the naked eye on the other. For instance, we have shown that differences in epidermal or stratum corneum (SC) thickness at different body sites may be important determinants of site variation in sensitivity to ultraviolet radiation (UVR) (1, 2). However, study of these factors is difficult (3); repeated biopsy at various ultraviolet doses and time-points is ethically problematic, and biopsy means that a single area of skin cannot be observed longitudinally, nor can the three-dimensional structure of skin in vivo be appreciated. The fact that the epidermis and the components of the epidermis are not flat regular two-dimensional sheets, but irregular undulating three-dimensional structures, is a quality that has relevance to many aspects of skin biology, including percutaneous absorption, UVR-induced carcinogenesis and ageing. The present study examined the use of reflectance confocal microscopy (RCM) to study epidermal morphology, comparing different methods of measuring SC thickness.RCM has been described as a new gold standard for the measurement of epidermal thickness (3, 4). It provides a non-invasive imaging tool capable of obtaining en face images of living tissue in vivo (3). It has none of the problems associated with biopsy-obtained samples that become more or less distorted (swelling or shrinkage) during different steps of the preparation procedure (5-8).The interpretation of RCM images is based largely on pattern recognition and histological knowledge of skin anatomy (4, 9, 10). For SC thickness one manufacturer of reflectance confocal microscopes suitable for use on human skin, Lucid (Rochester, NY, USA), have proposed a method that we refer to as the derivative method (DM) (pe...
the hair placode and the late germ (peg) stage, but instead remain oriented radially to the skin at all stages (Devenport and Fuchs, 2008). Our observation that Celsr1 mutant follicles are obliquely orientated suggests that a secondary orientation occurs during the early postnatal period.Body and leg hair-patterning defects similar to those described here are mimicked by inactivation of frizzled6, an ortholog of Drosophila Frizzled gene (Guo et al., 2004; Wang et al., 2006). In addition, mice deficient in Celsr3 and Frizzled3 have similar brain-wiring anomalies. This suggests that Celsr1-Frizzled6 and Celsr3-Frizzled3 act in similar pathways (Tissir et al., 2005). In flies, Frizzled controls patterning of skin appendages, together with Fmi/Stan and other core PCP genes such as Van Gogh, Disheveled, and Prickle (Wang and Nathans, 2007; Simons and Mlodzik, 2008). The hair-patterning phenotypes in Celsr1 and Frizzled6 mutant mice resemble the defects seen in Fmi/ Stan and Frizzled Drosophila mutants, thus providing further evidence that Frizzled and Celsr (Fmi/Stan) are key elements of PCP-related pathways that pattern ectodermal derivatives and are evolutionary conserved. In the Drosophila wing, Frizzled localizes to the distal side of cells, Van Gogh to the proximal side, and Fmi/Stan to both. This polarized distribution is thought to affect the hair orientation by controlling the cytoskeletal machinery responsible for hair assembly. Similarly, in the embryonic skin, polarization of the Celsr1, van gogh-like 2, and Frizzled6 is found in wildtype, but not in corresponding mutant mice (Devenport and Fuchs, 2008). It will be interesting to study the protein-protein interactions that generate this polarized distribution.
Robust experimental evidence supporting many attempts to facilitate early melanoma diagnosis is lacking. In an experimental study using a browser interface we have examined diagnostic accuracy, sensitivity and specificity of novices in distinguishing between melanomas and mimics of melanoma. We show that rule-based ABC methods and image training, based on random images of melanoma, improve specificity to similar degrees, with-out effects on sensitivity, leading to small improvements in overall accuracy. There was a significant effect of age with older subjects performing better. Although both the ABC method and image training groups showed improved performance over the control group, overall performance was poor. For instance, for a task in which 1 in 4 test images was a melanoma, and 3 out of 4 benign, both interventions (ABC or image training) increased accuracy from the control value of 53% to around 61%. For reference, dermatology trainees performed at a much higher level of accuracy. Our study provides little support for the use of such methods in public education, but suggests ways in which performance might be improved.
Using an experimental task in which lay persons were asked to distinguish between 30 images of melanomas and common mimics of melanoma, we compared various training strategies including the ABC(D) method, use of images of both melanomas and mimics of melanoma, and alternative methods of choosing training image exemplars. Based on a sample size of 976 persons, and an online experimental task, we show that all the positive training approaches increased diagnostic sensitivity when compared with no training, but only the simultaneous use of melanoma and benign exemplars, as chosen by experts, increased specificity and diagnostic accuracy. The ABCD method and use of melanoma exemplar images chosen by laypersons decreased specificity in comparison with the control. The method of choosing exemplar images is important. The levels of change in performance are however very modest, with an increase in accuracy between control and best-performing strategy of only 9%.
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