The Skin Molecular Ecosystem Holds the Key to Nevogenesis and Melanomagenesis.

Early detection of melanoma is critical to good patient outcomes, but we still know little about the mechanisms of early melanoma development. Normal epidermis has many of the sequence variants and genetic architecture disruptions found in both benign nevi, melanomas, and other skin cancers, yet continues to behave more or less normally. One hypothesis is that many melanocytes in this context are "tumor competent" but are regulated by the microenvironment provided by the surrounding keratinocytes to inhibit progress to nevi or melanoma. There is evidence of accumulating disorder in several measures of the genomic and epigenomic landscape from normal skin through nevi to melanoma that may be key to promoting nevogenesis and melanomagenesis.

Assessing the genetic risk of nodular melanoma using a candidate gene approach.

BACKGROUND: Nodular melanoma (NM) is a challenge to diagnose early due to its rapid growth and more atypical clinical presentation, making it the largest contributor to melanoma mortality. OBJECTIVES: Our study aim was to perform a rare-variant allele (RVA) analysis of whole-exome sequencing of patients with NM and non-NM (minor allele frequency ≤ 1% non-Finnish European) for a set of 500 candidate genes potentially implicated in melanoma. METHODS: This study recruited 131 participants with NM and 194 with non-NM from South-east Queensland and patients with NM from Victoria to perform a comparative analysis of possible genetic differences or similarities between the two melanoma cohorts. RESULTS: Phenotypic analysis revealed that a majority of patients diagnosed with NM were older males with a higher frequency of fair skin and red hair than is seen in the general population. The distribution of common melanoma polygenic risk scores was similar in patients with NM and non-NM, with over 28% in the highest quantile of scores. There was also a similar frequency of carriage of familial/high-penetrant melanoma gene and loss-of-function variants. We identified 39 genes by filtering 500 candidate genes based on the greatest frequency in NM compared with non-NM cases. The genes with RVAs of greatest frequency in NM included PTCH1, ARID2 and GHR. Rare variants in the SMO gene, which interacts with PTCH1 as ligand and receptor, were also identified, providing evidence that the Hedgehog pathway may contribute to NM risk. There was a cumulative effect in carrying multiple rare variants in the NM-associated genes. A 14.8-fold increased ratio for NM compared with non-NM was seen when two RVAs of the 39 genes were carried by a patient. CONCLUSIONS: This study highlights the importance of considering frequency of RVA to identify those at risk of NM in addition to known high penetrance genes.

Collagen (I) homotrimer potentiates the osteogenesis imperfecta (oim) mutant allele and reduces survival in male mice.

The osteogenesis imperfecta murine (oim) model with solely homotrimeric (α1)3 type I collagen, owing to a dysfunctional α2(I) collagen chain, has a brittle bone phenotype, implying that the (α1)2(α2)1 heterotrimer is required for physiological bone function. Here, we comprehensively show, for the first time, that mice lacking the α2(I) chain do not have impaired bone biomechanical or structural properties, unlike oim homozygous mice. However, Mendelian inheritance was affected in male mice of both lines, and male mice null for the α2(I) chain exhibited age-related loss of condition. Compound heterozygotes were generated to test whether gene dosage was responsible for the less-severe phenotype of oim heterozygotes, after allelic discrimination showed that the oim mutant allele was not downregulated in heterozygotes. Compound heterozygotes had impaired bone structural properties compared to those of oim heterozygotes, albeit to a lesser extent than those of oim homozygotes. Hence, the presence of heterotrimeric type I collagen in oim heterozygotes alleviates the effect of the oim mutant allele, but a genetic interaction between homotrimeric type I collagen and the oim mutant allele leads to bone fragility.

Current Trends in Circulating Biomarkers for Melanoma Detection.

Melanomas have increased in global incidence and are the leading cause of skin cancer deaths. Whilst the majority of early-stage, non-metastatic melanomas can be cured with surgical excision alone, ~5% of patients with early melanomas will experience recurrence following a variable disease-free interval and progression to metastatic melanoma and ultimately death. This is likely because of primary tumor heterogeneity and progressive clonal divergency resulting in the growth of more aggressive tumor populations. Liquid biomarkers have the advantage of real-time, non-invasive longitudinal monitoring of tumor burden and heterogeneity over tissue markers. Currently, the only serological marker used in the staging and monitoring of melanoma is serum lactate dehydrogenase, which is not sufficiently specific or sensitive, and is not used routinely in all centers. An ideal melanoma biomarker would be used to identify patients who are at high-risk of primary melanoma, screen for relapse, detect early-stage melanoma, provide treatment outcomes to personalize systemic treatment, follow tumor heterogeneity, provide prognostic data before, during and after treatment, and monitor response to treatment. This review provides a summary of the current research in this field with a specific focus on circulating tumor cells, circulating tumor DNA, microRNA, and extracellular vesicles which may serve to suit these goals.

On Naevi and Melanomas: Two Sides of the Same Coin?

Benign naevi are closely linked to melanoma, as risk factors, simulators, or sites of melanoma formation. There is a heavy genetic overlap between the two lesions, a shared environmental influence of ultraviolet radiation, and many similar cellular features, yet naevi remain locally situated while melanomas spread from their primary site and may progress systemically to distal organs. Untangling the overlapping contributors and predictors of naevi and melanoma is an ongoing area of research and should eventually lead to more personalized prevention and treatment strategies, through the development of melanoma risk stratification tools and early detection of evolving melanomas. This will be achieved through a range of complementary strategies: risk-adjusted primary prevention counseling; the use of lesion imaging technologies such as sequential 3D total body photography and consumer-performed lesion imaging; artificial intelligence deep phenotyping and clinical assistance; a better understanding of genetic drivers of malignancy, risk variants, clinical genetics, and polygenic effects; and the interplay between genetics, phenotype and the environment.

The Future of Precision Prevention for Advanced Melanoma.

Precision prevention of advanced melanoma is fast becoming a realistic prospect, with personalized, holistic risk stratification allowing patients to be directed to an appropriate level of surveillance, ranging from skin self-examinations to regular total body photography with sequential digital dermoscopic imaging. This approach aims to address both underdiagnosis (a missed or delayed melanoma diagnosis) and overdiagnosis (the diagnosis and treatment of indolent lesions that would not have caused a problem). Holistic risk stratification considers several types of melanoma risk factors: clinical phenotype, comprehensive imaging-based phenotype, familial and polygenic risks. Artificial intelligence computer-aided diagnostics combines these risk factors to produce a personalized risk score, and can also assist in assessing the digital and molecular markers of individual lesions. However, to ensure uptake and efficient use of AI systems, researchers will need to carefully consider how best to incorporate privacy and standardization requirements, and above all address consumer trust concerns.

Germline and somatic albinism variants in amelanotic/hypomelanotic melanoma: Increased carriage of TYR and OCA2 variants.

Amelanotic/hypomelanotic melanoma is a clinicopathologic subtype with absent or minimal melanin. This study assessed previously reported coding variants in albinism genes (TYR, OCA2, TYRP1, SLC45A2, SLC24A5, LRMDA) and common intronic, regulatory variants of OCA2 in individuals with amelanotic/hypomelanotic melanoma, pigmented melanoma cases and controls. Exome sequencing was available for 28 individuals with amelanotic/hypomelanotic melanoma and 303 individuals with pigmented melanoma, which were compared to whole exome data from 1144 Australian controls. Microarray genotyping was available for a further 17 amelanotic/hypomelanotic melanoma, 86 pigmented melanoma, 147 melanoma cases (pigmentation unknown) and 652 unaffected controls. Rare deleterious variants in TYR/OCA1 were more common in amelanotic/hypomelanotic melanoma cases than pigmented melanoma cases (set mixed model association tests P = 0.0088). The OCA2 hypomorphic allele p.V443I was more common in melanoma cases (1.8%) than controls (1.0%, X2 P = 0.02), and more so in amelanotic/hypomelanotic melanoma (4.4%, X2 P = 0.007). No amelanotic/hypomelanotic melanoma cases carried an eye and skin darkening haplotype of OCA2 (including rs7174027), present in 7.1% of pigmented melanoma cases (P = 0.0005) and 9.4% controls. Variants in TYR and OCA2 may play a role in amelanotic/hypomelanotic melanoma susceptibility. We suggest that somatic loss of function at these loci could contribute to the loss of tumor pigmentation, consistent with this we found a higher rate of somatic mutation in TYR/OCA2 in amelanotic/hypomelanotic melanoma vs pigmented melanoma samples (28.6% vs 3.0%; P = 0.021) from The Cancer Genome Atlas Skin Cutaneous Melanoma collection.

Cutaneous keratinocyte cancers of the head and neck: Epidemiology, risk factors and clinical, dermoscopic and reflectance confocal microscopic features.

Keratinocyte cancers are the most common malignancy among people with European ancestry, and are very common on sun-exposed areas of the head and neck. Incidence is directly correlated with latitude and annual ultraviolet radiation incidence, although there are a number of other environmental, occupational and genetic risk factors, and keratinocyte cancers become more common at middle age. Basal cell carcinomas (BCC) are the most common, comprising 80% of keratinocyte cancers, but have a very low rate of metastases and low mortality. Squamous cell carcinomas (SCC) make up 20% of keratinocyte cancers, and have relatively infrequent metastases, at 5-16%. While there are no precursor lesions for BCC, SCC represents the final stage in a spectrum of cellular atypia and dysplasia, from actinic keratoses to in situ SCC to invasive SCC. Dermoscopy is a well-established diagnostic tool for keratinocyte cancers, and reflectance confocal microscopy is emerging as another useful diagnostic tool, particularly on functionally and cosmetically sensitive sites like the face.

Identification and Characterization of Canine Ligament Progenitor Cells and Their Extracellular Matrix Niche.

Ligaments are prone to injury and degeneration in humans and animals, however the healing potential of ligament is poor and current treatment options ineffective. Stem cell-based therapies hold potential for treatment of ligament injuries. This study aimed to characterize a ligament progenitor cell (LPC) population and to identify specific niche components which could promote the survival and function of LPCs. LPCs were isolated from canine cranial cruciate ligament and characterized for clonogenicity, multipotency and marker expression. The extracellular matrix (ECM) composition was characterized by the novel application of a metabolic labeling and mass spectrometry technique. LPCs demonstrated clonogenicity, multipotency, and stem cell marker expression. A number of different collagens, glycoproteins, and proteoglycans were identified in the LPC niche using proteomics. Metabolic labeling of cells demonstrated unique turnover profiles for distinct ECM protein groups, indicating the importance of certain niche components for LPC survival and function. The newly synthesized niche components identified in this study could be exploited to aid identification of LPCs and to promote their survival and function for potential ligament repair strategies.

Recent trends in teledermatology and teledermoscopy.

Teledermatology is a useful alternative where specialized dermatological assistance is not available and has been used successfully to support health professionals in a wide range of settings worldwide, in either an asynchronous store-and-forward format or a real-time video conferencing format. Teledermoscopy, which includes dermoscopic images in the teleconsultation, is another addition that improves remote assessments of pigmented lesions. A more recent variant is mobile teledermoscopy, which uses a smartphone to deliver the same type of service. Teledermoscopy's greatest strength may be as a triage and monitoring tool, as it can reduce the number of unnecessary referrals, wait times, and the cost of providing and receiving dermatological care. While face-to-face (FTF) care remains the gold standard for diagnosis, drawbacks of not using FTF care as the primary method can be mitigated if teleconsultants are willing to refer to FTF care whenever there is uncertainty. Teledermatology has generally been well accepted by patients and practitioners alike. Barriers to the large-scale use of teledermatology remain. Assigning medicolegal responsibility and instituting a reimbursement system are critical to promoting widespread use by medical professionals, while privacy and security features and a mechanism to link teleconsultations to patients' existing health records are essential to maximize patient benefit. Direct-to-consumer services also need attention from regulators to ensure that consumers can enjoy the benefits of telemedicine without the dangers of unregulated or untested platforms.

Classifying dermoscopic patterns of naevi in a case-control study of melanoma.

Changes in dermoscopic patterns of naevi may be associated with melanoma; however, there is no consensus on which dermoscopic classification system is optimal. To determine whether different classification systems give comparable results and can be combined for analysis, we applied two systems to a case-control study of melanoma with 1037 participants: 573 classified using a "1/3 major feature" system, 464 classified based on rules of appearance, and 263 classified with both criteria. There was strong correlation for non-specific (Spearman R = 0.96) and reticular (Spearman R = 0.82) naevi, with a slight bias for globular naevi with the rules of appearance system. Inter-observer reliability was high for the rules of appearance system, particularly for reticular naevi (Pearson >0.97). We show that different classification systems for naevi can be combined for data analysis, and describe a method for determining what adjustments may need to be applied to combine data sets.

Skin Pigmentation Genetics for the Clinic.

Human pigmentation characteristics play an important role in the effects of sun exposure, skin cancer induction and disease outcomes. Several of the genes most important for this diversity are involved in the regulation and distribution of melanin pigmentation or enzymes involved in melanogenesis itself within the melanocyte cell present in the skin, hair and eyes. The single nucleotide polymorphisms and extended haplotypes within or surrounding these genes have been identified as risk factors for skin cancer, in particular, melanoma. These same polymorphisms have been under selective pressure leading towards lighter pigmentation in Europeans in the last 5,000-20,000 years that have driven the increase in frequency in modern populations. Although pigmentation is a polygenic trait, due to interactive and quantitative gene effects, strong phenotypic associations are readily apparent for these major genes. However, predictive value and utility are increased when considering gene polymorphism interactions. In melanoma, an increased penetrance is found in cases when pigmentation gene risk alleles such as MC1R variants are coincident with mutation of higher-risk melanoma genes including CDKN2A, CDK4 and MITF E318K, demonstrating an interface between the pathways for pigmentation, naevogenesis and melanoma. The clinical phenotypes associated with germline changes in pigmentation and naevogenic genes must be understood by clinicians, and will be of increasing relevance to dermatologists, as genomics is incorporated into the delivery of personalised medicine.

Acquired melanocytic naevus phenotypes and MC1R genotypes in Han Chinese: a cross-sectional study.

BACKGROUND: Early detection and treatment are the most important elements in reducing the incidence of melanoma deaths. Acquired melanocytic naevi (AMN) are well-known precursors of melanoma but most of our knowledge on the clinico-dermoscopic phenotypes of AMN is based on studies in European-background populations, particularly American and Australian populations. There has been little research in Chinese Han populations on clinico-dermoscopic variability of naevi or how naevi are affected by melanoma-linked variants of the melanocortin 1 receptor (MC1R) gene. METHODS: Clinical and dermoscopic features of 448 AMN in 115 patients from the Han ethnic group in mainland China were described. Germline polymorphisms in MC1R were determined for 98 of these patients. RESULTS: AMN were predominantly found on the head and neck. Dermoscopic patterns observed were nonspecific, reticular, globular, and parallel furrow, with most AMN having a nonspecific pattern. There were no associations between MC1R polymorphisms and clinical or dermoscopic features of AMN. DISCUSSION: Our results provide evidence that AMN in the Han population in China have similar dermoscopic patterns to those in European populations, but are present in much lower numbers. As there were no associations between clinical or dermoscopic features of AMN and MC1R polymorphisms, further studies should focus on candidate gene associations with AMN features and the risk of melanoma, with larger sample sizes and comparisons to AMN in other populations.

Dermoscopy, reflectance confocal microscopy and histopathology of a melanoma in situ from an individual homozygous for GSTP1*105Val/MC1R*92Met.

Glutathione S-transferase 1 is an enzyme involved in the detoxification of reactive oxygen species, and the rs1695*Val polymorphism has been proposed as a melanoma-associated variant with significant effect. We report a case of malignant melanoma in an individual homozygous for the rs1695*Val variant and discuss the non-invasive and histopathological tools used in diagnosis.