Risk Factor For Development Of Melanoma Research Articles

Nevi and Melanoma in Children: What to Do in Daily Medical Practice: Encyclopedia for Pediatricians and Family Doctors.

Melanocytic nevi, commonly known as moles, are benign skin lesions that often occur in children and adolescents. Overall, they are less common in children compared to adults. Understanding the diagnosis and management of melanocytic nevi and risk factors for melanoma development is crucial for their early detection and appropriate treatment. This paper presents children's most common melanocytic nevi, including their epidemiology, morphology, diagnostic methods, and treatment.

Prevention of cancer-Melanoma development and its diagnosis among Silesian Voivodeship residents: Preliminary results.

Melanoma is a malignant tumor with the highest growth rate in the incidence and is the leading cause of death due to skin cancers. In Poland, approximately 1500 cases of melanoma are detected annually in advanced or metastatic stages. Intensive preventive measures can contribute to its early-stage diagnosis, consequently reducing the number of fatalities. The aim of the study was to assess the occurrence of melanoma risk factors among the residents of Silesia region and their knowledge about the diagnosis and prevention of this cancer. An original questionnaire was used in the study, and its completion was anonymous. The study was conducted among the residents of the Silesian Voivodeship. A total of 400 (100%) individuals were examined. Among them were 243 women and 157 men. The participants' ages ranged from 16 to 84 years (mean age = 34.38 ± 18.39). The participants were burdened with melanoma development risk factors such as fair skin complexion (235; 58.75%), having more than 50 pigmented lesions (158; 39.50%) and sunburns (105; 26.25%). Over 40% (166; 41.50%) of the participants had never examined their pigmented lesions. A staggering 78% (311; 77.75%) of the respondents had never undergone dermatoscopic examination, and over 50% (215; 53.75%) did not know what this examination entailed. Just under 16% (63; 15.75%) of the participants stated that their family doctor had examined their pigmented lesions, and almost % (154; 97.47%) of those with numerous pigmented lesions had never been referred to a dermatologist for dermatoscopy. The surveyed residents of the Silesian Voivodeship were burdened with numerous risk factors for melanoma development, with the most common being fair skin complexion, having more than 50 pigmented lesions, and sunburns. The knowledge of the participants regarding the diagnosis and prevention of melanoma development was insufficient, thus highlighting the necessity for conducting systematic educational initiatives in the mentioned field. These initiatives should ultimately lead to the preservation of health and life, as well as the maintenance of its high quality.

Abstract 7472: Melanoma-intrinsic expression of signal-regulatory protein alpha (SIRPα) confers tumor cells resistance to anti-tumor adaptive immunity

Abstract Introduction: Melanoma patient survival rates have significantly improved recently owing to the development of both targeted therapies and immunotherapies. However, there are still around 50% of patients relapse. The limited response to immunotherapies and global rise in melanoma incidence, with around 290,000 cases newly diagnosed each year, highlight the need for identifying new biomarkers, modulatory pathways, and risk factors for melanoma development. Earlier studies have characterized that aberrant expression of CD47 (a.k.a. “don’t eat me” signal) is one of the mechanisms that tumors exploit to avoid innate immune surveillance. CD47 blockade has been demonstrated to restore myeloid effector function by reinvigorating phagocytosis of tumor cells, which further enhances anti-tumor T cell responses. However, melanoma tumors are resistant to CD47 blockade. Interestingly, we and others have discovered that human and mouse melanoma cells express high levels of SIRPα, the receptor for CD47, which is typically expressed in myeloid compartments. Experimental Procedure: To investigate the role of tumor SIRPα, we designed gRNAs to CRISPR out the SIRPα N-terminal region, where it interacts with CD47, in B16 melanoma and generated SIRPα+/+ (WT) and SIRPα-/- (KO) B16 tumors. We conducted multiple in vitro and in vivo experiments to investigate whether tumor SIRPα played a role in tumor growth and modulated anti-tumor immunity. The preclinical tumor model we used is B16-F10 melanoma and the murine strains we used are the immune-competent (C57BL/6j; B6) and the immune-deficient (RAGnull) mice. For phenotypic and functional assessments, we performed analysis using flow cytometry, immunohistochemistry (IHC) and single cell RNA-sequencing (scRNA-seq) derived from live-sorted CD45+ tumor infiltrating lymphocytes (TILs) of SIRPα-WT and SIRPα-KO B16 tumors. Summary of Unpublished Data Our preliminary data in a preclinical B16-F10 melanoma model revealed that surface SIRPα expression is necessary for optimal B16-F10 melanoma growth in immune-competent mice, but not in immune-deficient RAGnull mice, suggesting a potential crosstalk between tumor SIRPα and the host adaptive immune system. Intriguingly, we found that selective SIRPα deletion in melanoma cells results in a significant increase of immune infiltrates within melanoma tumors that further suppresses tumor growth. Concluding Remarks: SIRPα is required for optimal melanoma development by suppressing anti-tumor adaptive immunity. Ethics Approval: All mice were maintained in microisolator cages and treated in accordance with the NIH and American Association of Laboratory Animal Care regulations. All mouse procedures and experiments for this study were approved by the Weill Cornell Medicine Institutional Animal Care and Use Committee. Citation Format: Chien-Huan Weng, Chana Schochet, Linda Hamadene, Shabnam Eghbali, Sébastien Monette, Levi Mangarin, Cailian Liu, Fadi Samaan, Jedd D. Wolchok, Taha Merghoub. Melanoma-intrinsic expression of signal-regulatory protein alpha (SIRPα) confers tumor cells resistance to anti-tumor adaptive immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7472.

Educational level-dependent melanoma awareness in a high-risk population in Switzerland.

The worldwide incidence of melanoma has been increasing rapidly in recent decades with Switzerland having one of the highest rates in Europe. Ultraviolet (UV) radiation is one of the main risk factors for skin cancer. Our objective was to investigate UV protective behavior and melanoma awareness in a high-risk cohort for melanoma. In this prospective monocentric study, we assessed general melanoma awareness and UV protection habits in at-risk patients (≥100 nevi, ≥5 dysplastic nevi, known CDKN2A mutation, and/or positive family history) and melanoma patients using questionnaires. Between 01/2021 and 03/ 2022, a total of 269 patients (53.5% at-risk patients, 46.5% melanoma patients) were included. We observed a significant trend toward using a higher sun protection factor (SPF) in melanoma patients compared with at-risk patients (SPF 50+: 48% [n=60] vs. 26% [n=37]; p=0.0016). Those with a college or university degree used a high SPF significantly more often than patients with lower education levels (p=0.0007). However, higher educational levels correlated with increased annual sun exposure (p=0.041). Neither a positive family history for melanoma, nor gender or Fitzpatrick skin type influenced sun protection behavior. An age of ≥ 50 years presented as a significant risk factor for melanoma development with an odd's ratio of 2.32. Study participation resulted in improved sun protection behavior with 51% reporting more frequent sunscreen use after study inclusion. UV protection remains a critical factor in melanoma prevention. We suggest that melanoma awareness should continue to be raised through public skin cancer prevention campaigns with a particular focus on individuals with low levels of education.

Current Insights into the Role of BRAF Inhibitors in Treatment of Melanoma.

Melanomas represent only 4% of all skin cancers, but their mortality rate is more than 50 % of any other skin cancer. Alteration in genetic and environmental factors are the risk factors for melanoma development. The RAS/RAF/MEK/ERK or Mitogen-activated protein kinase (MAPK) pathway is activated in melanoma. BRAF activation is necessary to govern differentiation, proliferation, and survival. Mutations in BRAF were found in 80-90% of all melanomas. Over 90% of BRAF mutations occur at codon 600, and over 90% of them are BRAFV600E other common mutations are BRAFV600K, BRAFV600R, BRAF V600'E2', and BRAF V600D. Based on αC-helix and DFG motif (αC-helix-IN/DFG-IN), (αC-helix-IN/DFG-OUT), (αC-helix-OUT/DFG-IN) and (αC-helix-OUT/ DFG-OUT) are four structural types of inhibitors for targeting BRAF. Sorafenib, Vemurafenib, Dabrafenib, and Encorafenib are FDAapproved for the treatment of BRAF. Understanding melanoma pathogenesis, RAS/RAF/MEK/ERK or MAPK pathway, and BRAF conformations, mutations, the problems with FDA approved BRAF inhibitors will be important for new drug discovery, modification of existing BRAF barriers to improve target specific action, and prevent increasing response levels while minimizing toxicity.

Environmental factors’ contribution in skin cancer etiology

Skin cancers are the most frequent types of malignant tumors worldwide, being mostly found in light-skinned populations, with a ratio of 30%. Approximately 3 million non-melanoma skin cancers and 132000 melanoma cases are diagnosed globally each year. The most frequent skin cancers are the basal cell carcinoma, squamous cell carcinoma and malignant melanoma. The incidence, morbidity and mortality of skin cancers are on the rise and have become a major public health concern. We aim to review the most important environmental factors involved in the development of skin cancers, along with the incidence rates and preventive behaviors or strategies (including personal behavioral changes and public educational initiatives). Ultraviolet radiation (UVR) is a well-known physical hazard, responsible for photoaging, photoallergy and phototoxic reactions, being heavily involved in carcinogenesis, including melanoma development. Overexposure to natural and artificial UVR is a public health problem. Sunburns, especially in childhood, are an important risk factor for melanoma development. Excessive exposure causes cumulative damage which determines immune suppression and skin cancer initiation. Transplant patients and AIDS patients have an increased incidence of skin cancer. Some treatment methods, including radiotherapy, phototherapy and psoralen and ultraviolet A (PUVA) therapy can lead to skin cancer development. Viral infections such as those with human papilloma virus can trigger the initiation of squamous cell carcinoma. Patients with familial genetic syndromes are highly sensitive to certain types of skin cancers. Ionising radiation, environmental pollutants, chemical carcinogenic agents and work exposure have been associated with skin cancer. Artificial UV radiation exposure (tanning beds and lamps), aging, skin color, personal diet and smoking are important risk factors. Ultraviolet radiation is the main etiological agent in skin cancer development. A better understanding of the causative factors is an essential step in skin cancer prevention.

Schizophrenia and Parkinson ’s disease as Risk Factors for Melanoma Development and Progression!

Schizophrenia and Parkinson ’s disease as Risk Factors for Melanoma Development and Progression!

Effect of a Face-Aging Mobile App–Based Intervention on Skin Cancer Protection Behavior in Secondary Schools in Brazil

Because exposure to UV radiation early in life is an important risk factor for melanoma development, reducing UV exposure in children and adolescents is of paramount importance. New interventions are urgently required. To determine the effect of the free face-aging mobile app Sunface on the skin cancer protection behavior of adolescents. This cluster-randomized clinical trial included a single intervention and a 6-month follow-up from February 1 to November 30, 2018. Randomization was performed on the class level in 52 school classes within 8 public secondary schools (grades 9-12) in Itauna, Southeast Brazil. Data were analyzed from May 1 to October 10, 2019. In a classroom seminar delivered by medical students, adolescents' selfies were altered by the app to show UV effects on their future faces and were shown in front of their class, accompanied by information about UV protection. Information about relevant parameters was collected via anonymous questionnaires before and 3 and 6 months after the intervention. The primary end point of the study was the difference in daily sunscreen use at 6 months of follow-up. Secondary end points included the difference in daily sunscreen use at 3 months of follow-up, at least 1 skin self-examination within 6 months, and at least 1 tanning session in the preceding 30 days. All analyses were predefined and based on intention to treat. Cluster effects were taken into account. Participants included 1573 pupils (812 girls [51.6%] and 761 boys [48.4%]; mean [SD] age, 15.9 [1.3] years) from 52 school classes. Daily sunscreen use increased from 110 of 734 pupils (15.0%) to 139 of 607 (22.9%; P < .001) at the 6-month follow-up in the intervention group. The proportion of pupils performing at least 1 skin self-examination in the intervention group rose from 184 of 734 (25.1%) to 300 of 607 (49.4%; P < .001). Use of tanning decreased from 138 of 734 pupils (18.8%) to 92 of 607 (15.2%; P = .04). No significant changes were observed in the control group. The intervention was more effective for female students (number needed to treat for the primary end point: 8 for girls and 31 for boys). These findings suggest that interventions based on face-aging apps may increase skin cancer protection behavior in Brazilian adolescents. Further studies are required to maximize the effect and to investigate the generalizability of the effects. ClinicalTrials.gov Identifier: NCT03178240.

Matrix metalloproteinases MMP-1, MMP-2, and MMP-13 are overexpressed in primary nodular melanoma.

The spread and invasion of malignant melanoma cells involve degradation and reorganization of the extracellular matrix by the activation of several matrix metalloproteinases (MMPs). This study analyzed the expression of MMP-1, MMP-2, and MMP-13 proteins in primary nodular melanoma (NM) and dysplastic nevi (DN) as a significant risk factor for melanoma development. The secondary goal was to analyze the correlation of MMPs protein expression in NM with tumor invasion, BRAF V600 mutation status, and overall survival. Immunohistochemistry for MMP-1, MMP-2, and MMP-13 was performed on nodular melanoma (n = 52) and dysplastic nevi (n = 28) on tissue microarray (TMA). BRAF V600 mutation analysis on NM samples was performed by the Sanger sequencing method. A high level of MMPs expression in NM samples (>30%) compared with DN (<8%) was statistically significant (P < 0.001). BRAF V600 mutations were detected in 15 of 39 (38.5%) NM samples. This study revealed an interesting finding that MMP-1 and MMP-13 protein expression in the BRAF V600 mutated melanomas were significantly lower than in the BRAF V600 wild type (P < 0.05). Cox analysis revealed that Clark categories, Breslow thickness, and MMP-1 high protein expression are predictive factors for shorter overall survival (P < 0.05).

Melanocyte Hyaluronan Coat Fragmentation Enhances the UVB-Induced TLR-4 Receptor Signaling and Expression of Proinflammatory Mediators IL6, IL8, CXCL1, and CXCL10 via NF-κB Activation

Skin is constantly exposed to UVR, the most critical risk factor for melanoma development. Hyaluronan is abundant in the epidermal extracellular matrix and may undergo degradation by UVR. It is hypothesized that an intact hyaluronan coat around the cells protects against various agents including UVR, whereas hyaluronan fragments promote inflammation and tumorigenesis. We investigated whether hyaluronan contributes to the UVB-induced inflammatory responses in primary melanocytes. A single dose of UVB suppressed hyaluronan secretion and the expression of hyaluronan synthases HAS2 and HAS3, the hyaluronan receptor CD44, and the hyaluronidase HYAL2, as well as induced the expression of inflammatory mediators IL6, IL8, CXCL1, and CXCL10. Silencing HAS2 and CD44 partly inhibited the inflammatory response, suggesting that hyaluronan coat is involved in the process. UVB alone caused little changes in the coat, but its removal with hyaluronidase during the recovery from UVB exposure dramatically enhanced the surge of these inflammatory mediators via TLR4, p38, and NF-κB. Interestingly, exogenous hyaluronan fragments did not reproduce the inflammatory effects of hyaluronidase. We hypothesize that the hyaluronan coat on melanocytes is a sensor of tissue injury. Combined with UVB exposure, repeated injuries to the hyaluronan coat could maintain a sustained inflammatory state associated with melanomagenesis.

Abstract 4020: Hyaluronan fragments as inflammation mediators in the early stages of melanomagenesis

Abstract UV light exposure is the main risk factor for melanoma development. Skin is constantly exposed to UV light, which induces the formation of reactive oxygen species (ROS). ROS are able to degrade hyaluronan (HA), the main extracellular matrix component of the skin epidermis. HA participates in several biological and pathological processes like in inflammation and cancer. It is postulated that in skin an intact HA coat around the cells has a protective effect against UV-radiation, while HA fragments derived from HA degradation are biologically active and may have tumor promoting effects. The aim of the present work was to study the role of HA fragments in melanomagenesis. Does pericellular hyaluronan or its degradation products affect UVB tolerance, melanocyte viability, intracellular signaling and the expression of proinflammatory cytokines? In our experimental model, primary human melanocytes were pretreated with Streptomyces hyaluronidase (Strept. Hyal) for 10 min to degrade the pericellular HA coat and thereafter exposed to UVB (30 mJ/cm2). After the UVB exposure Strept. Hyal was added again to accelerate HA degradation and HA fragment accumulation. The expression levels of proinflammatory cytokines were determined using qRT-PCR. Signaling pathways activated after UVB exposure were studied by western blotting. Cell viability was examined and the influences of UVB and HA coat degradation on cell cycle and apoptosis were analyzed with FACS. In this study, we show that UVB induces the expression of the proinflammatory cytokines IL-1β and IL6 and the chemoattractant cytokines IL8 and CXCL-10. This induction was strongly elevated by the Strept. Hyal treatment suggesting that HA fragments produced by HA degradation are responsible for upregulation of these genes. The inhibition of p38 and NFkβ reversed the effect of UVB + Strept. Hyal treatment on IL6 and IL8 expression indicating that this signaling pathway is responsible for the upregulation of these genes. Moreover, silencing of hyaluronan synthase 2 (Has2) was also able to block the effect of UVB + Strept. Hyal on the studied genes suggesting that the fragmentation of endogenously produced HA generates biologically active, proinflammatory signals. Interestingly, blocking CD44, the main hyaluronan receptor, expression with siRNA was ineffective, suggesting that other upstream effectors than CD44 are involved. Regarding cell viability and apoptosis the Strept. Hyal –treatment showed only a slight difference compared to the UVB –treated melanocytes. Taken together, our results demonstrate that HA fragments strengthen the inflammatory response induced by UVB exposure. UVB + Strept. Hyal activated the p38-NFkβ signaling pathway causing the upregulation of proinflammatory cytokines. The present data suggest that HA fragments mediate sustained inflammation, which may be a trigger for tumor formation. Citation Format: Piia Takabe, Leena Rauhala, Markku Tammi, Raija Tammi, Sanna Pasonen-Seppänen. Hyaluronan fragments as inflammation mediators in the early stages of melanomagenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4020.

Unraveling the human protein atlas of metastatic melanoma in the course of ultraviolet radiation-derived photo-therapy

To explore the photo-therapeutic capacity of UV radiation in solid tumors, we herein employed an nLC-MS/MS technology to profile the proteomic landscape of irradiated WM-266-4 human metastatic-melanoma cells. Obtained data resulted in proteomic catalogues of 5982 and 7280 proteins for UVB- and UVC-radiation conditions, respectively, and indicated the ability of UVB/C-radiation forms to eliminate metastatic-melanoma cells through induction of synergistically operating programs of apoptosis and necroptosis. However, it seems that one or more WM-266-4 cell sub-populations may escape from UV-radiation's photo-damaging activity, acquiring, besides apoptosis tolerance, an EMT phenotype that likely offers them the advantage of developing resistance to certain chemotherapeutic drugs. Low levels of autophagy may also critically contribute to the selective survival and growth of UV-irradiated melanoma-cell escapers. These are the cells that must be systemically targeted with novel therapeutic schemes, like the one of UV radiation and Irinotecan herein suggested to be holding strong promise for the effective treatment of metastatic-melanoma patients. Given the dual nature of UV radiation to serve as both anti-tumorigenic and tumorigenic agent, all individuals being subjected to risk factors for melanoma development have to be appropriately informed and educated, in order to integrate the innovative PPPM concept in their healthcare-sector management. SignificanceThis study reports the application of nLC-MS/MS technology to deeply map the proteomic landscape of UV-irradiated human metastatic-melanoma cells. Data bioinformatics processing led to molecular-network reconstructions that unearthed the dual nature of UV radiation to serve as both anti-tumorigenic and tumorigenic factor in metastatic-melanoma cellular environments. Our UV radiation-derived “photo-proteomic” atlas may prove valuable for the identification of new biomarkers and development of novel therapies for the disease. Given that UV radiation represents a major risk factor causing melanoma, a PPPM-based life style and clinical practice must be embraced by all individuals being prone to disease's appearance and expansion.

Risk Factors and Clinical Outcomes in Patients with IBD with Melanoma.

Patients with inflammatory bowel disease (IBD) are at increased risk to develop malignant melanoma and this risk may increase with use of anti-tumor necrosis factor (TNF) therapy. Impaired survival of immunosuppressed melanoma patients is reported in transplant and rheumatology patients. This study aims to (1) identify risk factors for melanoma development in patients with IBD, (2) compare clinical characteristics of melanoma in patients with IBD to the general population, and (3) assess the influence of immunosuppressive medication on survival. We retrospectively searched the Dutch Pathology Database to identify all Dutch patients with IBD with cutaneous melanoma between January 1991 and December 2011. We then performed 2 case-control studies. To identify risk factors for melanoma development in IBD, we compared patients with IBD with melanoma to the general IBD population. To compare outcome and survival after melanoma diagnosis, we compared cases with non-IBD melanoma patients. We included 304 patients with IBD with melanoma, 1800 IBD controls, and 8177 melanoma controls. IBD cases had more extensive IBD (ulcerative colitis: pancolitis: cases 44.5% versus IBD controls without melanoma 28.1%; P < 0.01; Crohn's disease: ileal and colonic disease: cases 57.9% versus controls 48.9%; P = 0.02). Despite a lower Nodes (N)-stage in patients with IBD (N1+ 8.3% versus 18.2%; P < 0.01) with comparable Tumor (T) and Metastasis (M) stages, survival was similar between groups, regardless of immunosuppressive or anti-TNF therapy. This study showed that IBD extent is a risk factor for melanoma development. Despite the lower N-stage in patients with IBD, we could not confirm impaired survival after melanoma in patients with IBD, regardless of anti-TNF and/or thiopurine use.

Mechanisms and prevention of UV-induced melanoma.

Melanoma is the deadliest form of skin cancer and its incidence is rising, creating a costly and significant clinical problem. Exposure to ultraviolet (UV) radiation, namely UVA (315-400nm) and UVB (280-315nm), is a major risk factor for melanoma development. Cumulative UV radiation exposure from sunlight or tanning beds contributes to UV-induced DNA damage, oxidative stress, and inflammation in the skin. A number of factors, including hair color, skin type, genetic background, location, and history of tanning, determine the skin's response to UV radiation. In melanocytes, dysregulation of this UV radiation response can lead to melanoma. Given the complex origins of melanoma, it is difficult to develop curative therapies and universally effective preventative strategies. Here, we describe and discuss the mechanisms of UV-induced skin damage responsible for inducing melanomagenesis, and explore options for therapeutic and preventative interventions.

Choroidal nevi: clinical features

The prevalence of choroidal nevi (CN) ranges from 1% to 10%. It may be hard to differentiate a small melanoma from an atypical ("malignatized") CN, which occupies an intermediate position between typical nevi and actual melanomas and can be referred to as "progressive" or "suspicious". The risk of malignant transformation of a CN ranges from 0.78% to 7%, thus necessitating the need for a detailed description of its clinical features. To study clinical features of choroidal nevi in conjunction with their growth patterns. A total of 80 patients (84 eyes) with choroidal nevi were studied, including 23 men and 57 women aged 65.33±3.26 years on average. The follow-up period was 12-48 months. In 26 cases (30.95%) age-related macular degeneration (AMD) was also present. Choroidal nevus is generally more common in women (71.25%). The right eye was involved in 36 cases, the left--in 48. Bilateral CN was diagnosed in 5% of cases. The follow-up period was 12-48 months. The nevi were mostly located in the juxtapapillary (11.9%) and macular (29.76%) regions. In 10 eyes they spread to the parafovea and foveola. The shape was typically round (73.8%), in the rest of cases--oval (26.2%). The size at presentation varied from 1 mm to 9 mm (2.93 mm on average). Diagnostic features of a stationary nevus (does not require a follow-up) have been identified. Nevus enlargement and changes in the overlying retina are indicative of progression. On the basis of clinical presentation all choroidal nevi can be classified as either stationary or progressing. If progression is suspected, a close follow-up is required. Progressive destruction of the overlying retina and early signs of visual impairment are risk factors for melanoma development.

UV and melanoma: the TP53 link.

Ultraviolet radiation (UVR) is a major risk factor for melanoma development, but it has been unclear exactly how UVR leads to melanomagenesis. In a recent publication in Nature, Viros et al. identify TP53/Trp53 as a UVR-target gene in melanoma and show that UVR-induced TP53/Trp53 mutations accelerate BRAF(V600E)-driven melanomagenesis.

The Macrophage: A New Factor in UVR-Induced Melanomagenesis

UVR is one of the major risk factors for melanoma development. However, the mechanisms by which UVR leads to the development of melanoma are not fully understood. Handoko et al. (this issue) explicitly indicate that macrophages are essential for UVR-induced melanocyte proliferation and migration using a neonatal mouse model. Although the functions and mechanisms of macrophages on melanoma development must be investigated further, the link between macrophages and melanocyte responses is striking, suggesting that macrophages might be a target for preventing UVR-induced melanoma.

Association between HRAS rs12628 and rs112587690 polymorphisms with the risk of melanoma in the North American population.

HRAS belongs to the RAS genes superfamily. RAS genes are important players in several human tumors and the single-nucleotide polymorphism rs12628 has been shown to contribute to the risk of bladder, colon, gastrointestinal, oral, and thyroid carcinoma. We hypothesized that this SNP may affect the risk of cutaneous melanoma as well. HRAS gene contains a polymorphic region (rs112587690), a repeated hexanucleotide -GGGCCT- located in intron 1. Three alleles of this region, P1, P2, and P3, have been identified that contain two, three, and four repeats of the hexanucleotide, respectively. We investigated the clinical impact of these polymorphisms in a case–control study. A total of 141 melanoma patients and 118 healthy donors from the North America Caucasian population were screened for rs12628 and rs112587690 polymorphisms. Genotypes were assessed by capillary sequencing or fragment analysis, respectively, and rs12628 CC and rs112587690 P1P1 genotypes significantly associated with increased melanoma risk (OR = 3.83, p = 0.003; OR = 11.3, p = 0.033, respectively), while rs112587690 P1P3 frequency resulted significantly higher in the control group (OR = 0.5, p = 0.017). These results suggest that rs12628 C homozygosis may be considered a potential risk factor for melanoma development in the North American population possibly through the linkage to rs112587690.

Risk factors for melanoma development

Melanoma incidence has risen over the last 30 years; however, whether this increase is entirely genuine or caused, in part, by increased screening, needs to be addressed. A large number of nevi is the strongest risk factor for melanoma across all Caucasian populations. Number of nevi is heritable with 60% of the variation in their number attributed to additive genetic effects. Fair hair and skin is also a heritable risk factor but the magnitude of the risk is much smaller than nevi. There are different ‘at-risk’ phenotypes leading to melanoma: high number of nevi or alternatively sun damage with solar keratoses, and these two phenotypes are usually mutually exclusive. This suggests different pathways leading to melanoma. Sun exposure is linked to melanoma with an increased melanoma incidence with decreasing latitude. However, this association is very complex and is not dose dependent. Similar to all cancers, melanoma can cluster in families. Between 20 and 40% of melanoma-prone families have mutations in the tumor-suppressor gene p16 or CDKN2A. These mutations only explain a small proportion of sporadic melanomas. New common low-penetrance melanoma genes associated with pigmentation and nevi counts have recently been discovered. As for many cancers, melanoma is likely to be caused by complex interactions between environmental factors and common low-penetrance genes. Once melanoma genetic risk factors are better understood, it will be possible to further investigate genetic environment interactions and assess the role of sun exposure more accurately. Somatic mutations in p16, p53, BRAF and c-kit are found in melanoma tumors and some of these somatic mutations may be useful to offer melanoma-targeted therapy.

The Role of Gadd45a in the Survival of Melanocytes and Melanoma Cells

Despite improvements in prevention and screening, mortality from advanced melanoma has not improved (Geller et al., 2007) and ultraviolet radiation (UV) is a major risk factor for melanoma development (Fears et al., 2002). Greater understanding of the mechanisms of melanoma development may lead to novel treatment options. As opposed to keratinocytes, which routinely undergo apoptosis after UVB irradiation, melanocytes resist apoptosis. In previous work, melanocytes and melanoma cells responded to UVB by activating an original pathway involving Gadd45a, one of the several growth-arrest and DNA damage–inducible genes (Lefort et al., 2001).