Differential molecular profiling between skin carcinomas reveals four newly reported genes potentially implicated in squamous cell carcinoma development

Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are skin tumors with different invasive potential. In this work, we analysed mRNA differential expression between seven BCC and five SCC and their normal skin counterparts using 1176 cDNA macroarrays and verification by RT-PCR to identify genes modulated in each tumor type. We identified 37 genes commonly modulated in both tumors and four genes specifically modulated in SCC. Among these latter RhoC and EMMPRIN genes seem to be of particular interest and could participate in SCC aggressivity.     

连接蛋白43、Kai1和PTEN蛋白在皮肤基底细胞癌中的表达及意义

 目的 探讨皮肤基底细胞癌（basal cell carcinoma,BCC）发生发展及其特殊生物学行为的相关因素。方法 免疫组织化学SP法分别检测35例皮肤BCC、10例正常皮肤和18例皮肤鳞状细胞癌（squamous cell cacinoma,SCC）组织中Cx43、Kai1、PTEN蛋白的表达;核酸分子原位杂交法检测Cx43 mRNA的表达。应用计算机图像分析系统分别检测各组中各种检测指标的阳性面积和表达强度; SPSS（13.0）软件包进行统计分析。结果 （1）Cx43蛋白、Cx43 mRNA在皮肤表皮中的表达呈强阳性,在BCC组呈阳性或弱阳性,在SCC组呈阴性或弱阳性。Cx43及其 mRNA在BCC组的表达与正常皮肤组及SCC组比较,差异均有统计学意义（P<0.01）。（2）Kai1、PTEN蛋白在皮肤表皮中的表达呈强阳性,在BCC组呈阳性或弱阳性,在SCC组呈阴性或弱阳性。Kai1、PTEN蛋白在BCC组的表达与正常皮肤组及SCC组比较,差异均有统计学意义（P<0.05）。（3）相关分析显示,BCC组织中,PTEN蛋白的表达与Kai1蛋白呈正相关(r=0.629,P<0.01),与Cx43蛋白(r=0.519,P＜0.01)也呈正相关;Cx43蛋白的表达与Cx43 mRNA呈正相关(r=0.732,P<0.01)。结论 （1）与正常皮肤组织比较,BCC中Cx43、Kai1、PTEN蛋白和Cx43mRNA低表达,可能在BCC发生发展的过程中发挥重要作用;（2）与SCC组织相比较,BCC中Cx43、Kai1、PTEN蛋白和Cx43mRNA高表达,可能与BCC生长缓慢及极少转移的生物学特性有关。     

Role of IKKα in skin squamous cell carcinomas

Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) are two major types of skin cancer derived from keratinocytes. SCC is a more aggressive type of cancer than BCC in humans. One significant difference between SCC and BCC is that SCC development is generally associated with cell dedifferentiation and morphological changes. When SCC is converted to spindle cell carcinoma, the latest stage of cancer, the tumor cells change to a fibroblastic cell morphology (epithelial-to-mesenchymal transition) and lose their differentiation markers. Recently, several laboratories have reported altered IκB kinase α (IKKα) protein localization, downregulated IKKα, and IKKα gene deletions and mutations in human SCCs of the skin, lung, esophagus, and neck and head. In addition, IKKα reduction promotes chemical carcinogen- and ultraviolet B-induced skin carcinogenesis, and IKKα deletion in keratinocytes causes spontaneous skin SCCs, but not BCCs, in mice. Thus, IKKα emerges as a bona fide skin tumor suppressor. In this article, we will discuss the role of IKKα in skin SCC development.     

Lack of Increased P15INK4B Protein Expression in Basal Cell Carcinomas

Background: The basal cell carcinoma (BCC) is the most common non-melanoma skin cancer (NMSK). BCCmight develop because of the faulty cell cycle arrest. P15INK4b is a tumor suppressor gene, involved in cell cyclearrest and inactivated in most human cancers. The role of p15INK4b protein expression in the genesis of BCC is asyet unknown. In a previous study we showed the absence of p15INK4b expression in the majority of tissue microarraycores of cutaneous squamous cell carcinoma (SCCs), another type of non-melanoma skin cancer, indicating thatp15INK4b could possibly be involved in the pathogenesis of cutaneous SCC. The aim of this study was to investigatep15INK4b protein expression in BCCs. Materials and Method: Protein expression of p15INK4b in 35 cases of BCCtissue arrays and 19 cases of normal human skin tissue was studied using an immunohistochemical approach.Results: The expression of p15INK4b was not significantly different in the BCC cases as compared with normalhuman skin (p=0.356; p>0.05). In addition, there were no significant relationship between clinicopathologicvariables of patients (age and sex) and p15INK4b protein expression. Conclusions: Our finding may indicate thatp15INK4b protein expression does not play a role in the genesis of BCC.     

Molecular basis of basal cell carcinoma: analysis of differential gene expression by differential display PCR and expression array

Basal cell carcinoma (BCC) is the most common tumor in the Caucasian population. Although BCC rarely metastasize and cause death, they are problematic due to their destructive growth and the frequent localization on the face. Until now the knowledge of genes differentially expressed in BCC has been incomplete. To elucidate the complex alterations in BCC-associated gene expression, we took advantage of 2 techniques: the differential display RT-PCR (DD-PCR) and the differential hybridization of cDNA arrays. Using DD-PCR, we showed differential expression of genes known from other biological contexts (e.g., rac, ubiquitin hydrolase), which could now be associated with BCC. In addition, we detected unknown genes possibly contributing to the carcinogenesis of BCC. Of the 588 genes screened by differential hybridization of the Atlas human cDNA array, differences in the expression levels of BCC were observed for 10 genes. These data were obtained with RNA probes pooled from several BCC of different donors and were subsequently confirmed by semiquantitative RT-PCR for Janus protein tyrosine kinase 3 (Jak3), microsomal glutathione S-transferase 1 (GST 12), teratocarcinoma-derived growth factor cripto, glutaredoxin and the monocyte chemoattractant protein 1 (MCP-1) in 10 individual BCC specimens, 2 squamous cell carcinoma (SCC), the cell line HaCaT and cultured normal human keratinocytes (NHK) in comparison to normal skin. These genes are candidates from gene families with known association to tumors, but they have not been reported in the carcinogenesis of BCC yet. In summary, both approaches allow the detection of differentially expressed genes possibly involved in the carcinogenesis of BCC.     

Dietary fat intake and risk of skin cancer: A prospective study in Australian adults

Although intakes of dietary fat have been associated with both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin, the evidence is sparse and inconsistent. This study prospectively investigated the association between total dietary fat; saturated, polyunsaturated and monounsaturated fatty acids; and percent energy from fat in relation to BCC and SCC of the skin. At baseline in 1992, total fat intake and intake of fatty acids were assessed in an Australian community‐based longitudinal study, using a validated semi‐quantitative food frequency questionnaire in 1,057 adult residents (aged 25–75 years) in Nambour, Queensland. Information on demography, sun‐sensitivity history and sun exposure factors were obtained using self‐administered questionnaires. Associations with BCC and SCC in terms of persons newly affected and of tumor counts were assessed using Poisson and negative binomial regression models, respectively, based on incident, histologically‐confirmed tumors occurring between 1992 and 2002. No significant linear trends were observed in overall risk of BCC or SCC of the skin with increasing total fat intake. However, in participants with a history of skin cancer, total fat intake (multivariable adjusted RR = 2.42, 95% CI = 1.20–4.88; p for trend = 0.01) was associated with increased numbers of SCC tumors comparing the highest to lowest tertile. In conclusion, SCC tumor risk increased as total fat intake increased in people with a history of skin cancer. Dietary fats were not associated with BCC occurrence. © 2009 UICC     

P16INK4a Immunostaining but Lack of Human Papilloma Virus Type 16 in Cutaneous Squamous Cell Carcinoma and Basal Cell Carcinoma: a Report from West Iran

The tumor suppressor p16 is a biomarker for transforming human papilloma virus (HPV) infections that can lead to contradictory results in skin carcinomas. The aim of this study was to evaluate p16 expression and HPV-16 infection in the cutaneous basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). This case-control study was performed on paraffin blocks of BCCs and SCCs and normal skin (53, 36, and 44 cases, respectively), between 2006 to 2015. Initial sections for groups were stained with hematoxylin and eosin (H and E). Immunohistochemistry was performed for p16 expression and human papilloma virus type 16 (HPV-16) infection. Normal group was skin of mammoplasty specimens and normal skin tissue in the periphery of tumors. The mean age at diagnosis was 42.1, 61.7 and 71.4 years for normal, BCC and SCC groups, respectively. P16 positivity was more in SCC and BCC groups compared to normal group (P<0.05) and HPV was negative in all patients in three groups. Also, the mean age at diagnosis and P16-positivity were higher for the SCC group than the BCC group (P<0.005). In conclusion, in non-melanoma skin cancers (SCC and BCC), p16-positivity can be a prognostic factor but there is no correlation between HPV-16 and p16 in these tumors.     

Carcinoma of the lip and selected sites of head and neck skin. A clinical study of 896 patients

During a period of over 20 years, 896 patients were treated with radiation in Wadsworth Medical Center, Los Angeles, for carcinoma of the lip and selected sites of skin of the head and neck. Basal cell carcinoma (BCC) was found in 467 (52%) patients, squamous cell carcinoma (SCC) in 362 (40%), and the remaining 67 (8%) had tumors with mixed basal and squamous cell features. BCC was the most common tumor (72%) among the 646 skin cancer patients while SCC predominated (99%) among the 250 lip cancer patients. Tumor control correlated well with the size of the lesion, p less than 0.0001. Histology of the lesion also had a significant (p = 0.021) influence on the tumor control rate, which was the highest among the BCC patients when compared with SCC or mixed cell patients. This study has again demonstrated the effectiveness of radiotherapy in controlling small and intermediate size epithelial tumors of the skin and lip. Additionally, irradiation, if administered properly, results in excellent cosmesis and a low incidence of treatment complications. Severe complications of radiotherapy reported in the literature took place at the beginning of this century and are no longer pertinent in the practice of modern radiation oncology. Larger lesions remain a challenge to radiation or surgical dermato-oncologists. A lack of tumor control in such lesions frequently results in a death of patient.     

A role for ultraviolet radiation immunosuppression in non-melanoma skin cancer as evidenced by gene-environment interactions

The genotoxic effects of ultraviolet (UV) radiation are well-known causes of skin cancers; however, UV radiation also suppresses the immune system, decreasing the body's surveillance for tumor cells. In experimental systems, UV radiation immunosuppression is at least partially mediated through urocanic acid (UCA), an UV radiation-absorbing molecule in the stratum corneum. We tested the hypothesis that genetic variation in the histidase gene (HAL), which catalyzes the formation of UCA in the skin, modifies risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in a population-based study (914 BCC, 702 SCC and 848 controls). We observed no evidence of a main gene effect for the HAL I439V polymorphism (rs7297245) and BCC or SCC. However, we found a HAL genotype-sunburn interaction in association with BCC (P for interaction = 0.040) and SCC (P for interaction = 0.018). A HAL genotype-SCC association was observed primarily among women (odds ratio = 1.5, 95% confidence interval 1.1-2.2), and among women, we found an interaction between HAL genotype and oral contraceptive use on SCC risk (P = 0.040). The variant HAL allele likewise appeared to modify the SCC risk associated with glucocorticoid steroid usage (P for interaction = 0.0004). In conclusion, our findings are a first step in determining the genetic underpinnings of UV immune suppression and have identified important new genetic interactions contributing to the etiology of skin cancer.     

Occupation and keratinocyte cancer risk: a population-based case–control study

Objective The aim of our study was to identify occupations associated with increased risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Methods We conducted a population-based case–control study of BCC and SCC in New Hampshire. Cases (n = 599 BCC, n = 290 SCC) and controls (n = 524) completed a self-administered residence and work history questionnaire and personal interview regarding major risk factors for skin cancer. Reported jobs were coded using the Standardized Occupational Classification system (SOC). Odds ratios (ORs) and confidence intervals (CIs) for BCC and SCC were calculated for men and women separately using unconditional logistic regression models taking into account age, education, skin reaction to sun, history of painful sunburns, time spent outdoors, and for SCC, smoking. Results Among men, we observed elevated risks of both BCC and SCC among groundskeepers and gardeners, except farm (SOC 5622). We also found that garage and service station-related occupations (SOCs 873) and to some extent food/beverage preparation/service occupations (SOC 521) were associated with BCC risk among men. Women in health services occupations (SOC 523) had elevated risks for both tumors, especially for BCC. Additionally, administrative support (SOC 46/47) occupations were related to BCC risk among women. Other occupations were associated with excess risks, but without consistent trends by duration of employment. Conclusion We observed several occupations associated with elevated BCC and SCC risk. These results resemble reported findings for cutaneous melanoma and are generally consistent with the few available studies on keratinocyte cancers.     

Common phenotypic expression of gangliosides GM3 and GD3 in normal human tissues and neoplastic skin lesions.

The expression of gangliosides in non-malignant tissues (epidermis and pigmented nevus) and neoplastic lesions (melanoma, squamous cell carcinoma [SCC] and basal cell carcinoma [BCS]) of the human skin was analyzed immunohistochemically and biochemically to characterize the features associated with malignancy. Immunohistochemical staining with an anti-II3NeuAc-LacCer (GM3) monoclonal antibody (M2590 mAb) and an anti-II3(NeuAc)2-LacCer (GD3) mAb (R24) showed the expression of the gangliosides GM3 and GD3 to vary among the different tissues. M2590 clearly stained epidermal keratinocytes and the tumor cells of BCC and SCC, and strongly stained melanocytes and melanoma cells. In contrast, R24 did not stain epidermal keratinocytes and only faintly stained SCC cells, while it clearly stained BCC cells, and intensely stained melanocytes and melanoma cells. GM3 showed a similar level of staining among the tissue specimens, while the level of GD3 staining was quite variable among the tumor specimens. Biochemical analysis by thin-layer chromatography (TLC) with resorcinol staining and TLC immunostaining with either M2590 or R24 showed both GM3 and GD3 to be commonly expressed by both the normal and malignant skin tissues, including SCC. There was no close correlation between the intensity of immunohistochemical staining and the biochemically detected amounts of these gangliosides. This may have been partly due to the so-called cryptic expression of cell membrane gangliosides. Our results thus suggest that analysis of the tumor-associated expression of gangliosides requires several methods, since the sensitivity of the methods used may have a considerable effect on the diagnostic value of gangliosides as skin cancer markers.     

bcl-2、p53在皮肤肿瘤中的表达及意义

目的探讨bcl-2、p53在几种皮肤肿瘤中的表达及意义。方法采用流式细胞术(FCM)和免疫荧光技术对皮肤鳞状细胞癌(SCC)、恶性黑色素瘤(MM)、基底细胞癌(BCC)、色素痣(PN)bcl-2、p53蛋白的表达进行定量分析,以荧光指数(FI)作为定量表达指标。结果鳞状细胞癌、基底细胞癌的bcl-2、p53基因蛋白的FI值均显著性高于正常对照(P<0.05),基底细胞癌的bcl-2基因的FI值显著性高于鳞状细胞癌(P<0.05),而二者的p53基因蛋白的FI值无显著性差异(P>0.05);恶性黑色素瘤、色素痣的bcl-2、p53基因蛋白的FI值均显著性高于正常对照(P<0.05),恶性黑色素瘤的p53基因的FI值显著性高于色素痣(P<0.05),而二者的bcl-2基因蛋白的FI值无显著性差异(P>0.05)。结论鳞状细胞癌、恶性黑色素瘤、基底细胞癌、色素痣中均有bcl-2的表达,基底细胞癌bcl-2表达显著高于鳞状细胞癌,说明基底细胞癌的发生发展可能与细胞凋亡受抑密切相关;p53在恶性黑色素瘤的表达高于色素痣,说明p53为黑色素瘤的恶性标志,检测p53表达可以作为鉴别皮肤黑色素瘤恶性病变的辅助手段。     

Co-Expression of Putative Cancer Stem Cell Markers,CD133 and Nestin,in Skin Tumors

Background: Cancer stem cells (CSC) are populations of cells responsible for tumor initiation, progression andtherapeutic resistance in many cancers. In the present study, we aimed to investigate the expression pattern andclinical significance of two CSC markers, CD133 and Nestin, in a series of skin tumors. Materials and Methods:One hundred and thirteen paraffin blocks from skin cancers including 16 (14%) cases of melanoma, 37 (33%)of squamous cell cancer (SCC) and 60 (53%) of basal cell cancer (BCC) were collected and assembled in a tissuemicroarray (TMA). The samples were immunohistochemically examined for the expression of CD133 and Nestin.Expression of these markers was also correlated with clinicopathological parameters. Results: A significantdifference was observed in the expression of CD133 and Nestin in melanomas, SCC and BCC (p value=0.001).Furthermore, the level of expression was significantly higher in the melanomas compared to the SCC and BCCtumors. Expression of CD133 in the melanoma was significantly associated with increased tumor invasiveness (pvalue=0.05), a higher rate of metastasis (p value=0.04) and the presence of ulceration (p value=0.02). Increasedexpression of Nestin was observed in metastatic melanoma (p value=0.04), while no statistically significantcorrelation was found with other clinicopathological parameters including Breslow thickness, Clark level andulceration. Conclusions: Elevated expression levels of CD133 and Nestin in the melanomas are associated withadvanced disease, with more aggressive and metastatic skin tumors. Therefore, these markers could be potentialtherapeutic targets for malignant tumors of the skin.     

Mohs micrographic surgery: established uses and emerging trends

Mohs micrographic surgery is a surgical technique that seeks to ensure the clearance of cutaneous tumors while maximizing normal tissue conservation. This is accomplished through the sequential removal of thin layers of tissue in which the entire peripheral and deep margins are examined for residual tumor. This approach appears to be superior to conventional surgical excision in the treatment of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), the two most common cancers of the skin. Its efficacy in treating BCC and SCC has led clinicians to explore the role of Mohs micrographic surgery in the management of less common cutaneous neoplasms, such as melanoma, Merkel cell carcinoma, dermatofibrosarcoma protuberans, extramammary Paget's disease, and microcystic adnexal carcinoma.     

Cyclooxygenase-dependent signaling is causally linked to non-melanoma skin carcinogenesis: pharmacological, genetic, and clinical evidence

Cyclooxygenase (COX)-derived prostaglandins (PGs) exhibit manifold functions in acute and chronic skin inflammation induced by a number of physical (ultraviolet (UV) light, wounding) and chemical (12-O-tetradecanoylphorbol 13-acetate (TPA), arachidonic acid) noxious stimuli. Depending on the challenge and the context, constitutively expressed COX-1 or the transiently induced COX-2 isoform are of relevance. Moreover, squamous cell carcinoma (SCC) of skin is a prominent example of epithelial neoplasia that consistently overexpresses COX-2 in the parenchyme and the mesenchyme of premalignant and malignant lesions, while COX-1 expression remains unaltered. Pharmacological, clinical, and experimental animal studies as well as a few epidemiological studies document the importance of PG signaling in non-melanoma skin cancer including SCC and basal cell carcinoma (BCC) in humans and mice. Increased levels of PGE(2) and PGF(2α) in premalignant and/or malignant epithelial skin cancers are due to the constitutive upregulation of enzymes involved in PG biosynthesis, such as COX-2, and downregulation of the tumor suppressor gene 15-hydroxy-prostaglandin dehydrogenase (15-PGDH), which is involved in the inactivation of PG, thus counteracting the activities of COX. Most remarkably, genetic studies show that mice which are deficient in COX-2 or COX-1 are protected from the development of SCC when applying the multi-stage chemical carcinogenesis protocol. Conversely, the forced overexpression of COX-2 in the proliferative basal compartment of the stratified skin epidermis results in spontaneous hyperplasia and dysplasia in transgenic mice and furthermore a sensitization for cancer development by conferring an auto-promoted skin phenotype. In multi-stage carcinogenesis, it also becomes clear that aberrant COX-2 overexpression and activity are causally involved in tumor promotion and tumor progression rather than initiation. In contrast, using as inducer of carcinogenesis the complete carcinogen UV B light, depletion of COX-2 but not of COX-1 makes mouse skin resistant for SCC, indicating that here, only COX-2 is essential. Depending on the type of challenge, COX-2-dependent signaling contributes to the pre-invasive growth of the skin epidermis by a delayed onset of terminal differentiation, or stimulation of hyperproliferation and survival. With respect to BCC, the genetic ablation of COX-2 but also of COX-1 leads to a strongly reduced tumor burden in the skin of Patched (Ptch)1(+/-) mice, which due to the deletion of a Ptch1 allele, spontaneously develop BCC resembling human familial basal cell nevus syndrome and sporadic BCC. Nonsteroidal anti-inflammatory drugs and the COX-2-selective inhibitors (COXibs) exhibit impressive efficacy inhibiting tumor burden in various mouse models of SCC and BCC. Most importantly, in humans the interruption of COX-2 signaling is an effective strategy to treat and chemo-prevent non-melanoma skin cancer in individuals who are at high risk for the disease. However, any potential beneficial effect of this medicine has to be balanced against the adverse effects that are known to be associated with these drugs in a subset of patients.     

The role of TP53 and MDM2 polymorphisms in TP53 mutagenesis and risk of non-melanoma skin cancer

P53 is a key regulatory molecule in the cellular response to ultraviolet radiation, and TP53 mutation is the most common alteration in non-melanoma skin cancer. The MDM2 oncogene negatively regulates p53 protein levels, and both genes have functional polymorphisms that may modify skin cancer risk. Furthermore, prior research suggests that TP53 mutations preferentially occur on the arginine allele to selectively inactivate the p63 pathway. We tested these hypotheses of susceptibility and preferential mutation in non-melanoma skin cancer. The TP53 Arg72Pro and MDM2 309 polymorphisms were genotyped in a population-based case-control study of non-melanoma skin cancer, and TP53 alteration (mutation and immunohistochemistry staining) was evaluated in case tumors. In 902 cases of basal cell carcinoma (BCC), 676 cases of squamous cell carcinoma (SCC) and 812 controls, no association was found between the TP53 polymorphism and risk of non-melanoma skin cancer [odds ratio (OR)(BCC) 0.98, 95% confidence interval (CI) 0.80-1.20; OR(SCC) 0.93, 95% CI 0.75-1.16]. However, carriers of the MDM2 SNP309 G allele did have an elevated risk of non-melanoma skin cancer (OR(BCC) 1.15, 95% CI 0.93-1.42; OR(SCC) 1.29, 95% CI 1.02-1.63). We observed an association between TP53 alterations in the tumors and constitutive TP53 genotype (P < 0.01), with alterations preferentially occurring on the proline allele. Collectively, these data highlight the significant effects of genotype on gene-specific mutation events in carcinogenesis.     

Histologic characteristics of skin cancer in Hiroshima and Nagasaki: background incidence and radiation effects

Skin cancers, though rare in Japan, have reportedly been on the rise, but little else is known about epidemiologic features of different histologic types of skin cancer. The Life Span Study cohort, which consists of 93,700 atomic-bomb survivors, many of whom were exposed to negligibly low radiation doses, and 26,600 people not exposed to radiation, enables a population-based study of spontaneous as well as radiation-related cancer risk. Skin tumor incident cases diagnosed between 1958 and 1987 were ascertained by linkage to the Hiroshima and Nagasaki tumor registries augmented by searches of other data sources. Study pathologists reviewed tumor specimens and pathology reports and classified tumors using the World Health Organization classification scheme. They identified 274 primary incident skin cancers, of which 106 were basal cell carcinoma (BCC), 81 were squamous cell carcinoma (SCC), and 14 were malignant melanomas. Background incidence rates and radiation effects were assessed by Poisson regression models allowing for the effects of demographic and other covariates. BCC and SCC background incidence rates were both about 3 per 100,000 per year. BCCs were mainly on the head/neck (81%), whereas SCCs occurred most frequently on the arms/legs (45%) and head/neck (29%), consistent with the presumed role played by solar UV exposure in skin cancer. The BCC rates increased significantly between 1958 and 1987, whereas the SCC rates remained unchanged. The excess absolute risk of BCC per unit skin surface area related to atomic-bomb radiation exposure did not differ between UV-exposed and shielded parts of the body, suggesting the additivity of the radiation-related and background BCC risks.     

The Role of Stem Cell Factor in Hyperpigmented Skin Lesions

Background: Skin hyperpigmentation usually results from an increased number, or activity, of melanocytes. The degree of pigmentation of skin depends on the amount and type of melanin, degree of skin vascularity, presence of carotene, and thickness of the stratum corneum. Common causes of hyperpigmentation include post-inflammatory hyperpigmentation, melasma, solar lentigines, ephelides (freckles), and café-au-lait macules. Some skin tumors can be hyperpigmented as basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and malignant melanoma (MM). Stem cell factor (SCF) is a growth factor and its interaction with its receptor, c-kit, is well known to be critical to the survival of melanocytes. Methods: This study was carried out on 60 patients complaining of hyperpigmented skin lesions (20 melasma, 20 solar lentigines, and 20 freckles) and 36 patients with skin tumors (14 BCC, 12 SCC, and 10 MM). Punch skin biopsies were taken from the previous lesions. Immunohistochemical staining of these samples was done using the stem cell factor (SCF). Results: There was positive expression of SCF in all cases of melasma, solar lentigines and freckles with significant increase in the intensity of expression in the lesional areas than the non-lesional ones (P=0.004). There was also a statistically significant increase in the expression of SCF in BCC and melanoma tumor cells. Conclusion: SCF has a great role in skin hyperpigmented disorders and this can be used as a target for the developing of new antipigmentary lines of treatment by inhibiting SCF. SCF can also be involved in the emergence of some skin tumors.     

A germline variant in the interferon regulatory factor 4 gene as a novel skin cancer risk locus

Genome-wide association studies on pigmentary phenotypes provide a pool of candidate genetic markers for skin cancer risk. The SNPs identified from a genome-wide association study of natural hair color were assessed for associations with the risk of three types of skin cancer simultaneously in a nested case-control study within the Nurses' Health Study [218 melanoma, 285 squamous cell carcinoma (SCC), and 300 basal cell carcinoma (BCC) cases, and 870 common controls]. Along with two known pigmentation loci, MC1R and OCA2, the IRF4 rs12203592 T allele was associated with an increased risk of each type of skin cancer (P value, 6.6 × 10(-4) for melanoma, 7.0 × 10(-7) for SCC, and 0.04 for BCC). This association was further replicated in additional samples (190 melanoma, 252 SCC, and 634 common controls). The P value in the replication set was 0.03 for melanoma and 4.2 × 10(-3) for SCC. The risk of BCC was replicated in an independent set of 213 cases and 718 controls (P value, 0.02). The combined results showed that the association with SCC reached the genome-wide significance level [odds ratio (OR) for additive model = 1.61, 95%CI, 1.36-1.91, P = 3.2 × 10(-8)]. The OR was 1.49 for melanoma (95%CI, 1.23-1.80; P = 4.5 × 10(-5)), and 1.32 for BCC (95%CI, 1.11-1.57; P = 1.6 × 10(-3)). Given that the T allele was shown previously to be associated with increased expression of IRF4 locus, further studies are warranted to elucidate the role of the IRF4 gene in human pigmentation and skin cancer development.