The Nordic profile of skin cancer incidence. A comparative epidemiological study of the three main types of skin cancer

The data used for the inter-Nordic comparison of the incidence of skin cancer are based on the material of the national cancer registries of the 5 Nordic countries. It is typical of these countries that the ratio between the incidence of non-melanoma and melanoma skin cancer is much smaller than in regions near the Equator. For the detailed comparative epidemiological study of basal-cell carcinoma (BCC), squamous-cell carcinoma (SCC) and cutaneous malignant melanoma (CMM), the material from the Norwegian Cancer Registry 1955-1988 is used. The etiology of CMM has frequently been debated during recent decades. There are still some obscure points, however, particularly as regards the influence of host factors and UV exposure, and their interaction. The analysis of the incidence trend of CMM on the female breast during the time interval 1970-1988 contributes to the elucidation of these problems. Differences in the epidemiological characteristics of the 2 main types of non-melanoma skin cancer, BCC and SCC, are described. The results indicate that the effect of UV light is not a dominating for BCC as for SCC.     

Association between dietary fat and skin cancer in an Australian population using case-control and cohort study designs

Background  

Human studies of dietary fat as a possible risk factor for cutaneous malignant melanoma (CMM) and non-melanoma skin cancer (NMSC) – principally basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) – have produced inconsistent results. We had the opportunity to examine the association concurrently for all three types of skin cancer in a population-based study in Tasmania, Australia, involving 652 cases of CMM, BCC and SCC and a common set of 471 controls.     

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.     

Elevated c-Src and c-Yes expression in malignant skin cancers

Abstracts

Background

Src family kinases (SFKs) play an important role in cancer proliferation, survival, motility, invasiveness, metastasis, and angiogenesis. Among the SFKs, c-Src and c-Yes are particularly over-expressed or hyper-activated in many human epithelial cancers. However, only a few studies have attempted to define the expression and role of c-Src and c-Yes in cutaneous carcinomas.

Objectives

To investigate the expression of c-Src and c-Yes in cutaneous carcinomas to include malignant melanoma (MM), squamous cell carcinoma (SCC) and basal cell carcinoma (BCC).

Methods

We examined 6 normal skin tissues and 18 malignant skin tumor tissues using western blotting for the expression of c-Src and c-Yes. In another set, 16 specimens of MM, 16 SCCs and 16 BCCs were analyzed for the expression of c-Src and c-Yes using immunohistochemical staining.

Results

Western blotting showed that c-Src was expressed in all malignant skin tumors, but not in normal skin, while c-Yes was expressed in MM and SCC, but not in BCC and normal skin. Immunohistochemical staining results of c-Src and c-Yes in MM, SCC, and BCC mirrored those of the western blot analysis.

Conclusions

c-Src, rather than c-Yes, plays a key role in the proliferation and progression of malignant skin cancers.     

Targets for molecular therapy of skin cancer

Cancers of the skin encompass the first and second most common neoplasms in the United States, epidermal basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), respectively, as well as the melanocytic malignancy, malignant melanoma (MM). Recently identified alterations in the function of specific genes in these cancers provide new potential therapeutic targets. These alterations affect conserved regulators of cellular proliferation and viability, including the Sonic Hedgehog, Ras/Raf, ARF/p53, p16(INK4A)/CDK4/Rb and NF-kappaB pathways. New modalities designed to target these specific proteins may represent promising approaches to therapy of human skin cancers.     

Non-solar ultraviolet radiation and the risk of basal and squamous cell skin cancer.

A case-control study of non-melanocytic skin cancer was conducted among men in the province of Alberta, Canada. Two hundred and twenty-six cases of basal cell carcinoma (BCC), 180 cases of squamous cell carcinoma (SCC) and 406 age-matched controls provided information concerning skin pigmentation, occupational history, recreational activity, exposure to sunlight and sources of non-solar ultraviolet radiation (NSUVR) and other potential risk factors. Our analyses show no evidence of elevated risk for BCC or SCC among subjects exposed to various types of NSUVR. This is in opposition to studies of melanoma that have shown elevated risks for exposure to fluorescent lighting, sunlamps and sunbeds.     

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.     

Polymorphisms in DNA double-strand break repair genes and skin cancer risk

UV can cause a wide range of DNA lesions. UVA-induced oxidative DNA damage and blocked DNA replication by UVB-induced photoproducts can lead to double-strand breaks (DSBs). We selected 11 haplotype-tagging single nucleotide polymorphisms in three DSB repair genes XRCC2, XRCC3, and LigaseIV and evaluated their associations with skin cancer risk in a nested case-control study within the Nurses' Health Study [219 melanoma, 286 squamous cell carcinoma (SCC), 300 basal cell carcinoma (BCC), and 873 controls]. We observed that the XRCC3 18085T (241Met) allele and its associated haplotype were significantly inversely associated with the risks of SCC and BCC, whereas the XRCC3 4552C allele along with its associated haplotype and the XRCC2 30833A allele were significantly associated with increased BCC risk. The LigaseIV 4044T and 4062T alleles were associated with decreased BCC risk; two of four haplotypes were significantly associated with altered BCC risk. A trend toward decreased risk of nonmelanoma skin cancer was found in those harboring a greater number of putative low risk alleles (P for trend, 0.05 for SCC, <0.0001 for BCC). The main effects of these genotypes were essentially null for melanoma risk. This study provides evidence to suggest the role of the DSB repair pathway in skin cancer development, especially for BCC.     

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.     

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.     

Impaired notch signaling promotes de novo squamous cell carcinoma formation

Signaling through Notch receptors in the skin has been implicated in the differentiation, proliferation, and survival of keratinocytes, as well as in the pathogenesis of basal cell carcinoma (BCC). To determine the composite function of Notch receptor-mediated signaling in the skin and overcome potential redundancies between receptors, conditional transgenic mice were generated that express the pan-Notch inhibitor, dominant-negative Mastermind Like 1 (DNMAML1), to repress all canonical [CBF-1/Suppressor of hairless/LAG-1 (CSL)-dependent] Notch signaling exclusively in the epidermis. Here, we report that DNMAML1 mice display hyperplastic epidermis and spontaneously develop cutaneous squamous cell carcinoma (SCC) as well as dysplastic precursor lesions, actinic keratoses. Mice expressing epidermal DNMAML1 display enhanced accumulation of nuclear beta-catenin and cyclin D1 in suprabasilar keratinocytes and in lesional cells from SCCs, which was also observed in human cutaneous SCC. These results suggest a model wherein CSL-dependent Notch signaling confers protection against cutaneous SCC. The demonstration that inhibition of canonical Notch signaling in mice leads to spontaneous formation of SCC and recapitulates the disease in humans yields fundamental insights into the pathogenesis of SCC and provides a unique in vivo animal model to examine the pathobiology of cutaneous SCC and for evaluating novel therapies.     

Niacin intake and risk of skin cancer in US women and men

A recent clinical trial found a protective role of niacinamide, a derivative of niacin, against skin cancer recurrence. However, there is no epidemiologic study to assess the association between niacin intake and risk of skin cancer [basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and melanoma]. We prospectively evaluated whether total, dietary and supplemental niacin intake was associated with skin cancer risk based on 72,308 women in the Nurses' Health Study (1984–2010) and 41,808 men in the Health Professionals Follow‐up Study (1986–2010). Niacin intake was assessed every 2 to 4 years during follow‐up and cumulative averaged intake. Cox proportional hazard models were used to compute the hazard ratios (HR) and 95% confidence intervals (CI) and cohort‐specific results were pooled using a random‐effects model. During the follow‐up, we documented 23,256 BCC, 2,530 SCC and 887 melanoma cases. Total niacin intake was inversely associated with SCC risk; the pooled HR for top vs. bottom quintiles was 0.84 (95% CI = 0.74–0.95; p_trend = 0.08). However, there were a marginally positive association between total niacin intake and BCC risk; the pooled HR for top versus bottom quintiles was 1.05 (95% CI = 1.01–1.10; p_trend < 0.01). Higher total niacin intake was also marginally positively associated with melanoma risk in men, but not in women. The results were similar in stratified analyses according to sun exposure related factors and by body location of melanoma and SCC. Our study supports a potential beneficial role of niacin intake in relation to SCC but not of BCC or melanoma.     

Predictors for cutaneous basal- and squamous-cell carcinoma among actinically damaged adults

Risk factors for non-melanoma skin cancer among populations with evidence of precursor damage are not well described. We examined and compared risk factors associated with the development of cutaneous basal-cell (BCC) or squamous-cell (SCC) carcinoma among a group of 918 adults with significant sun damage (> or = 10 clinically assessable actinic keratoses) but no prior history of skin cancer. These adults were participants in a 5-year skin chemoprevention trial between 1985 and 1992, who had been randomized to the placebo group and followed for occurrence of skin cancer. During the study, a total of 129 first SCC and 164 first BCC lesions were diagnosed. The overall BCC and SCC incidence rates for this group of men and women, mean age 61 years, were 4,106 and 3,198 per 100,000 person-years, respectively. Different constitutional and exposure factors were independently associated with BCC compared to SCC. Only increased age independently predicted BCC occurrence among this population. In contrast, older age along with male gender, natural red hair color and adult residence in Arizona for 10 or more years independently predicted SCC occurrence. The substantial incidence of skin cancer found among this population confirms the need for active dermatological monitoring among individuals with multiple visible actinic lesions.     

Epigenetic biomarkers in prostate cancer: Current and future uses

Epigenome alterations are characteristic of nearly all human malignancies and include changes in DNA methylation, histone modifications and microRNAs (miRNAs). However, what induces these epigenetic alterations in cancer is largely unknown and their mechanistic role in prostate tumorigenesis is just beginning to be evaluated. Identification of the epigenetic modifications involved in the development and progression of prostate cancer will not only identify novel therapeutic targets but also prognostic and diagnostic markers. This review will focus on the use of epigenetic modifications as biomarkers for prostate cancer.     

Aberrant promoter CpG methylation and its translational applications in breast cancer

Breast cancer is a complex disease driven by multiple factors including both genetic and epigenetic alterations.Recent studies revealed that abnormal gene expression induced by epigenetic changes,including aberrant promoter methylation and histone modification,plays a critical role in human breast carcinogenesis.Silencing of tumor suppressor genes(TSGs) by promoter CpG methylation facilitates cells growth and survival advantages and further results in tumor initiation and progression,thus directly contributing to breast tumorigenesis.Usually,aberrant promoter methylation of TSGs,which can be reversed by pharmacological reagents,occurs at the early stage of tumorigenesis and therefore may serve as a potential tumor marker for early diagnosis and therapeutic targeting of breast cancer.In this review,we summarize the epigenetic changes of multiple TSGs involved in breast pathogenesis and their potential clinical applications as tumor markers for early detection and treatment of breast cancer.     

Melanocortin 1 receptor variants and skin cancer risk

Melanocortin 1 receptor (MC1R) gene variants are associated with red hair and fair skin color. We assessed the associations of common MC1R genotypes with the risks of 3 types of skin cancer simultaneously in a nested case-control study within the Nurses' Health Study (219 melanoma, 286 squamous cell carcinoma (SCC), and 300 basal cell carcinoma (BCC) cases, and 873 controls). We found that the 151Cys, 160Trp and 294His variants were significantly associated with red hair, fair skin color and childhood tanning tendency. The MC1R variants, especially the 151Cys variant, were associated with increased risks of the 3 types of skin cancer, after controlling for hair color, skin color and other skin cancer risk factors. Carriers of the 151Cys variant had an OR of 1.65 (95% CI, 1.04-2.59) for melanoma, 1.67 (1.12-2.49) for SCC and 1.56 (1.03-2.34) for BCC. Women with medium or olive skin color carrying 1 nonred hair color allele and 1 red hair color allele had the highest risk of melanoma. A similar interaction pattern was observed for red hair and carrying at least 1 red hair color allele on melanoma risk. We also observed that the 151Cys variant contributed additional melanoma risk among red-haired women. The information on MC1R status modestly improved the risk prediction; the increase was significant for melanoma and BCC (p, 0.004 and 0.05, respectively). These findings indicated that the effects of the MC1R variants on skin cancer risk were independent from self-reported phenotypic pigmentation.     

Epigenetic changes in colorectal cancer

Epigenetic silencing is now recognized as a third pathway in Knudson's model of tumor-suppressor gene inactivation in cancer and can affect gene function without genetic changes. DNA methylation within gene promoters and alterations in histone modifications appear to be primary mediators of epigenetic inheritance in cancer cells. For selected genes, epigenetic changes are tightly related to neoplastic transformation in colorectal cancers (CRCs). In the colon, aberrant DNA methylation arises very early, initially in normal appearing mucosa, and may be part of the age-related field defect observed in sporadic CRCs. Aberrant methylation also contributes to later stages of colon cancer formation and progression through a hypermethylator phenotype termed CpG Island Methylator Phenotype (CIMP), which appears to be a defining event in about half of all sporadic tumors. CIMP+ CRCs are distinctly characterized by pathology, clinical and molecular genetic features. Histone modifications, recently recognized as a histone code that affects chromatin structure and gene expression also play an important role in the establishment of gene silencing during tumorigenesis. DNA methylation and histone H3 lysine 9 hypoacetylation and methylation appear to form a mutually reinforcing silencing loop that contributes to tumor-suppressor gene inactivation in CRCs. Understanding epigenetic alterations as a driving force in neoplasia opens new fields of research in epidemiology, risk assessment, and treatment in CRCs.     

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。     

Pigmentary and cutaneous risk factors for non-melanocytic skin cancer--a case-control study

The roles of ethnic origin, pigmentary traits, sun sensitivity and other cutaneous characteristics as risk factors for basal-cell carcinoma (BCC) and squamous-cell carcinoma (SCC) were examined in a case-control study of prevalent and incident cases of histopathologically confirmed skin cancers. Two hundred and twenty six confirmed cases of BCC, 45 of SCC and 1,015 controls with no lesions were identified in a population-based survey of skin cancer in 1987 in Geraldton, Western Australia. The risk of both cancers was higher in native-born Australians than in migrants. The risk of BCC decreased with increasing age at arrival in Australia. Southern European ancestry was strongly protective against BCC (for any southern European grandparents) and SCC (no case of SCC had any grandparents of southern European origin). Inability to tan was the strongest pigmentary risk factor for both BCC and SCC. Among factors that incorporated a measure of sun exposure as well as sun sensitivity, freckling on the arm in childhood was important for both cancers, the number of moles on the back was important for BCC, and forearm skin colour and having a permanent colour difference between the neck and adjacent protected areas were important for SCC. Among measures of sun damage to the skin, solar elastosis of the neck was a strong risk factor for both BCC and SCC, loss of fine texture of the skin of the back of the hands (as measured by cutaneous microtopography) was important for BCC and telangiectasia of the face for SCC. When all important variables for each cancer were examined together in a single model with age, sex, migrant status or age at arrival in Australia, and ethnicity, in ability to tan, solar elastosis of the neck, and the number of moles on the back were independently significant risk factors for BCC and solar elastosis of the neck and having a permanent colour difference between the neck and adjacent protected areas were independently significant risk factors for SCC. The effects of age at arrival or migrant status and ethnic origin remained important in the models incorporating these factors. A history of ever having acne and a history of warts were protective for BCC and a history of acne was protective for SCC.     

Modulation of basal and squamous cell carcinoma by endogenous estrogen in mouse models of skin cancer

Patched1 heterozygous mice (Ptch1^+/–) are useful for basalcell carcinoma (BCC) studies, being remarkably susceptible toBCC induction by ultraviolet or ionizing radiation. Analogously,skin carcinogenesis-susceptible (Car-S) mice are elective forstudies of papilloma and squamous cell carcinoma (SCC) induction.We previously reported a striking effect of gender on BCC inductionin Ptch1^+/– mice, with total resistance of females; likewise,Car-S females show increased skin tumor resistance relativeto males. Here, we investigated the protective role of endogenousestrogen in skin keratinocyte tumorigenesis. Control (CN) andovariectomized Ptch1^+/– or Car-S females were irradiatedfor BCC induction or topically treated with chemical carcinogensfor SCC induction. Susceptibility to BCC or SCC was dramaticallyincreased in ovariectomized Ptch1^+/– and Car-S femalesand restored to levels observed in males. Remarkably, progressionof initially benign papillomas to malignant SCC occurred onlyin ovariectomized Car-S females. We explored the mechanismsunderlying tumor progression and report overexpression of estrogenreceptor (ER)-, downregulation of ERβ and upregulationof cyclin D1 in papillomas from ovariectomized Car-S relativeto papillomas from CN females. Thus, an imbalanced ER/ERβexpression may be associated with estrogen-mediated modulationof non-melanoma skin carcinogenesis, with a key role playedby cyclin D1. Our findings underscore a highly protective roleof endogenous estrogen against skin tumorigenesis by diverseagents in two independent mouse models of skin cancer. Abbreviations: BCC, basal cell carcinoma; CN, control; Car-S, carcinogenesis susceptible; DMBA, 9,10-dimethyl-1,2-benzanthracene; ER, estrogen receptor; NMSC, non-melanoma skin cancer; OVX, ovariectomized; PTCH, patched; SCC, squamous cell carcinoma; SHH, Sonic Hedgehog; TPA, 12-O-tetradecanoyl-phorbol-13-acetate; UV, ultraviolet