An assessment of the CDKN2A variant Ala148Thr as a nevus/melanoma susceptibility allele

Melanocytic nevi are the most potent risk factors for melanoma yet identified. Variation in the nevus phenotype within a population is predominantly genetically determined. Genes that determine nevus expression may therefore act as low penetrance melanoma susceptibility genes. Rare germline mutations in CDKN2A predispose to melanoma and appear to be nevogenic, although the correlation between nevus phenotype and mutation status is poor. It is plausible that more common CDKN2A variants may influence both melanoma susceptibility and nevus susceptibility. Ala148Thr is a G to A missense polymorphism of CDKN2A, which is found in 4%-6% of the general population. We have investigated the role of Ala148Thr as a low penetrance melanoma or nevus susceptibility allele in two separate groups of individuals. The first was a sample of 488 adults recruited from 179 families of patients with the atypical nevus phenotype and/or a family history of melanoma, and the second was a population-based sample of 599 women. Similar prevalences of Ala148Thr (4.9% and 5.2%) were found in both samples but significant variation in the prevalence of the polymorphism was seen across geographic areas within England. There was no association between Ala148Thr status and nevus number or history of melanoma, and therefore the results did not support the hypothesis that the Ala148Thr variant is a low penetrance melanoma or nevus susceptibility allele. A significant protective role of Ala148Thr on the number of atypical nevi was observed in the family sample (mean of 1 atypical nevus in those with the allele and 3.5 nevi in those without, p = 0.02). After allowing for potential confounders this was not evident in the population-based sample.     

An assessment of a variant of the DNA repair gene XRCC3 as a possible nevus or melanoma susceptibility genotype

Inheritance of the T allele in exon 7 (position 18067) of the DNA repair gene XRCC3 has been reported to be associated with susceptibility to melanoma in a study from Oxford. We report a study in which an attempt was made to confirm this association in a similar population. The most potent risk factor for melanoma in the general population is a phenotype characterized by the presence of multiple melanocytic nevi: the atypical mole syndrome. Our hypothesis is that the atypical mole syndrome may be a marker of genetic susceptibility to melanoma. We have therefore investigated whether the XRCC3 polymorphism influences the nevus phenotype. The XRCC3 genotype was investigated using PCR in a general-practice-based sample of 565 women and 475 patients from a cohort enriched for the atypical mole syndrome, of whom 140 had had melanoma. Allele frequencies were the same in the healthy women, the melanoma cases from this study, and the melanoma cases reported in the Oxford study, but were different from those in the Oxford control group. We found no evidence therefore that the T allele of this XRCC3 polymorphism is indicative of susceptibility to melanoma. There was a marginal relationship with nevus phenotype, but this was no longer statistically significant in multivariate analysis. The previous association between XRCC3 and melanoma may be a result of the choice of control group and we emphasize the need for appropriate choice of controls.     

The EGF A61G polymorphism is associated with disease-free period and survival in malignant melanoma

An earlier study reported that a common polymorphism in the 5' untranslated region of the epidermal growth factor (EGF) gene is associated with increased risk for cutaneous malignant melanoma (MM) and Breslow thickness. Since then, several independent studies have reported conflicting results that have challenged this hypothesis. However, none of the previous studies examined survival as the primary outcome. We therefore sought to study the association between this polymorphism and survival. One hundred and thirty patients diagnosed with MM with a Breslow thickness of >1.5 mm were included in this study. In our collective, the G/G genotype represented a significant risk factor for both shorter disease-free period (hazard ratio of 2.246, 95% CI: 1.06-4.78, P=0.036) and overall MM-specific survival (hazard ratio of 3.8, 95% CI: 1.5-9.5, P=0.004) compared with the A/A genotype, while the heterozygous A/G genotype showed an intermediate risk. In the present study, we demonstrate for the first time that the EGF A61G polymorphism is associated with survival. Our data suggest that this polymorphism is a potential marker for disease severity that predicts earlier progression of MM.     

Associations between eNOS polymorphisms and susceptibility to Behcet's disease: a meta-analysis

Objective To determine whether endothelial nitric oxide synthase (eNOS) polymorphisms confer susceptibility to Behcet’s disease (BD). Methods A meta‐analysis was conducted on the associations between the G894T and 4b/a polymorphisms of eNOS and BD using: (i) the allele contrast, (ii) the recessive model, (iii) the dominant model and (iv) the additive model. Results A total of eight studies, which included 841 cases and 866 controls, were included in the meta‐analysis. Meta‐analysis of the G894T polymorphism revealed no association with BD in all study subjects or in Turkish and Asian populations. However, one Tunisian study of the T allele showed a significant association with BD (OR = 0.707, 95% CI = 0.510–0.980, P = 0.038), but the OR of the T allele among Tunisians was lower, whereas it was higher in Europeans (OR = 2.129, 95% CI = 1.407–3.220, P = 0.0003). Meta‐analysis showed no association between BD and the 4b/a polymorphism in all study subjects. Stratification by ethnicity indicated no significant association between the a allele of the 4b/a polymorphism and BD in Turkish and Asian populations. Conclusions This meta‐analysis shows that the eNOS G894T and the 4b/a polymorphisms are not associated with BD in the Turkish and Asian populations. These data suggest that the G894T and the 4b/a polymorphisms may not confer susceptibility to BD in the Turkish and Asian populations.     

Comparison between familial and sporadic cutaneous melanoma in Valencia, Spain

Some clinical, pathological and genetic features have been associated to familial melanoma, particularly multiple melanoma and earlier age at diagnosis.
To compare the clinical, epidemiological and pathological differences between familial and sporadic melanoma patients in Valencia, Spain, a series of 959 patients with cutaneous melanoma were selected at a single institution. For this study the following variables were selected: age, sex, melanoma site and presence of solar lentigines on the melanoma surrounding skin, histological subtype, tumor thickness, stage, family and personal history of cutaneous melanoma and of other neoplasias, personal history of non-melanoma skin cancer, past personal history of severe sunburns, cutaneous phenotype (phototype, hair and eyes colors number of common nevus, number of atypical nevi, presence of solar lentigines).
Forty-one (4.28%) familial and 918 sporadic melanoma were identified. Among the multiple variables studied, a younger age at diagnosis (median age of 42 vs 53 years), higher frequency of the presence of at least one clinically atypical nevus (36.1% vs 17.7%), multiple melanomas (12.2% vs 3.4%) and red/blonde hair (33.3% vs 18.9%), and a lower rate of cases with solar lentigines in melanoma site (33.3% vs 56.3%) were found for familial cases. Except for hair color and age, the other variables remained statistically significant after the multivariate study. Interestingly, no acral melanomas were found among the familial cases.
In summary, phenotypic risk factors for familial melanoma are a tendency to develop multiple melanomas, to have clinically atypical nevi and to present less actinic damage at the melanoma site. All these results enhance the relevancy of genetic susceptibility associated to the ability to produce atypical nevi and partly to a higher sensitivity to the sun.     

白介素27基因多态性与广西壮族系统性红斑狼疮的相关性研究

目的 探讨白介素27（IL-27）基因单核苷酸多态性与广西壮族系统性红斑狼疮（SLE）易感性之间的关系。方法 以135例SLE患者和150例正常人对照者为研究对象,应用聚合酶链反应-限制性片段长度多态性和DNA测序的方法对IL-27基因-964 A/G、2905 T/G单核苷酸多态性进行基因分型。结果 SLE组和正常人对照组中IL-27基因2905 T/G多态性分布差异无统计学意义（χ2 = 1.63,P > 0.05）,而IL-27基因-964 A/G多态性的分布差异有统计学意义（χ2 = 9.88,P < 0.01）。等位基因频率的相对风险分析发现,-964 G等位基因携带者患SLE的风险是-964 A等位基因的1.725倍（OR = 1.725,95% CI：1.227 ～ 2.425）。联合基因型分析发现,IL-27的-964 G /2905 G等位基因频率SLE组（10.7%）显著高于对照组（5.3%）（P < 0.01）,-964 G/2905 G等位基因携带者显著增加了SLE的发病风险（OR = 2.351,95% CI：1.228 ～ 4.501）。结论 IL-27基因-964 A/G多态性与SLE的发病具有相关性,其中-964 G等位基因可能是SLE的遗传易感基因。     

雌激素受体-α基因多态性与白癜风相关性研究

目的探讨雌激素受体-α(ER-α)基因多态性与白癜风的相关性。方法应用PCR-RFLP分析技术,检测690例汉族白癜风患者和700例汉族对照者ER-α基因内含子1PvuⅡT/C和XbaIA/G酶切位点基因多态性。结果白癜风组与对照组之间C/T基因型频率(P=0.000)差别有显著性意义,其C等位基因频率亦明显高于对照组(P=0.000,OR1.33,95%CI1.14~1.51);女性患者C/T基因型频率(P=0.001)、C等位基因频率(P=0.002,OR1.41,95%CI1.13~1.75)亦明显高于女性对照组;男性患者和男性对照组C等位基因频率(P=0.043,OR1.25,95%CI1.01~1.56)差别有显著性意义;ER-α基因内含子1XbaⅠA/G酶切多态性男性患者G等位基因频率(P=0.040,OR1.32,95%CI1.01~1.71)明显高于男性对照组;其余各组间差别无显著性意义(P>0.05)。结论ER-α基因PvuII酶切多态性与白癜风存在相关性,携带C等位基因的女性患者更易患白癜风。XbaI酶切多态性可能与男性白癜风患者之间存在相关性。提示ER-α可能是白癜风患者易感性的备选因素。     

Three cases of primary acquired melanosis of the conjunctiva as a manifestation of the atypical mole syndrome

We report three patients with the atypical mole syndrome (AMS) [also known as dysplastic naevus or FAMMM syndrome] who presented with primary acquired melanosis (PAM). PAM is a melanocytic lesion of the conjunctiva which may progress to conjunctival melanoma. The association of this rare condition with the AMS phenotype in three individuals suggests that PAM may he a conjunctival manifestation of the AMS.     

系统性红斑狼疮患者白介素10受体cDNA基因多态性研究

目的 探讨白介素10受体(IL-10R)的两个基因位点G241A和G520A基因多态性与系统性红斑狼疮(SLE)患者发病的相关性.方法 采用聚合酶链反应-单链构象多态性(PCR-SSCP)和聚合酶链反应限制性片段多态性(PCR-RFLP)及DNA测序方法进行基因分型.结果 IL-10R2基因型与SLE易感性显著相关.G520/G520基因型增加SLE发病危险性,P=0.004,OR=0.515,95%的可信区间为0.444-0.579;G520/A520基因型增加SLE发病危险性,P=0.055,OR=1.968,95%的可信区间为0.981-3.949.IL-10R1基因型与SLE易感性无显著相关.各个基因型组合的分布情况和优势比显示具有IL-10R1 G241/G241基因型和IL-10R2 G520/G520的个体SLE发病危险性明显高于其他的基因型组合,P=0.004,OR=0.515,95%的可信区间为0.444-0.597.结论 IL-10R2基因型与SLE易感性显著相关,G520/G520基因型增加SLE发病危险性.具有IL-10R1 G241/G241基因型和IL-10R2 G520/G520的个体SLE发病危险性明显高于其他的基因型组合.     

Dermatologist detection and skin self-examination are associated with thinner melanomas: results from a survey of the Italian Multidisciplinary Group on Melanoma

OBJECTIVE: To investigate patterns of detection and variables associated with early diagnosis of melanoma in a population at intermediate melanoma risk. DESIGN: Survey. SETTING: Hospital and university centers belonging to the Italian Multidisciplinary Group on Melanoma. PATIENTS: Eight hundred sixteen patients who were consecutively diagnosed as having melanoma and treated at 11 participating centers. MAIN OUTCOME MEASURE: Relationship between patterns of detection and patient's and physician's delay with melanoma thickness, assessed by multivariate analysis. RESULTS: A statistically significant association with early diagnosis was found for female sex (odds ratio [OR] for a lesion >1 mm in thickness, 0.70; 95% confidence interval [CI], 0.50-0.97), higher educational level (OR, 0.44; 95% CI, 0.24-0.79), residence in northern and central Italy (compared with southern Italy) (OR, 0.44; 95% CI, 0.30-0.65 and OR, 0.24; 95% CI, 0.15-0.37, respectively), and the habit of performing a skin self-examination (OR, 0.65; 95% CI, 0.45-0.93). When adjusted for all the previously mentioned variables, only melanoma detection made by a dermatologist, maybe incidentally, was associated with a statistically significant additional effect on early diagnosis (OR, 0.45; 95% CI, 0.28-0.73). No significant effect of anatomical site (trunk compared with other sites: OR, 0.83; 95% CI, 0.59-1.17), presence of atypical nevi (OR, 0.78; 95% CI, 0.52-1.17), and patient's delay (>3 months compared with < or =3 months: OR, 1.12; 95% CI, 0.78-1.60) was found. CONCLUSION: Future melanoma early diagnosis strategies should adequately stress the role of skin self-examination among the adult population, and should recommend that dermatologists perform a total skin examination to identify suspect lesions (such an examination should also be performed during consultations for other reasons).     

Association between TERT-CLPTM1L rs401681[C] allele and NMSC cancer risk: a meta-analysis including 45,184 subjects

Single-nucleotide polymorphism of CLPTM1L-rs401681(C > T) at the 5p15.33 locus is significantly associated with cancer risk as reported in genome-wide association studies, but the reported studies for non-melanoma skin cancer (NMSC) are inconclusive. To assess the association between rs401681[C] allele and NMSC risk, we performed this meta-analysis with four case–control studies involving 5,469 cases and 39,715 controls. Our meta-analysis showed that rs401681[C] allele was associated with NMSC susceptibility in the overall subjects (C vs. T, OR 1.13, 95 % CI 1.07–1.20). In the stratified analysis, the rs401681[C] allele confers susceptibility in Icelanders (C vs. T, OR 1.15, 95 % CI 1.06–1.26) and non-Icelanders (C vs. T, OR 1.13, 95 % CI 1.03–1.24). In the subtype analysis, we found that rs401681[C] allele was a risk factor for BCC, but not SCC in the overall subjects.     

Lack of association between the G-2548A polymorphism of the leptin gene and psoriasis in a Turkish population

BACKGROUND: Psoriasis is a multifactorial disease in which genetic and inflammatory factors play important roles. Leptin is classified as a cytokine and plays an important role in the regulation of the T-helper response. A common polymorphism in the promoter of the human leptin gene (G-2548A) may have a role in the pathogenesis of psoriasis. AIM: To investigate the association between psoriasis and leptin gene polymorphism (G-2548A). METHODS: The study involved 109 patients with psoriasis and 125 healthy controls. Analyses of G-2548A polymorphism of the leptin gene were made by the polymerase chain reaction-restriction fragment length polymorphism technique. The genotypes (GG, GA, and AA of leptin gene G-2548A) and alleles (G and A) were scored and the frequencies were estimated. The frequencies of alleles and genotypes in patients and controls were compared. The relationship between leptin gene polymorphism and the clinical features of the patients was analyzed. RESULTS: Both genotype [odds ratio (OR), 0.921; 95% confidence interval (CI), 0.501-1.694; P = 0.792] and allele (OR, 0.864; 95% CI, 0.600-1.242; P = 0.429) frequencies were not significantly different between patient and control groups. In addition, there was no significant association between genotype and allele frequencies and the clinical characteristics of psoriasis. CONCLUSION: In this case-control study, no evidence of association between the G-2548A variant of the leptin gene and psoriasis was found.     

Teaching non-specialist health care professionals how to identify the atypical mole syndrome phenotype: a multinational study

The atypical mole syndrome (AMS) phenotype is the strongest known risk factor for cutaneous melanoma but recognition of the phenotype has been claimed to be problematic and to require specialist assessment. This study determined the ability of previously unskilled doctors and nurses in five countries to recognize the phenotype after brief training. The system used was the AMS scoring system. This incorporates melanocytic naevus counts, clinical atypia of naevi and distribution of naevi. The agreement in scoring between the dermatologist and trained personnel was determined in 986 patients; overall agreement in diagnosis was 94.5% (kappa 0.70, P < 0.0001). The kappa scores in different countries ranged from 0.65 to 0.77 for individual naevus characteristics, indicative of good agreement. Accurate diagnosis of the atypical mole syndrome phenotype is possible by non-specialists. This has implications for collaborative studies of naevi, for screening and for both primary and secondary prevention of melanoma.     

"Atypical" Spitz's nevus, "malignant" Spitz's nevus, and "metastasizing" Spitz's nevus: a critique in historical perspective of three concepts flawed fatally

Our purpose in undertaking this Arbeit was to review all articles published about "atypical" Spitz's nevus, "malignant" Spitz's nevus, and "metastasizing" Spitz's nevus, to criticize them in a fashion that illuminates, and to come to conclusions compellingly about those subjects. We found that an overwhelming majority of neoplasms that claimed to be "atypical Spitz's nevus," "metastasizing Spitz's nevus," and "malignant Spitz's nevus" were, in fact, melanomas ( Table 1). Moreover, in our estimation, those designations, and variants of them, like "atypical Spitz's lesion," "atypical dermal melanocytic lesion with features of Spitz's nevus," "atypical Spitzoid melanocytic neoplasm," and "problematic Spitzoid melanocytic lesion," are mere evasions from a diagnosis, straightforwardly, of either Spitz's nevus or melanoma. Diagnoses in pathology equally bogus are "minimal deviation melanoma," "borderline melanoma," "nevoid melanoma," "potentially low-grade melanocytic neoplasm," and "melanocytic lesion of uncertain biologic potential." Rather than admit uncertainty forthrightly, those who employ circumlocutions like those just mentioned resort to linguistic maneuvers that, at first blush, seem to be "academic" and constructed in such a way as to appear to convey confidence, rather than tentativeness, on the part of a histopathologist. On further scrutiny, however, each of those cliches is revealed to be devoid of content. For example, "malignant" Spitz's nevus and "metastasizing" Spitz's nevus not only are contradictions in terms, but they are outrageous violations of fundamental principles of classic Virchowian pathology, and "atypical" Spitz's nevus not only is a redundancy because the neoplasm was so atypical to Spitz, herself, she insisted (from the time she spawned the idea in 194 through 1951 it was a "malignant melanoma," but is abject intellectually, those who invoke it never setting forth, in clear-cut fashion, criteria for what constitutes a "typical" Spitz's nevus in contradistinction to an "atypical" one.     

Malignant blue nevus with metastases to the lung

A malignant blue nevus of the right upper arm with hematogeneous lung metastases is presented. Histological examination showed that the tumor was composed of spindle, dendritic, and globular cells with hyperchromatic and polymorphic nuclei, atypical mitoses, and tumor cell necrosis. There was no proliferation of atypical melanocytes at the dermoepidermal junction. Histologically, malignant blue nevus should be distinguished from benign cellular blue nevus, primary cutaneous malignant melanoma, cutaneous metastases of malignant melanoma, and clear cell sarcoma.     

Androgen receptor gene polymorphisms and risk for androgenetic alopecia: a meta-analysis

Background. Numerous studies have shown an association between polymorphisms in the androgen receptor gene (AR) and the risk for androgenetic alopecia (AGA), but the overall results are still controversial. Aim. To determine, by conducting a meta‐analysis, whether the common AR gene polymorphisms confer susceptibility to AGA. Methods. Publications addressing the association between AR gene polymorphisms and risk for AGA were selected from the PubMed, EMBASE and CBMdisc databases. Data were extracted from the studies by two independent reviewers. The meta‐analysis was performed using the software programs RevMan (version 5.0.25) and STATA (version 9.2). From these data, odds ratio (OR) with 95% confidence interval (CI) was calculated. Results. Only eight studies were found, reporting a total of 2074 patients with AGA and 1115 healthy controls. Three common polymorphisms of the AR gene were addressed: a StuI restriction‐site polymorphism (rs6152, G>A), and CAG and GGC triplet‐repeat polymorphisms. Meta‐analysis results identified a significant association between the G allele of the AR StuI polymorphism and the risk for AGA (OR = 2.68, 95% CI 1.71–4.19, P < 0.01), especially in white populations (OR = 2.76, 95% CI 1.71–4.45, P < 0.01). No association was found between the CAG or GGC polymorphism and the risk for AGA (OR = 0.81, 95% CI 0.49–1.34, P = 0.41; OR = 1.01, 95% CI 0.47–2.14, P = 0.99, respectively). Conclusion. Our meta‐analysis suggests that the G allele of AR StuI polymorphism might be a potential risk factor for AGA, especially in white populations. However, we did not find any obvious association of the CAG and GGC triplet‐repeat polymorphisms of the AR gene with risk for AGA.     

Excision of melanoma after initial biopsy: An immunohistochemical study

An immunohistochemical method for the demonstration of S-100 protein was used to identify melanocytes in fourteen cases of malignant melanoma subsequently excised after initial punch biopsy. Although S-100 protein-containing cutaneous nerves and dermal dendritic cells could be identified within the area of dermal repair, there was no evidence of physical movement of atypical melanocytes or nevus cells downward into the scarified area. This study cannot confirm the concept that punch biopsy of melanoma physically seeds atypical cells into the dermis.     

Spitz nevus: a case report and the use of dermoscopy

The Spitz nevus is a benign melanocytic lesion with clinical and histopathological features similar to those of melanoma. It was first described in 1948 but great controversy still remains today with respect to its diagnosis and management. The use of dermoscopy may increase diagnostic accuracy. In Spitz nevus, the most common dermoscopic finding is a starburst-like pattern, followed by globular and atypical patterns. Diagnosis must be confirmed by histopathology, particularly in atypical cases.     

Impact of tumour necrosis factor-α polymorphisms on irritant contact dermatitis

Background. Genetic variations in genes coding for cytokines involved in skin inflammation may alter their expression, thus changing the susceptibility to irritant contact dermatitis (ICD). Objectives. To determine the prevalence of polymorphisms in the cytokine genes TNFA‐238 and TNFA‐308 in patients with occupational ICD, and to compare it with that in controls. Methods. In a case–control study, 478 patients with occupational ICD of the hands were genotyped for TNFA‐238 and TNFA‐308 polymorphisms. The results were compared with those for 393 apprentices from the same high‐risk occupations (controls). Results. For a carrier of a variant TNFA‐238A allele, the odds ratio (OR) of acquiring ICD was 0.57 [95% confidence interval (CI) 0.34–0.97], suggesting a protective effect of the A allele. The genotype distributions were 94.4% wild type (G/G), 5.6% heterozygous (G/A) and 0% homozygous for variant allele (A/A) in patients, and 90.9%, 8.5%, and 0.6%, respectively in controls. In contrast, carriers of the variant TNFA‐308A allele had an increased risk of ICD [OR 1.33; 95% CI 1.05–1.74; G/G 66.4%, G/A 31.2%, and A/A 2.4% (patients) versus 73.5%, 24.6%, 1.9% in controls]. Conclusions. Individuals with a TNFA‐238 polymorphism are less prone and those with a TNFA‐308 polymorphism are more prone to develop ICD of the hands, suggesting a protective versus a detrimental effect of the A allele respectively.