Genetic Variants in Telomerase Reverse Transcriptase Contribute to Solar Lentigines.

Solar lentigines (SLs) are a hallmark of human skin aging. They result from chronic exposure to sunlight and other environmental stressors. Recent studies also imply genetic factors, but findings are partially conflicting and lack of replication. Through a multi-trait based analysis strategy, we discovered that genetic variants in telomerase reverse transcriptase were significantly associated with non-facial SL in two East Asian (Taizhou longitudinal cohort, n = 2,964 and National Survey of Physical Traits, n = 2,954) and one Caucasian population (SALIA, n = 462), top SNP rs2853672 (P-value for Taizhou longitudinal cohort = 1.32 × 10‒28 and P-value for National Survey of Physical Traits = 3.66 × 10‒17 and P-value for SALIA = 0.0007 and Pmeta = 4.93 × 10‒44). The same variants were nominally associated with facial SL but not with other skin aging or skin pigmentation traits. The SL-enhanced allele/haplotype upregulated the transcription of the telomerase reverse transcriptase gene. Of note, well-known telomerase reverse transcriptase‒related aging markers such as leukocyte telomere length and intrinsic epigenetic age acceleration were not associated with SL. Our results indicate a previously unrecognized role of telomerase reverse transcriptase in skin aging‒related lentigines formation.

Prevalence of nevi, atypical nevi, and lentigines in relation to tobacco smoking.

BACKGROUND: Melanocytic nevi have a complex evolution influenced by several endogenous and exogenous factors and are known risk factors for malignant melanoma. Interestingly, tobacco use seems to be inversely associated with melanoma risk. However, the association between tobacco use and nevi and lentigines has not yet been evaluated. METHODS: We investigated the prevalence of nevi, atypical nevi, and lentigines in relation to tobacco smoking in a cohort of 59 smokers and 60 age- and sex-matched nonsmokers, using a questionnaire and performing a total body skin examination by experts. RESULTS: No significant differences were detected between smokers and nonsmokers in the numbers of nevi, atypical nevi, and lentigines in sun-exposed areas (p = 0.966, 0.326, and 0.241, respectively) and in non-sun-exposed areas (p = 0.095, 0.351, and 0.546, respectively). CONCLUSION: Our results revealed no significant differences in the prevalence of nevi, atypical nevi, and lentigines between smokers and nonsmokers in sun-exposed and non-sun-exposed areas.

Lifetime UVR Dose and Skin Cancer Risk, Determined by Their Common Relation to Solar Lentigines.

BACKGROUND/AIM: Ultraviolet radiation (UVR) causes solar lentigines (SL) and skin cancer (SC) in humans. The association between measured lifetime UVR dose and SC has not been investigated. This study investigated this relation through their common relationship to SL. MATERIALS AND METHODS: First we investigated the association between lifetime UVR dose and SL for 16,897 days in 38 healthy participants, and secondly, the relation between SL and SC was investigated in 2,898 participants, including 149 with SC. By combining both studies, SC risk related to lifetime UVR dose and skin phototype was estimated. RESULTS: A positive association was found between SL and lifetime UVR dose (p=0.060). Skin phototype (p=0.001) and SL (p<0.001) were associated with SC. Combined SC risk increased 1.23 by doubling the average lifetime UVR dose and was 34.9 times higher for those with very fair skin compared to dark Mediterranean skin. CONCLUSION: The estimate of SC risk shows that skin phototype is of greater relative importance than lifetime UVR dose.

Development and external validation study of a melanoma risk prediction model incorporating clinically assessed naevi and solar lentigines.

BACKGROUND: Melanoma risk prediction models could be useful for matching preventive interventions to patients' risk. OBJECTIVES: To develop and validate a model for incident first-primary cutaneous melanoma using clinically assessed risk factors. METHODS: We used unconditional logistic regression with backward selection from the Australian Melanoma Family Study (461 cases and 329 controls) in which age, sex and city of recruitment were kept in each step, and we externally validated it using the Leeds Melanoma Case-Control Study (960 cases and 513 controls). Candidate predictors included clinically assessed whole-body naevi and solar lentigines, and self-assessed pigmentation phenotype, sun exposure, family history and history of keratinocyte cancer. We evaluated the predictive strength and discrimination of the model risk factors using odds per age- and sex-adjusted SD (OPERA) and the area under curve (AUC), and calibration using the Hosmer-Lemeshow test. RESULTS: The final model included the number of naevi ≥ 2 mm in diameter on the whole body, solar lentigines on the upper back (a six-level scale), hair colour at age 18 years and personal history of keratinocyte cancer. Naevi was the strongest risk factor; the OPERA was 3·51 [95% confidence interval (CI) 2·71-4·54] in the Australian study and 2·56 (95% CI 2·23-2·95) in the Leeds study. The AUC was 0·79 (95% CI 0·76-0·83) in the Australian study and 0·73 (95% CI 0·70-0·75) in the Leeds study. The Hosmer-Lemeshow test P-value was 0·30 in the Australian study and < 0·001 in the Leeds study. CONCLUSIONS: This model had good discrimination and could be used by clinicians to stratify patients by melanoma risk for the targeting of preventive interventions. What's already known about this topic? Melanoma risk prediction models may be useful in prevention by tailoring interventions to personalized risk levels. For reasons of feasibility, time and cost many melanoma prediction models use self-assessed risk factors. However, individuals tend to underestimate their naevus numbers. What does this study add? We present a melanoma risk prediction model, which includes clinically-assessed whole-body naevi and solar lentigines, and self-assessed risk factors including pigmentation phenotype and history of keratinocyte cancer. This model performs well on discrimination, the model's ability to distinguish between individuals with and without melanoma, and may assist clinicians to stratify patients by melanoma risk for targeted preventive interventions.

A cross-sectional analysis of skin cancer risk in patients receiving narrow-band ultraviolet B phototherapy: an evaluation of 100 patients.

Narrow-band ultraviolet B (NB-UVB) phototherapy is an effective and widely used treatment modality for psoriasis and other inflammatory skin diseases. The carcinogenic effect of PUVA treatment has been investigated extensively, but there is very scarce data about the role of NB-UVB in the development of skin cancer. The aim of this study was to investigate the potential carcinogenic risk of NB-UVB therapy in various skin disorders. In this cross-sectional study, we evaluated 100 patients who had received whole-body NB-UVB treatment and 100 age- and sex-matched controls. Phototherapy unit database was used to identify patients. A total of 100 patients (53 males and 47 females) treated with NB-UVB and 100 controls were included in the study. The patient group revealed no cases of melanoma or non-melanoma skin cancer, while ten of them were found to have solar lentigines. Basal cell carcinoma in a patient and nine patients with solar lentigines were detected in the control group. There was no statistically significant difference between patient and control groups in terms of skin cancer and solar lentigines. This study does not provide evidence for an increased skin cancer risk in patients treated with NB-UVB phototherapy. However, we have detected the occurence of 10 cases of solar lentigines. Still, definitive prospective longitudinal studies with a greater number of patients and prolonged follow-up are required to specifically address skin cancer risk in relation to NB-UVB phototherapy.

Association of sunbed use with skin cancer risk factors in Europe: an investigation within the Euromelanoma skin cancer prevention campaign.

INTRODUCTION: Sunbed use has been significantly associated with increased risk of melanoma and non-melanoma skin cancer (NMSC), but its relationship with melanoma's risk factors such as high nevus count, atypical nevi and lentigines is poorly studied. Euromelanoma is a skin cancer prevention campaign conducted all over Europe. It offers a once-a-year screening during which participants' data, including sunbed use and phenotype, are collected via questionnaires. OBJECTIVES: To investigate the association of sunbed use with nevus count, atypical nevi, lentigines and suspicion of skin cancer. METHODS: To ensure reliability of the data, we defined inclusion and exclusion criteria for countries' eligibility for the risk analysis. Multivariate logistic regression models (including age, gender, education, skin type, family history of melanoma, personal history of skin cancer, any sun exposure and any sunscreen use) were used to calculate summary odds ratios (SORs) of each clinical endpoint for ever sunbed use. RESULTS: Overall, 227 888 individuals from 30 countries completed the Euromelanoma questionnaire. After the data quality check, 16 countries were eligible for the multivariate analysis, for a total of 145 980 participants (64.8% females; median age 43 years; 62.3% highly educated; 28.5% skin type I-II; 11.0% ever sunbed use). Ever sunbed use was independently associated with nevus count >50 [SOR = 1.05 (1.01-1.10)], atypical nevi [SOR = 1.04 (1.00-1.09)], lentigines [SOR = 1.16 (1.04-1.29)] and suspicion of melanoma [SOR = 1.13 (1.00-1.27)]. Conversely, no significant association was found between ever sunbed use and suspicion of NMSC [SOR = 1.00 (0.91-1.10)]. CONCLUSIONS: Indoor tanning is significantly associated with well-recognized risk factors for melanoma (including high nevus count, presence of atypical nevi and lentigines) as well as suspicion of melanoma within the Euromelanoma screenees. In order to reduce the prevalence of melanoma risk factors, avoidance/discontinuation of sunbed use should always be encouraged, especially but not exclusively for individuals with high-risk phenotypes.

Contributions by MC1R Variants to Melanoma Risk in Males and Females.

Importance: Recently, the red hair variants of MC1R were found to contribute differently to pigmentation phenotype in males and females. Objective: To investigate the role of these variants in melanoma risk in males and females separately because carriers of the red hair variants of MC1R are at increased risk of melanoma. Design, Setting, and Participants: In this hospital-based, case-control study, we evaluated the effect of MC1R and melanoma risk for males and females separately by performing multivariate logistic regression analyses. Main Outcomes and Measures: Association of MC1R variants and melanoma risk in males and females. Results: A total of 905 females (473 melanoma cases, 432 controls) and 886 males (518 melanoma cases, 368 controls) were included in the analyses. The mean (SD) age of the study population was 59.2 (15.6). In females, carrying any MC1R red hair variants remained an independent risk factor of melanoma in a multivariable analysis (adjusted odds ratio [OR], 2.19 [95% CI, 1.60-2.99]), whereas in males, only signs of actinic skin damage (lentigines on the back [OR, 2.56; 95% CI, 1.47-4.45; P = .001] and the hands [OR, 2.31; 95% CI, 1.24-4.29; P = .008] and wrinkling on the neck [OR, 2.17; 95% CI, 1.23-3.82; P = .007]) and sunburns (OR, 1.65; 95% CI, 1.12-2.42; P = .01) remained significant risk factors. Conclusions and Relevance: MC1R variants contribute differently to melanoma risk in males and females. This could be helpful to better classify melanoma risk factors between the sexes.

Xeroderma pigmentosum at a tertiary care center in Saudi Arabia.

BACKGROUND: Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder caused by defective DNA repair that results in extreme sensitivity to ultraviolet (UV) rays. Depending on the type of XP, the disease may affect the skin, eyes and nervous system. OBJECTIVES: Describe the dermatologic manifestations in patients suffering from XP. DESIGN: Retrospective, descriptive review of medical records. SETTING: Dermatology clinic at tertiary care center in Riyadh. PATIENTS AND METHODS: This study included Saudi patients with clinically confirmed XP. MAIN OUTCOME MEASURE(S): Demographic and clinical data including pathology and associated conditions and outcomes. RESULTS: Of 21 patients with XP, the most common manifestation was lentigines, affecting 18 patients (86%). The most common skin cancer was basal cell carcinoma followed by squamous cell carcinoma (SCC) affecting 15 (71.4%) and 9 (42.8%), respectively. Other skin findings included neurofibroma, trichilemmoma and seborrheic keratosis. Ocular involvement included photophobia, which was the most common finding followed by dryness and ocular malignancies. Two patients showed neurological involvement, which correlated with the type of mutation. CONCLUSION: Considering that XP is a rare genetic disease, this description of our patient population will aid in early recognition and diagnosis. LIMITATIONS: Retrospective and small number of patients. Genetic analyses were done for only 5 of the 21 patients.

Exposure to fine particulate matter associated with senile lentigo in Chinese women: a cross-sectional study.

BACKGROUND: Skin ageing especially senile lentigo directly affects self-esteem. For decades, senile lentigo has been associated with chronic exposure to solar radiation. However, a study conducted recently in Caucasian subjects suggested that exposure to air pollution was significantly correlated with extrinsic skin ageing, in particular senile lentigines. OBJECTIVE: To investigate the association between fine particulate matter (PM2.5 ) and skin ageing, particularly senile lentigo and seborrheic keratosis. METHODS: The study enrolled 400 Chinese women aged 40-90 years including 210 from the Yanqing county in Beijing (low PM2.5 exposure group) and 190 from the Xuanwumen in Beijing (high PM2.5 exposure group). Skin ageing symptoms, particularly senile lentigines and seborrheic keratoses, were clinically assessed using scores of intrinsic and extrinsic skin ageing. An ordinal logistic regression model was used to analyse the effect of PM2.5 on skin ageing adjusted for factors underlying skin ageing. RESULTS: In the study population of Xuanwumen, we found that senile lentigo on cheeks and back of hands was 1.48 times and 2.8 times higher, respectively, compared with those from Yanqing county. However, no association was found between PM2.5 and seborrheic keratosis. We found that other variables such as smoking, second-hand smoking, contact with fossil fuels and skin types were significantly associated with skin ageing. CONCLUSION: These results indicate that PM2.5 was another extrinsic factor promoting skin ageing.

Could a specific dietary intake be a risk factor for cutaneous melanoma?

The incidence of cutaneous melanoma (CM) has increased in the last decade. Some risk factors are well known, but there are other possible risk factors being studied, such as those involving nutrition. The objective of this case-control study was to assess the association between diet and CM. Classical risk factors, dietary intake, and body mass index were assessed. Binary logistic regression was used to study the association between dietary intake and the risk for CM. Classical risk factors associated with CM were confirmed. The findings suggest that some foods rich in vitamins A and D and phytochemicals may be related to CM.

A genome-wide association study in Caucasian women suggests the involvement of HLA genes in the severity of facial solar lentigines.

Solar lentigines are a common feature of sun-induced skin ageing. Little is known, however, about the genetic factors contributing to their development. In this genome-wide association study, we aimed to identify genetic loci associated with solar lentigines on the face in 502 middle-aged French women. Nine SNPs, gathered in two independent blocks on chromosome 6, exhibited a false discovery rate below 25% when looking for associations with the facial lentigine score. The first block, in the 6p22 region, corresponded to intergenic SNPs and also exhibited a significant association with forehead lentigines (P = 1.37 × 10(-8) ). The second block, within the 6p21 HLA region, was associated with decreased HLA-C expression according to several eQTL databases. Interestingly, these SNPs were also in high linkage disequilibrium with the HLA-C*0701 allele (r(2)  = 0.95). We replicated an association recently found by GWAS in the IRF4 gene. Finally, a complementary study on 44 selected candidate SNPs revealed novel associations in the MITF gene. Overall, our results point to several mechanisms involved in the severity of facial lentigines, including HLA/immunity and the melanogenesis pathway.

Síndrome LEOPARD sin sordera ni estenosis pulmonar: a propósito de 2 casos / LEOPARD Syndrome Without Hearing Loss or Pulmonary Stenosis: A Report of 2 Cases

El síndrome LEOPARD es una enfermedad autosómica dominante producida por mutaciones germinales en la vía RAS-MAPK. El acrónimo agrupa las manifestaciones más importantes de la enfermedad (Lentiginosis, ECG conduction anomalies, Ocular hypertelorism/hypertrophic Obstructive cardiomyopathy, Pulmonary stenosis, Abnormalities of genitalia, growth Retardation and Deafness), pero ninguna de ellas es patognomónica ni constante, por lo que muchos pacientes no las presentan en el momento del diagnóstico. Presentamos 2 casos de síndrome LEOPARD sin sordera ni estenosis pulmonar en los que la detección de la mutación en el gen PTPN11 permitió confirmar la enfermedad, y señalamos la importancia del seguimiento continuado para la detección precoz de las complicaciones, ya que las mismas pueden aparecer en el transcurso de la enfermedad

LEOPARD syndrome is an autosomal dominant disease caused by germline mutations in the RAS-MAPK (mitogen-activated protein kinase) pathway. LEOPARD is an acronym for the main manifestations of the syndrome, namely, multiple Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormalities of genitalia, Retardation of growth, and sensorineural Deafness. None of these characteristic features however, are pathognomonic of LEOPARD syndrome, and since they are highly variable, they are often not present at the time of diagnosis. We describe 2 cases of LEOPARD syndrome without hearing loss or pulmonary stenosis in which diagnosis was confirmed by identification of a mutation in the PTPN11 gene. Regular monitoring is important for the early detection of complications, as these can occur at any time during the course of disease

Age-related characteristics of cutaneous melanoma in a Spanish Mediterranean population.

BACKGROUND: Melanoma is considered a heterogeneous tumor with genetic and environmental factors involved in its pathogenesis. The impact of these factors varies depending on age. OBJECTIVE: The aim of this study was to characterize the epidemiological, phenotypic, and histological features of patients with melanoma according to three age groups: ≤40, 41-65, and >65 years. METHODS: A total of 1122 consecutive patients with invasive melanoma definitively treated in our institution since January 2000 were selected from our melanoma database. Epidemiological, phenotypic, and histological data were retrieved and analyzed as a function of age. RESULTS: Female patients predominated in the younger age group. The location of cutaneous malignant melanoma differed with age. In the younger and middle age groups, tumors presented mainly on the trunk, while in the older group they were mainly found on the head/neck. Signs of actinic damage such as actinic keratoses, solar lentigines, or other skin tumors increased with age, while genetic factors such as family history of melanoma or a high number of common melanocytic nevi were more frequent in the younger group. CONCLUSION: Our results suggest that melanoma development in younger patients is the result of genetic factors, particularly related to multiple nevi, whereas in older patients environmental factors such as severe chronic sun exposure play a major role.

Extrinsic skin ageing symptoms in seafarers subject to high work-related exposure to UV radiation.

OBJECTIVES: As outdoor workers, seafarers have high levels of work-related exposure to UV radiation. Considering the various ethnic shipboard crews, this study aimed to assess the prevalence of UV induced skin ageing symptoms among seafarers and their attitude towards sunlight exposure. METHODS: One dermatologist examined 514 seafarers and documented the presence of 11 extrinsic skin ageing symptoms. Based on a questionnaire, the seafarers' attitudes and sun protection were evaluated. RESULTS: On average, 4 extrinsic skin ageing symptoms were found among the seafarers without significant differences between ethnic groups. Teleangiectasis (n = 381), coarse wrinkles (n = 315) and lentigines solares (n = 228) were the most frequently observed extrinsic symptoms. In the multivariate analysis, the parameters current smoking (OR 1.52 (1.01-2.27)), shipboard rank (deck personnel, galley staff vs. engine room personnel; (OR 1.40 (1.01-1.94)), and age (OR 1.07 (1.05-1.10)) were significantly associated with developing skin ageing symptoms. Only half of the seafarers examined were aware of their elevated risk of photodamage due to their high UV exposure at sea. More non-Caucasian than Caucasian seafarers perceived tanned skin as rather positive (78.0% vs. 52.4%; p = 0.002); however, more Caucasian than non-Caucasian seafarers enjoyed intensive sunbathing (17.0% vs. 14.0%). Furthermore, 55.7% of the seafarers (significantly more often Caucasians) used sunscreens during sunlight exposure at sea. CONCLUSIONS: The various ethnic groups examined differed in their attitude and behaviour towards shipboard sun exposure. Education of shipboard crews is required about possible severe health effects due to sun exposure at sea.

Freckles and solar lentigines have different risk factors in Caucasian women.

BACKGROUND: To date, few epidemiological data on the relationships between solar lentigines, freckles and behavioural and constitutional risk factors in Caucasian populations exist. OBJECTIVES: To investigate the potential impact of behavioural and phenotypic variables, as well as the MC1R genetic background, on the history of facial freckles and the severity of solar lentigines in Caucasian women. METHODS: The severity of solar lentigines was graded from facial digital images of 523 French middle-aged women by a dermatologist and summarized by a score afterwards. The history of facial freckles was assessed and the sun-exposure behaviour was characterized using a six-category typology. Risk factors including MC1R polymorphism were evaluated using logistic regression models. RESULTS: Two constitutive host factors were found to be independently associated with a history of facial freckles: frequent sunburns and the presence of diminished function variants of the MC1R gene. In addition to age, five factors were independently associated with solar lentigines: constitutive host factors (dark skin colour and tanning capacity), a history of freckles, sun-exposure behaviour and current intake of oral contraceptive or progestogen treatments. CONCLUSION: These results strengthen the hypothesis that solar lentigines are markers of photoaging, whereas freckles are mainly determined by genetic factors. The finding that hormonal treatment is associated with a higher risk for solar lentigines merits further investigations.

Risk factors for basal cell carcinoma in a southern Brazilian population: a case-control study.

BACKGROUND: Basal cell carcinoma (BCC) is the most common cancer to occur in Caucasian populations, and its incidence is increasing. Despite its frequency, there is a paucity of data on risk factors for BCC in some regions. OBJECTIVES: This study investigated the association between pigmentary characteristics, distinctive patterns of solar exposure, habits and lifestyle, and risk for BCC among patients attending a dermatology center in a region in southern Brazil. METHODS: We conducted a hospital-based, case-control study that included 127 case patients with histologically confirmed BCC and 280 cancer-free control subjects with other dermatologic conditions, observed between January 2006 and December 2007. The study was conducted using a questionnaire and physical examination by a dermatologist. Relative risks were estimated using exposure odds ratios generated by cross-tabulation and logistic regression models. RESULTS: Risk for BCC was associated with family history of skin cancer, Fitzpatrick skin type I, and the presence of actinic keratoses, solar lentigines, leukoderma, and elastosis romboidalis nuchae. No effect was found for different patterns of solar exposure, eye, hair or skin color, exposure to non-solar ultraviolet radiation (UVR), or lifestyle-related habits such as sunscreen use and cigarette smoking. CONCLUSIONS: The results of this study suggest that skin type and family history of skin cancer may be important in establishing risk for developing BCC. Additionally, the detection by clinical examination of skin markers related to UVR action is important in establishing which patients are more likely to develop BCC.