Multifactorial predisposition to melanoma includes genes involved in pigmentation, immunity and DNA repair. Nonetheless, missing heritability in melanoma is still important. We studied the role of 335 candidate SNPs in melanoma susceptibility by using a dedicated chip and investigating 110 genes involved in different pathways. A discovery set was comprised of 1069 melanoma patients and 925 controls from France. Data were replicated using validation phases II (1085 cases and 801 controls from Spain) and III (1808 cases and 1894 controls from Germany and a second set of Spanish samples). In addition, an exome sequencing study was performed in three high-risk French melanoma families. Nineteen SNPs in 17 genes were initially associated with melanoma in the French population. Six SNPs were replicated in phase II, including two new SNPs in the WNT3 (rs199524) and VPS41 (rs11773094) genes. The role of VPS41 and WNT3 was confirmed in a meta-analysis (3940 melanoma cases and 3620 controls) with two-side p values of 0.002, (OR = 0.86) and 4.07 × 10(-10) (OR = 0.80), respectively. Exome sequencing revealed a non-synonymous VPS41 variant in one family that was shown to be strongly associated with familial melanoma (OR = 4.46, p = 0.001) in an independent sample of 178 melanoma families. WNT3 belongs to WNT pathway known to play a crucial role in melanoma, whereas VPS41 regulates vesicular trafficking and is thought to play a role in pigmentation. Our work identified two new pathways involved in melanoma predisposition. These results may be useful in the future for identifying individuals highly predisposed to melanoma.
Genetic Predisposition to Disease/genetics , Melanoma/genetics , Signal Transduction/genetics , Wnt3 Protein/genetics , Case-Control Studies , Female , Gene Frequency/genetics , Genotype , Humans , Male , Pigmentation/genetics , Polymorphism, Single Nucleotide/genetics , Risk Factors , Skin Neoplasms/genetics , Vesicular Transport Proteins/genetics
Telomere length has been associated with the development of cancer. Studies have shown that shorter telomere length may be related to a decreased risk of cutaneous melanoma. Furthermore, deregulation of the telomere-maintaining gene complexes, has been related to this oncogenic process. Some variants in these genes seem to be correlated with a change in telomerase expression. We examined the effect of 10 single nucleotide polymorphisms (SNPs) in the TERT gene (encoding telomerase), one SNP in the related TERT-CLPTM1L locus and one SNP in the TRF1 gene with telomere length, and its influence on melanoma risk in 970 Spanish cases and 733 Spanish controls. Genotypes were determined using KASP technology, and telomere length was measured by quantitative polymerase chain reaction (PCR) on DNA extracted from peripheral blood leucocytes. Our results demonstrate that shorter telomere length is associated with a decreased risk of melanoma in our population (global p-value, 2.69×10(-11)), which may be caused by a diminution of proliferative potential of nevi (melanoma precursor cells). We also obtained significant results when we tested the association between rs401681 variant (TERT-CLPTM1L locus) with melanoma risk (Odds ratio, OR; 95% confidence interval, CI=1.24 (1.08-1.43); p-value, 3×10(-3)). This is the largest telomere-related study undertaken in a Spanish population to date. Furthermore, this study represents a comprehensive analysis of some of the most relevant telomere pathway genes in relation to cutaneous melanoma susceptibility.
Melanoma/genetics , Membrane Proteins/genetics , Polymorphism, Single Nucleotide/genetics , Skin Neoplasms/genetics , Telomerase/genetics , Telomere/genetics , Adult , Case-Control Studies , Female , Gene Frequency , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Risk Factors , Telomeric Repeat Binding Protein 1/genetics , Melanoma, Cutaneous Malignant
BACKGROUND: Few high penetrance genes are known in Malignant Melanoma (MM), however, the involvement of low-penetrance genes such as MC1R, OCA2, ASIP, SLC45A2 and TYR has been observed. Lately, genome-wide association studies (GWAS) have been the ideal strategy to identify new common, low-penetrance susceptibility loci. In this case-control study, we try to validate in our population nine melanoma associated markers selected from published GWAS in melanoma predisposition. METHODS: We genotyped the 9 markers corresponding to 8 genes (PARP1, MX2, ATM, CCND1, NADSYN1, CASP8, IRF4 and CYP2R1) in 566 cases and 347 controls from a Spanish population using KASPar probes. Genotypes were analyzed by logistic regression and adjusted by phenotypic characteristics. RESULTS: We confirm the protective role in MM of the rs3219090 located on the PARP1 gene (p-value 0.027). Additionally, this SNP was also associated with eye color (p-value 0.002). A second polymorphism, rs12203592, located on the IRF4 gene was associated with protection to develop MM for the dominant model (p-value 0.037). We have also observed an association of this SNP with both lentigines (p-value 0.014) and light eye color (p-value 3.76 × 10(-4)). Furthermore, we detected a novel association with rs1485993, located on the CCND1 gene, and dark eye color (p-value 4.96 × 10(-4)). Finally, rs1801516, located on the ATM gene, showed a trend towards a protective role in MM similar to the one firstly described in a GWAS study. CONCLUSIONS: To our knowledge, this is the first time that these SNPs have been associated with MM in a Spanish population. We confirmed the proposed role of rs3219090, located on the PARP1 gene, and rs12203592, located on the IRF4 gene, as protective to MM along the same lines as have previous genome-wide associated works. Finally, we have seen associations between IRF4, PARP1, and CCND1 and phenotypic characteristics, confirming previous results for the IRF4 gene and presenting novel data for the last two, suggesting that pigmentation characteristics correlated with eye color are potential mediators between PARP1 and MM protection.
Genetic Predisposition to Disease/genetics , Interferon Regulatory Factors/genetics , Melanoma/genetics , Poly(ADP-ribose) Polymerases/genetics , Case-Control Studies , Female , Genetic Variation , Genome-Wide Association Study , Genotype , Humans , Male , Middle Aged , Phenotype , Poly (ADP-Ribose) Polymerase-1 , Polymorphism, Single Nucleotide , Spain
BACKGROUND: Base excision repair (BER) and nucleotide excision repair (NER) pathways eliminate a wide variety of DNA damage, including UV photoproducts. The ability of each individual to repair DNA damage following different causes might explain at least in part the variability in cancer susceptibility. Moreover, inflammatory response to UV exposure may further contribute to skin carcinogenesis by oxidative stress mechanisms. Single nucleotide polymorphisms in genes encoding various DNA-repair enzymes and oxidative stress factors may be candidate low-penetrance variants with a role in susceptibility to different cancers, particularly in those with aetiologies linked to environmental exposure, such as malignant melanoma (MM). METHODS: In this case-control study, 684 Spanish sporadic MM patients and 406 cancer-free control subjects were included and the role of 46 polymorphisms belonging to 16 BER and NER genes as well as 11 genes involved in oxidative stress processes were investigated. RESULTS: One polymorphism was identified to be individually associated with MM in the Spanish population. The variant was found in the NOS1 oxidative stress gene (rs2682826; p-value=0.01). These results suggest a putative role of oxidative stress processes in the genetic predisposition to melanoma. CONCLUSION: To the authors' knowledge, this is the largest DNA repair-related SNP study in melanoma risk conducted in the Spanish population up to now. Furthermore, it also represents a comprehensive genetic study of several oxidative stress polymorphisms tested in relation to MM susceptibility.
DNA Repair/genetics , Genetic Predisposition to Disease , Melanoma/genetics , Oxidative Stress/genetics , Polymorphism, Single Nucleotide/genetics , Skin Neoplasms/genetics , Alleles , Case-Control Studies , Female , Gene Frequency , Genotype , Humans , Male , Multivariate Analysis , Nitric Oxide Synthase Type I/genetics , Spain
As the incidence of Malignant Melanoma (MM) reflects an interaction between skin colour and UV exposure, variations in genes implicated in pigmentation and tanning response to UV may be associated with susceptibility to MM. In this study, 363 SNPs in 65 gene regions belonging to the pigmentation pathway have been successfully genotyped using a SNP array. Five hundred and ninety MM cases and 507 controls were analyzed in a discovery phase I. Ten candidate SNPs based on a p-value threshold of 0.01 were identified. Two of them, rs35414 (SLC45A2) and rs2069398 (SILV/CKD2), were statistically significant after conservative Bonferroni correction. The best six SNPs were further tested in an independent Spanish series (624 MM cases and 789 controls). A novel SNP located on the SLC45A2 gene (rs35414) was found to be significantly associated with melanoma in both phase I and phase II (P<0.0001). None of the other five SNPs were replicated in this second phase of the study. However, three SNPs in TYR, SILV/CDK2 and ADAMTS20 genes (rs17793678, rs2069398 and rs1510521 respectively) had an overall p-value<0.05 when considering the whole DNA collection (1214 MM cases and 1296 controls). Both the SLC45A2 and the SILV/CDK2 variants behave as protective alleles, while the TYR and ADAMTS20 variants seem to function as risk alleles. Cumulative effects were detected when these four variants were considered together. Furthermore, individuals carrying two or more mutations in MC1R, a well-known low penetrance melanoma-predisposing gene, had a decreased MM risk if concurrently bearing the SLC45A2 protective variant. To our knowledge, this is the largest study on Spanish sporadic MM cases to date.
Antigens, Neoplasm/genetics , Genetic Predisposition to Disease , Melanoma/genetics , Membrane Transport Proteins/genetics , Oligonucleotide Array Sequence Analysis , Polymorphism, Single Nucleotide , Adult , Aged , Aged, 80 and over , Female , Gene Frequency , Genetic Variation , Genotype , Haplotypes , Humans , Male , Melanoma/epidemiology , Middle Aged , Mutation , Risk , Spain
We report an exceptional case of umbilical basal cell carcinoma (BCC) in a 21-year-old man, whose correct diagnosis was suggested by dermoscopy during initial complete body mole mapping. Although BCC is a common skin tumor, only 7 cases of BCC arising within the umbilicus have been reported previously. To the best of our knowledge, our patient is unique because of his age, being the youngest case of umbilical BCC described in the literature. Complete examination and digital dermoscopic monitoring let us identify an asymptomatic, nonpigmented papule at the umbilicus. Dermoscopy images revealed signs of superficial ulceration and several types of vascular structures, which gave us the clue for the diagnosis and helped us differentiate it from other lesions such as Spitz nevus or amelanotic melanoma. The diagnosis was confirmed with histopathology after excision and there was no evidence of relapse in the following four years.
Carcinoma, Basal Cell/pathology , Skin Neoplasms/pathology , Carcinoma, Basal Cell/diagnosis , Dermoscopy , Humans , Male , Neoplasms, Multiple Primary , Nevus, Pigmented/pathology , Skin Neoplasms/diagnosis , Umbilicus , Young Adult
Lipodystrophy syndromes comprise a group of rare, heterogeneous disorders characterized by progressive loss of fat tissue, mainly from subcutaneous compartment and occasionally affecting visceral fat. Lipoatrophy may be partial, localized, or generalized. The latter cases are usually accompanied by metabolic-related disorders, including insulin resistance, diabetes mellitus, hyperlipemia, progressive hepatic disease and anabolic state. Treatment for lipodystrophy has increased interest in recent years because a new lipoatrophic population-patients who have HIV-associated lipodystrophy--is much more numerous than the whole number of patients affected by classic lipodystrophy entities.
Adipose Tissue/pathology , Lipodystrophy/diagnosis , Diagnosis, Differential , Humans , Lipodystrophy/classification , Syndrome
We present a female patient who developed mucosal and skin hyperpigmentation due to metastatic malignant melanoma. Diffuse cutaneous melanosis is a rare entity that complicates a small percentage of metastatic melanomas, confering a fatal prognosis. We discuss briefly the current evidence on pathogenesis of melanosis arising from metastatic melanoma.
Ascites/diagnosis , Melanoma/diagnosis , Melanoma/secondary , Melanosis/diagnosis , Skin Neoplasms/diagnosis , Aged , Ascites/etiology , Female , Humans , Melanoma/complications , Melanosis/etiology , Skin Neoplasms/complications
El tratamiento de las metástasis cutáneas de melanoma puede ser difícil en muchos casos debido a la edad de los pacientes, así como al número, tamaño y localización de las lesiones. Se presenta el caso de un varón de 82 años con metástasis cutáneas de melanoma en el cuero cabelludo que respondieron satisfactoriamente al tratamiento con imiquimod al 5% en crema. El imiquimod es un inmunomodulador de uso tópico con actividad antiviral y antineoplásica. El presente caso, junto con otros recientemente publicados, apoya la utilidad de este tratamiento en casos seleccionados de metástasis cutáneas de melanoma, al menos con un fin paliativo
The treatment of skin metastases of melanoma can be difficult in many cases because of the patients age, as well as the number, size and location of the lesions. We present the case of an 82-year-old male with melanoma skin metastases on the scalp, which responded satisfactorily to treatment with 5% imiquimod cream. Imiquimod is a topical immunomodulator with antiviral and antineoplastic action. This case, along with others that have recently been published, supports the usefulness of this treatment in selected cases of melanoma skin metastases, at least for palliative purposes
Male , Aged , Humans , Melanoma/diagnosis , Melanoma/therapy , Antineoplastic Agents/therapeutic use , Skin Neoplasms/diagnosis , Skin Neoplasms/therapy , Scalp/pathology , Melanoma/radiotherapy , Neoplasm Metastasis/pathology , Neoplasm Metastasis/radiotherapy , Neoplasm Metastasis/therapy
The treatment of skin metastases of melanoma can be difficult in many cases because of the patients age, as well as the number, size and location of the lesions. We present the case of an 82-year-old male with melanoma skin metastases on the scalp, which responded satisfactorily to treatment with 5 % imiquimod cream. Imiquimod is a topical immunomodulator with antiviral and antineoplastic action. This case, along with others that have recently been published, supports the usefulness of this treatment in selected cases of melanoma skin metastases, at least for palliative purposes.
Aminoquinolines/administration & dosage , Antineoplastic Agents/administration & dosage , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/secondary , Melanoma/drug therapy , Melanoma/secondary , Scalp , Skin Neoplasms/drug therapy , Skin Neoplasms/secondary , Administration, Topical , Aged , Aged, 80 and over , Humans , Imiquimod , Male
El carcinoma sebáceo es un tumor cutáneo maligno poco frecuente. Aparece en el 75% de los casos en localización oculopalpebral, rica en varios tipos de glándulas sebáceas. La cabeza y cuello son las regiones extraoculares donde se han descrito con mayor frecuencia. Su curso clínico es agresivo y son habituales las recurrencias locales y las metástasis a distancia. Se presenta un caso de una mujer de 79 años que fue diagnosticada de un carcinoma sebáceo extraocular en mejilla derecha, varias hiperplasias sebáceas y un carcinoma intraepidérmico con diferenciación sebácea. Tras realizar una completa evaluación de historia familiar y personal de la paciente se descartó la asociación con el síndrome de Muir-Torre (AU)
Aged , Female , Humans , Adenocarcinoma, Sebaceous/pathology , Sebaceous Gland Neoplasms/pathology , Sebaceous Gland Neoplasms/surgery
Las limitaciones de la cirugía oncológica cutánea han llevado a buscar nuevas modalidades terapéuticas que, con una seguridad y eficacia similares a las de la cirugía, la superen en resultado estético y funcional. En el tratamiento de lesiones cutáneas malignas y premalignas es cada vez más frecuente el uso de la laserterapia, la criocirugía y los inmunomoduladores tópicos o intralesionales. En la mayoría de los casos se recurre a estos tratamientos cuando la cirugía va a ser excesivamente mutilante, desfiguradora, o técnicamente difícil, lo cual suele ser relativamente frecuente en localizaciones como la cara o las zonas acrales. La respuesta favorable observada en el tratamiento con interferón (IFN) intralesional de metástasis cutáneas inoperables de melanoma ha llevado a probar su utilidad en casos seleccionados de melanoma primario, y existen ya varios trabajos que sugieren la eficacia y seguridad de este fármaco en el lentigo maligno. Se describe un caso de lentigo maligno localizado en el canto externo del ojo izquierdo que fue tratado con interferón alfa-2b (IFN-alfa2b) intralesional. Se objetivó la desaparición clínica e histológica de la lesión sin efectos adversos destacables y con un resultado estético excelente. El IFN intralesional puede ser una opción terapéutica válida para casos seleccionados de lentigo maligno (AU)
Humans , Interferon-alpha/therapeutic use , Angiogenesis Inhibitors/therapeutic use , Hutchinson's Melanotic Freckle/drug therapy , Antineoplastic Agents/therapeutic use , Skin Neoplasms/drug therapy , Interferon-alpha/administration & dosage , Antineoplastic Agents/administration & dosage
La enfermedad de Fox-Fordyce es un trastorno inflamatorio poco frecuente caracterizado por la aparición de pápulas pruriginosas con distribución folicular localizadas en las áreas dotadas de glándulas apocrinas. La etiopatogenia no se conoce con claridad, involucrándose la obstrucción del conducto excretor apocrino como fenómeno precoz en el proceso. Se presenta un caso de enfermedad de Fox-Fordyce, confirmado histológicamente, en una mujer de 16 años, con gran expresividad clínica (AU)
Adolescent , Female , Humans , Adrenal Cortex Hormones/therapeutic use , Fox-Fordyce Disease/pathology , Fox-Fordyce Disease/drug therapy
No disponible
Male , Middle Aged , Humans , Carcinoma, Basal Cell/drug therapy , Retinoids/administration & dosage , Administration, Topical
El tricoblastoma es una neoplasia benigna de origen tricogénico de escasa frecuencia, cuya presentación clínica suele ser anodina debido a la ausencia de datos clínicos específicos que permitan diferenciarlo de otros tumores de origen epitelial y/o anexial. Presentamos el caso de un tricoblastoma en un varón de edad avanzada de presentación atípica debido a la presencia de intensa pigmentación y ulceración central. Con este aspecto clínico se planteó el diagnóstico inicial de melanoma nodular. La dermatoscopia, en cambio, mostró ausencia de retículo pigmentado y orientó el diagnóstico hacia lesión no melanocítica, presentando un patrón compatible con un carcinoma basocelular pigmentado. El diagnóstico histopatológico fue de tricoblastoma pigmentado. Comentamos los aspectos clínicos e histológicos más importantes de esta rara neoplasia y la utilidad de la dermatoscopia en la evaluación inicial de los tumores cutáneos pigmentados (AU)
Humans , Male , Aged , Skin Neoplasms/diagnosis , Pigmentation Disorders/pathology , Neoplasms, Complex and Mixed/pathology , Endoscopy , Diagnosis, Differential , Melanoma/pathology , Carcinoma, Basal Cell/pathology
Durante el seguimiento de una paciente con múltiples nevus melanocíticos se detectó una lesión pigmentada con crecimiento focal. El examen dermoscópico reveló en el área en crecimiento una zona ligeramente azulada y un sector con un retículo pigmentado negativo. En el diagnóstico diferencial se consideró la posibilidad de melanoma incipiente. El estudio histológico mostró en el área en crecimiento un nevus compuesto con atipia arquitectural pero sin atipia citológica (AU)
Humans , Female , Adolescent , Endoplasmic Reticulum/ultrastructure , Nevus, Pigmented/pathology , Pigmentation Disorders/pathology , Diagnosis, Differential
No disponible
Adolescent , Adult , Aged , Female , Male , Middle Aged , Child , Humans , Melanocytes/pathology , Nevus, Pigmented/diagnosis , Nevus, Pigmented/epidemiology , Nevus, Pigmented/pathology , Paraneoplastic Syndromes/diagnosis , Paraneoplastic Syndromes/pathology , Melanocytes , Carcinoma/complications , Carcinoma/diagnosis , Carcinoma/pathology , Angiomatosis/complications , Angiomatosis/diagnosis , Hypertrophy/complications , Hypertrophy/diagnosis
