ABSTRACT
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.
Subject(s)
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 , SpainABSTRACT
The fibrosing disorders represent a diverse group of uncommon chronic diseases that include systemic sclerosis, eosinophilic fasciitis, eosinophilia-myalgia syndrome, toxic oil syndrome, and localized forms of fibrosis. A rare case of eosinophilic fasciitis is reported. The patient was a 61-year-old female who presented with generalized massive edema and eosinophilia. Signs of common edema-producing diseases, such as heart failure, were absent. Corticosteroids were initiated with slow improvement in edema. Over the ensuing months, miliary tuberculosis and tenosynovitis of her left hand and left foot developed, which responded to appropriate treatment. Moreover, prominent induration, hyperpigmentation, and coarse puckering of the skin gradually took place. Other conditions, especially neoplasms and infections, have been described in association with eosinophilic fasciitis, but this is the first reported case of miliary tuberculosis associated with the disease.
