ABSTRACT
In an ongoing screen for DNA sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conduct a genome-wide association study (GWAS) of 24,988,228 SNPs and small indels detected through whole-genome sequencing of 2,636 Icelanders and imputed into 4,572 BCC patients and 266,358 controls. Here we show the discovery of four new BCC susceptibility loci: 2p24 MYCN (rs57244888[C], OR=0.76, P=4.7 × 10(-12)), 2q33 CASP8-ALS2CR12 (rs13014235[C], OR=1.15, P=1.5 × 10(-9)), 8q21 ZFHX4 (rs28727938[G], OR=0.70, P=3.5 × 10(-12)) and 10p14 GATA3 (rs73635312[A], OR=0.74, P=2.4 × 10(-16)). Fine mapping reveals that two variants correlated with rs73635312[A] occur in conserved binding sites for the GATA3 transcription factor. In addition, expression microarrays and RNA-seq show that rs13014235[C] and a related SNP rs700635[C] are associated with expression of CASP8 splice variants in which sequences from intron 8 are retained.
Subject(s)
Carcinoma, Basal Cell/genetics , Caspase 8/genetics , GATA3 Transcription Factor/genetics , Homeodomain Proteins/genetics , Nuclear Proteins/genetics , Oncogene Proteins/genetics , Proteins/genetics , Skin Neoplasms/genetics , Transcription Factors/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Case-Control Studies , Child , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Iceland , Male , Membrane Proteins , Middle Aged , N-Myc Proto-Oncogene Protein , White People/genetics , Young AdultABSTRACT
To search for new sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conducted a genome-wide association study of 38.5 million single nucleotide polymorphisms (SNPs) and small indels identified through whole-genome sequencing of 2230 Icelanders. We imputed genotypes for 4208 BCC patients and 109 408 controls using Illumina SNP chip typing data, carried out association tests and replicated the findings in independent population samples. We found new BCC susceptibility loci at TGM3 (rs214782[G], P = 5.5 × 10(-17), OR = 1.29) and RGS22 (rs7006527[C], P = 8.7 × 10(-13), OR = 0.77). TGM3 encodes transglutaminase type 3, which plays a key role in production of the cornified envelope during epidermal differentiation.
Subject(s)
Antigens, Surface/genetics , Carcinoma, Basal Cell/genetics , GTP-Binding Protein Regulators/genetics , Genetic Variation , Germ-Line Mutation , Transglutaminases/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Child , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Genotype , Germ Cells/metabolism , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Skin Neoplasms/genetics , Young AdultABSTRACT
In a follow-up to our previously reported genome-wide association study of cutaneous basal cell carcinoma (BCC), we describe here several new susceptibility variants. SNP rs11170164, encoding a G138E substitution in the keratin 5 (KRT5) gene, affects risk of BCC (OR = 1.35, P = 2.1 x 10(-9)). A variant at 9p21 near CDKN2A and CDKN2B also confers susceptibility to BCC (rs2151280[C]; OR = 1.19, P = 6.9 x 10(-9)), as does rs157935[T] at 7q32 near the imprinted gene KLF14 (OR = 1.23, P = 5.7 x 10(-10)). The effect of rs157935[T] is dependent on the parental origin of the risk allele. None of these variants were found to be associated with melanoma or fair-pigmentation traits. A melanoma- and pigmentation-associated variant in the SLC45A2 gene, L374F, is associated with risk of both BCC and squamous cell carcinoma. Finally, we report conclusive evidence that rs401681[C] in the TERT-CLPTM1L locus confers susceptibility to BCC but protects against melanoma.
Subject(s)
Carcinoma, Basal Cell/genetics , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide/genetics , Skin Neoplasms/genetics , Carcinoma, Basal Cell/complications , Carcinoma, Squamous Cell/genetics , Chromosomes, Human, Pair 7/genetics , Chromosomes, Human, Pair 9/genetics , Coronary Artery Disease/complications , Coronary Artery Disease/genetics , Genome-Wide Association Study , Humans , Keratin-5/genetics , Linkage Disequilibrium/genetics , Melanoma/pathology , Membrane Proteins/genetics , Molecular Sequence Data , Neoplasm Proteins/genetics , Skin Neoplasms/complicationsABSTRACT
To search for new sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conducted a genome-wide SNP association study of 930 Icelanders with BCC and 33,117 controls. After analyzing 304,083 SNPs, we observed signals from loci at 1p36 and 1q42, and replicated these associations in additional sample sets from Iceland and Eastern Europe. Overall, the most significant signals were from rs7538876 on 1p36 (OR = 1.28, P = 4.4 x 10(-12)) and rs801114 on 1q42 (OR = 1.28, P = 5.9 x 10(-12)). The 1p36 locus contains the candidate genes PADI4, PADI6, RCC2 and ARHGEF10L, and the gene nearest to the 1q42 locus is the ras-homolog RHOU. Neither locus was associated with fair pigmentation traits that are known risk factors for BCC, and no risk was observed for melanoma. Approximately 1.6% of individuals of European ancestry are homozygous for both variants, and their estimated risk of BCC is 2.68 times that of noncarriers.
Subject(s)
Carcinoma, Basal Cell/genetics , Chromosomes, Human, Pair 1/genetics , Genetic Predisposition to Disease , Melanoma/genetics , Mutation/genetics , Pigmentation/genetics , Skin Neoplasms/genetics , Adipose Tissue/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Aging , Alleles , Carcinoma, Basal Cell/diagnosis , Carcinoma, Squamous Cell/genetics , Chromosomal Proteins, Non-Histone/genetics , Chromosomal Proteins, Non-Histone/metabolism , Guanine Nucleotide Exchange Factors/genetics , Guanine Nucleotide Exchange Factors/metabolism , Humans , Middle Aged , Models, Genetic , Polymorphism, Single Nucleotide/genetics , Quantitative Trait, Heritable , RNA/metabolism , Skin Neoplasms/diagnosisABSTRACT
Fair color increases risk of cutaneous melanoma (CM) and basal cell carcinoma (BCC). Recent genome-wide association studies have identified variants affecting hair, eye and skin pigmentation in Europeans. Here, we assess the effect of these variants on risk of CM and BCC in European populations comprising 2,121 individuals with CM, 2,163 individuals with BCC and over 40,000 controls. A haplotype near ASIP, known to affect a similar spectrum of pigmentation traits as MC1R variants, conferred significant risk of CM (odds ratio (OR) = 1.45, P = 1.2 x 10(-9)) and BCC (OR = 1.33, P = 1.2 x 10(-6)). The variant in TYR encoding the R402Q amino acid substitution, previously shown to affect eye color and tanning response, conferred risk of CM (OR = 1.21, P = 2.8 x 10(-7)) and BCC (OR = 1.14, P = 6.1 x 10(-4)). An eye color variant in TYRP1 was associated with risk of CM (OR = 1.15, P = 4.6 x 10(-4)). The association of all three variants is robust with respect to adjustment for the effect of pigmentation.
Subject(s)
Agouti Signaling Protein/genetics , Carcinoma, Basal Cell/genetics , Melanoma/genetics , Monophenol Monooxygenase/genetics , Pigmentation/genetics , Skin Neoplasms/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Carcinoma, Basal Cell/pathology , Case-Control Studies , Europe , Eye Color/genetics , Gene Frequency , Genetic Predisposition to Disease , Humans , Melanoma/pathology , Membrane Glycoproteins/genetics , Middle Aged , Neoplasm Metastasis , Odds Ratio , Oxidoreductases/genetics , Polymorphism, Single Nucleotide , Receptor, Melanocortin, Type 1/genetics , Registries , Skin Neoplasms/pathologyABSTRACT
Este artículo ofrece una amplia revisión de 105 aspectos etiopatogénicos y clínicos del pénfigo benigno familiar, incidiendo especialmente en las diferentes modalidades terapéuticas ensayadas con mayor o menor éxito. Modalidades de tratamiento: tópico (corticoesteroides, antifúngicos, antibióticos, tacalcitol, ciclosporina, tacrolimus); sistémico: (corticoesteroides, vitamina E, vitamina D, talidomida, dapsona, retinoides, ciclosporina, metotrexato); quirúrgico: (dermabrasión, lásers, PUVA, radioterapia superficial, terapia fotodinámica); excisión-injerto y toxina botulínica
This article provides a revision the pathophysiology and clinical aspects of familial/ chronic benign pemphigus, especially concerning to the different Therapeutic modalities: topical/ treatment (steroids, antifungal agents, antibiotics, tacalcitol, cyclosporine A, tacrolimus); systemic treatment (steroids, vitamin E, vitamin D, thalidomide, dapsona, retinoids, cyclosporine A, methotrexate); physical/ procedures (dermabrasion, lasers, PUVA, x-ray therapy, photodynamic therapy); surgical/ excision and botulimun toxin
Subject(s)
Humans , Pemphigus, Benign Familial/therapy , Administration, Topical , Antifungal Agents/therapeutic use , Botulinum Toxins/therapeutic use , Vitamin D/therapeutic use , Vitamin E/therapeutic useABSTRACT
El acantoma de células grandes es una tumoración epidérmica, localizada preferentemente en la cara y miembros superiores. A menudo el diagnóstico es histológico ya que, clínicamente, las lesiones vienen diagnosticadas de queratosis solar, queratosis seborreica o lentigo senil. Presentamos 3 casos de mujeres afectadas; dos de ellas presentan el caso típico de acantoma de células grandes localizado, mientras que la otra presenta lesiones múltiples. La histología es similar en los casos solitarios y en las lesiones múltiples. Probablemente, el acantoma de células grandes es una entidad mucho más frecuente, y posiblemente esté infradiagnosticada. Así pues, este proceso debe incluirse en el diagnóstico diferencial de lesiones únicas o múltiples localizadas en áreas fotoexpuestas (AU)
Subject(s)
Aged , Female , Middle Aged , Humans , Solar System , Sunlight/adverse effects , Skin Neoplasms/diagnosis , Cryotherapy , Skin Neoplasms/etiology , Skin Neoplasms/pathology , Skin Neoplasms/therapyABSTRACT
El nevus lipomatoso cutáneo superficial, es una rara anormalidad idiopática, siendo una variante de nevus del tejido conectivo, que se caracteriza histológicamente por la presencia de tejido adiposo maduro ectópico en dermis. La variante más rara, de Hoffmann-Zurhelle o variante clásica, está constituida por lesiones nodulares o mamelonadas que se agrupan en placas de aspecto cerebriforme, con una disposición zonal o segmentaria. Suele ser congénito o aparecer en las tres primeras décadas de la vida, siendo la localización principal la cintura pelviana y los glúteos. Presentamos cinco nuevos casos con una clínica característica. El estudio histológico confirmó el diagnóstico clínico inicial, y ayudó a descartar otras patologías como la neurofibromatosis segmentaria. Se realiza también revisión de la literatura (AU)
